Review of the management of adverse effects associated with ...

Review of the management of adverse events associated with
Panvax and Fluvax
Professor John Horvath ao mbbs fracp
Final Report
10 March 2011

Review of the management of adverse events associated with
Panvax and Fluvax
Professor John Horvath ao mbbs fracp
Final Report
10 March 2011

Review of the management of adverse events associated with Panvax and Fluvax
Print ISBN 978-1-74241-463-8
Online: 978-1-74241-464-5
Publications Number: D0371
Paper-based publications
© Commonwealth of Australia 2011
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Contents
Acronyms
v
1. EXECUTIVE SUMMARY VII
1.1 Background vii
1.2 Method vii
1.3 Findings vii
1.4 Recommendations ix
2. INTRODUCTION 1
2.1 Background to the Review 1
2.2 Terms of Reference 2
2.3 Matters outside the Terms of Reference 3
2.4 Method of the Review 3
2.5 Structure of the Report 3
3. THE AUSTRALIAN REGULATORY SYSTEM FOR DRUGS AND VACCINES 5
3.1 Premarket assessment and registration of vaccines 5
3.2 Premarket assessment and authorisation of seasonal influenza vaccine 6
3.3 Post-market surveillance and monitoring of vaccines 6
3.4 International post-market surveillance and monitoring of vaccines 9
4. THE NATIONAL IMMUNIZATION PROGRAM 13
4.1 The National Immunisation Program 13
4.2 Governance of the NIP 13
5. INFLUENZA AND THE ROLE OF IMMUNISATION 17
5.1 Influenza 17
5.2 Pandemic influenza 17
5.3 Australia’s preparation for a pandemic 17
5.4 The 2009 H1N1 influenza pandemic 18
5.5 Pandemic H1N1 Vaccine (Panvax®) 19
5.6 The National Pandemic (H1N1) 2009 Vaccination Program 20
5.7 Pharmacovigilence arrangements for the National Pandemic (H1N1)
2009 Vaccination Program 20
5.8 Seasonal Influenza Vaccine 21
Contents
v

5.9 Seasonal influenza vaccination in Australia 21
5.10 Febrile reactions and convulsions following immunisation 22
6. THE FINDINGS OF THE REVIEW 23
6.1 Rates of febrile convulsions related to previous influenza vaccination
(seasonal and pandemic) in Australia 23
6.1.1 Was there a safety signal from the use of previous seasonal influenza
vaccines in children under 5 years of age? 23
6.1.2 Was there a safety signal from the Panvax program in 2009? 23
6.2 The national response to the reporting of adverse events in young children
following receipt of the 2010 seasonal influenza vaccine 24
6.2.1 When were the adverse events following Fluvax immunisation first
detected and what actions were taken? 24
6.2.2 Were the actions of the Commonwealth timely and appropriate? 29
6.3 Improving the monitoring of AEFI in Australia 30
6.3.1 Governance arrangements 30
6.3.2 Clarifying the objectives and processes of AEFI monitoring in Australia 31
6.3.3 Harmonising AEFI reporting and improving information flows between
TGA and jurisdictions 31
6.3.4 Transparency and Communications 32
6.3.5 Improving vaccine administration data 33
6.4 Other findings 34
6.4.1 Review of the premarket authorisation of influenza vaccines by the TGA 34
7. RECOMMENDATIONS OF THE REVIEW 35
8. REFERENCES 37
APPENDICES 39
Appendix I:
Documents and other source materials reviewed 39
Appendix II:
People interviewed 41
Appendix III:
International arrangements for post-market surveillance and monitoring of vaccines 42
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Acronyms
ACIR
ACSOM
ADRAC
ADRS
AE
AEFI
AESI
AHMAC
AHMC
AHMPPI
AHPC
AIH
APSU
ARTG
ATAGI
CAEFISS
CDC
CDI
CDCD
CDNA
CHO
CIOMS
CMO
DoHA
EMA/EMEA
EU
FDA
GBS
GISN
GMP
IB
JIC
Australian Childhood Immunisation Register
Advisory Committee on the Safety of Medicines
Adverse Drug Reactions Advisory Committee
Adverse Drug Reactions System
Adverse event
Adverse event following immunisation
Adverse event of special interest
Australian Health Ministers’ Advisory Committee
Australian Health Ministers’ Council
Australian Health Management Plan for Pandemic Influenza
Australian Health Protection Committee
Australian Immunisation Handbook
Australian Paediatric Surveillance Unit
Australian Register of Therapeutic Goods
Australian Technical Advisory Group on Immunisation
Canadian Adverse Events Following Immunisation Surveillance System
United States Centers for Disease Control and Prevention
Communicable Diseases Intelligence
Communicable Diseases Control Directorate Western Australian Department of Health
Communicable Diseases Network Australia
Chief Health Officer (each jurisdiction)
United Nations Council for International Organizations of Medical Sciences
Chief Medical Officer of Australia
Australian Government Department of Health and Ageing
European Medicines Agency
European Union
US Food and Drug Administration
Guillain-Barré Syndrome
WHO Global Influenza Surveillance Network
Good Manufacturing Practice
Immunisation Branch of the Office of Health Protection
Jurisdictional Immunisation Coordinators
Contents
vii

MedDRA
Medsafe
NCIRS
NIBSC
NIC
NIS
NNDSS
OHP
PBAC
RMP
SA
SAEFVIC
TGA
UMC
US
VAERS
VPD
VSD
WA
WHO
Medical Dictionary for Regulatory Activities
New Zealand Medicines and Medical Devices Safety Authority
National Centre for Immunisation Research and Surveillance of Vaccine Preventable Diseases
National Institute of Biological Standards and Control (UK)
National Immunisation Committee
National Immunisation Strategy
National Notifiable Diseases Surveillance System
Office of Health Protection
Pharmaceutical Benefits Advisory Committee
Risk Management Plan
South Australia
Surveillance of Adverse Events Following Vaccination in the Community
Therapeutic Goods Administration
Uppsala Monitoring Centre, the WHO Collaborating Centre for International Drug Monitoring
United States of America
US Vaccine Adverse Event Reporting System
Vaccine preventable disease
US CDC Vaccine Safety Datalink project
Western Australia
World Health Organization
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1
EXECUTIVE SUMMARY
1.1 Background
On 23 April 2010, the Chief Medical Officer
(CMO) of Australia suspended the use of seasonal
influenza vaccines for all children aged 5 years
and under, pending further investigation of an
apparent increase in febrile convulsions following
administration of the vaccines in this age group.
The previous evening, the Western Australian (WA)
Government had announced the suspension of its
program of seasonal influenza vaccination for well
children under the age of 5 years.
A Ministerial Review of the public health response
to the adverse events to seasonal influenza vaccine
was undertaken for the WA Minister for Health, the
Hon Dr Kim Hames MP, by Professor Bryant Stokes.
The report of the Stokes review (‘the Stokes Report’)
was tabled in the WA Parliament on 11 August
2010. It contained a number of criticisms of both
the WA and the national response, which were
subsequently aired in the media.
In October 2010, the Australian Government
Parliamentary Secretary for Health and Ageing, the
Hon Ms Catherine King MP, asked the former Chief
Medical Officer, Professor John Horvath AO, to
undertake an independent review of the national
response to the reported adverse events following
immunisation which resulted in suspension of the
seasonal influenza vaccine program for children
throughout Australia.
The aim of the Review has been to consider
the national response to the 2010 influenza
vaccine adverse event reporting, look at
international reporting arrangements and identify
improvements that could be made to the current
Australian system.
1.2 Method
The Review interviewed key informants, examined
data, documents and communications relating
to the national response to the reported adverse
events and sought and considered information
provided by Chief Health Officers of Australia and
overseas national regulatory bodies. The Review
was also informed by the outcomes of a Meeting
of Experts convened by the Chief Medical Officer,
Professor Jim Bishop AO, on 1 December 2010.
1.3 Findings
The Review has found there was no safety signal
from the use of seasonal influenza vaccine in WA
in 2008 and 2009 or from the use of Panvax in the
pandemic H1N1 influenza vaccination program
that would have indicated a need to change the
use of Fluvax in the subsequent seasonal influenza
vaccination program in 2010.
Executive summary
ix

The Review has found that the Australian system
has a number of strengths. It is similar to passive
adverse event surveillance systems in comparable
countries and was able to detect the safety signal
associated with the use of the 2010 seasonal
influenza vaccine, take appropriate action and
undertake a rigorous investigation.
The Review has found that the reporting of
adverse events following immunisation could be
more timely. Factors that impact on the timeliness
of reporting include: health professional and
consumer knowledge of how to report; delays in
information exchange between the jurisdictions
and the TGA; reports being sent in batches;
differing forms and protocols used in each
jurisdiction; and a lack of agreed case definitions.
The Review considers that, once the first batch
of case reports had been received by the TGA,
its actions in starting a thorough investigation
were appropriate and timely. The decision of the
CMO to suspend the use of all seasonal influenza
vaccines in young children was also appropriate,
timely and proportionate. The subsequent
investigation was extensive and thorough.
Updates were provided by the CMO to keep
jurisdictions, health professionals, consumers
and the media informed of the findings of the
investigation as they became available.
The Review has found that knowledge and
awareness of the vaccine surveillance system and
its processes and procedures among jurisdictions,
health professionals and consumers could be
improved.
Some health professionals and consumers
felt they were not sufficiently informed of the
unfolding events surrounding the suspension of
the use of seasonal influenza vaccines and the
subsequent investigation, particularly in the early
stages before the suspension was announced.
The Review notes there are significant challenges
in determining how to communicate with health
professionals and the community during the early
stages of an investigation, when there is a level of
doubt about the significance of the events.
There is a perception amongst some stakeholders
that there is a lack of transparency in the
TGA vaccine surveillance processes and that
information about investigations into adverse
events associated with vaccines is slow to be
made public.
The Review has found that the Governance
arrangements for vaccine safety issues
are complex. While the TGA has legislated
responsibility to monitor the safety of vaccines,
many organisations, committees and individuals
have a role, and there is a lack of clarity of the
relationships between these groups and their
roles and responsibilities in vaccine safety
monitoring and responding to the identification
of a possible signal. The Review notes that
there are no Standard Operating Procedures for
responding to a vaccine safety issue that does
not require regulatory action but which has
possible implications for the use of a vaccine in a
vaccination program.
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1.4 Recommendations
Recommendation 1
The Governance of the Vaccine Safety System
That the Department establishes a Working Party
to consider the current governance arrangements
for monitoring and responding to vaccine safety
issues in Australia and make recommendations
for an improved system of governance for vaccine
safety monitoring. Options for achieving improved
governance recommended for consideration by
the Working Party include:
i. maintaining the current organisations and
structures but developing more robust and
clear governance and reporting through
clearly defining the roles and key areas
of responsibility of each of the existing
committees and organisations and their
relationships to each other.
or
ii. establishing and resourcing a Vaccine
Safety Committee (VSC), a new body with
responsibility for monitoring vaccine safety
in Australia. The new body could be a
subcommittee of the Therapeutic Goods
Administration (TGA) Advisory Committee
on the Safety of Medicines (ACSOM).
It should have a broad membership of
experts with knowledge of vaccines,
vaccine safety, pharmacoepidemiology
and vaccine program implementation.
or
iii. restructuring immunisation governance
in Australia to provide a consolidated and
simpler governance pathway by creating
a new independent body to carry out
vaccine safety monitoring functions.
Recommendation 2
Defining Surveillance Objectives and
Establishing Protocols and Procedures
for Managing Adverse Events Following
Immunisation
That the Department establishes a Working
Party of Experts, including state and territory
health authority representatives, to develop,
in consultation with the TGA and key national
immunisation bodies, the principles and
objectives of the Australian adverse events
following immunisation (AEFI) surveillance
system, agreed case definitions for AEFIs, agreed
triggers for when further investigation should be
undertaken and protocols and procedures for
such investigations. This Working Party will need
to evaluate the benefits of additional surveillance
mechanisms to ensure the safety of vaccines.
Recommendation 3
Improving the National System for Timely
Reporting of Adverse Events Following
Immunisation
That the Department requests the TGA to
establish a joint TGA/National Immunisation
Committee working group to develop
mechanisms for improved and timely information
flows between TGA and the jurisdictions and
agreed templates for nationally consistent
reporting of adverse events following
immunisation.
Executive summary
xi

Recommendation 4
Raising Community and Health Professional
Awareness of Vaccine Safety Monitoring to
Ensure More Complete Reporting of Adverse
Events Following Immunisation
That the Department considers the development
of a communications strategy to inform
jurisdictions, health professionals and consumers
of the vaccine safety monitoring processes in
Australia.
Recommendation 5
Nationally Agreed Protocols for Program Action
and Communication
That the Department develops and agrees
with jurisdictions a protocol for taking program
action, including informing health professionals,
consumers and the media, in the event a possible
safety signal is detected affecting a National
Immunisation Program vaccine.
Recommendation 6
Transparency and the Functions of the TGA
to Ensure Better Access to Vaccine Safety
Information for Consumers and Health
Professionals
Improvements to the transparency of the TGA’s
vaccine safety monitoring processes should be
considered by the independent Transparency
Review of the TGA being chaired by Professor
Dennis Pearce.
Recommendation 7
Vaccine Usage and Safety Monitoring Data
The collection of vaccine usage and safety
monitoring data should be a key priority for future
e-health planning and development.
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2
INTRODUCTION
Immunisation has been repeatedly demonstrated
to be one of the most effective medical
interventions for preventing disease. As with
all medicines, vaccines can cause adverse
events in some people but serious reactions
to immunisation are rare. All vaccines used in
Australia are made to very high quality standards.
They have been demonstrated to be safe and
effective prior to being approved for use and
post-marketing monitoring of all vaccines is
undertaken to ensure their continued safety.
Safety monitoring is considered an essential
part of every immunisation program in which
vaccines are administered on a large scale to
healthy individuals. Adverse events following
immunisation may be related to the vaccine
or may have occurred by chance. The aim of
monitoring is to identify any signal that there
may be a safety concern in order to investigate it
and take appropriate action. Maintaining public
confidence in vaccines and the immunisation
program through effective safety monitoring is
also important.
In 2010, an increase in febrile convulsions among
young children following seasonal influenza
vaccination was observed in Western Australia.
The identification of and response to this finding
is the subject of this document.
2.1 Background to the Review
On 23 April 2010, the Chief Medical Officer
(CMO) of Australia suspended the use of seasonal
influenza vaccines for all children aged 5 years
and under, pending further investigation of an
apparent increase in febrile convulsions following
administration of the vaccines in this age group.
The previous evening, the Western Australian (WA)
Government had announced the suspension of
its program of seasonal influenza vaccination for
children under the age of 5 years.
The use of all seasonal influenza vaccines in
young children remained suspended until a
detailed evaluation by the Therapeutic Goods
Administration (TGA) and the Australian Technical
Advisory Group on Immunisation (ATAGI)
confirmed an increased occurrence of febrile
convulsions related to the use of the CSL trivalent
(seasonal) influenza vaccine, Fluvax®. On 27 July
2010, the CMO advised that seasonal influenza
vaccination of young children under the age of
5 years could be resumed using the two
alternative brands of the vaccine available for use
in this age group in Australia in 2010, Vaxigrip®
(Sanofi Paster) and Influvac® (Abbott/Solvay).
On 16 May 2010, a Ministerial Review of the
public health response to the adverse events to
seasonal influenza vaccine was announced by the
Introduction
1

WA Minister for Health, the Hon Dr Kim Hames
MP, and on 24 May 2010 Professor Bryant Stokes,
the former Western Australian Chief Medical
Officer, was appointed as the reviewer. The
report of the Stokes review (‘the Stokes Report’)
was tabled in the WA Parliament on 11 August
2010. It contained a number of criticisms of both
the WA and the national response, which were
subsequently aired in the media.
In October 2010, the Australian Government
Parliamentary Secretary for Health and Ageing,
the Hon Ms Catherine King MP, asked the
Department of Health and Ageing (DoHA) to
initiate an independent review of the national
response to the reported adverse events following
immunisation which resulted in suspension
of the seasonal influenza vaccine program for
children throughout Australia. She requested
the former Chief Medical Officer, Professor John
Horvath AO, undertake the Review. Professor
Horvath commenced his work on the Review in
mid-November 2010.
The aim of the Review has been to consider
the national response to the 2010 influenza
vaccine adverse event reporting, look at
international reporting arrangements and identify
improvements that could be made to the current
Australian system. The Review did not aim to
provide a point by point response to issues raised
in Stokes Report, but to consider more broadly
the lessons that can be learned from the national
response to the 2010 events.
The Review took place concurrently with two other
projects with a potential for overlap and linkage.
The first is the Transparency Review of the TGA,
which was announced by the Hon Mrs Catherine
King MP on 16 November 2010. This comprehensive
review of the way in which the TGA communicates
its regulatory processes and decisions is being
undertaken by a panel chaired by Professor Dennis
Pearce AO and is focused on improving the TGA’s
transparency in relation to all therapeutic goods.
Some aspects of safety monitoring of vaccines under
consideration through the adverse events Review
will be best addressed by referring them to the
Transparency Review.
Work is currently underway to develop a
National Immunisation Strategy (NIS) to
improve immunisation coverage and reduce
vaccine preventable diseases. The work is being
undertaken as a joint Australian and state/territory
government process, overseen by the National
Immunisation Committee (NIC). Through the
Office of Health Protection (OHP) within the
DoHA, Professor Michael Frommer has been
engaged as a consultant to develop the Strategy.
Within its broad scope, the NIS will address issues
of vaccine safety and it will be important to ensure
that the findings and recommendations from the
adverse events Review are taken into account in
the development of the NIS.
2.2 Terms of Reference
1. Examine data relating to recent influenza
vaccine adverse event reporting put
forward by the:
1. Government of Western Australia
(including that contained in the
‘Stokes review’);
2. Therapeutic Goods Administration;
3. Australian Technical Advisory Group on
Immunisation; and
4. meeting of the chairs of expert groups
and committees involved in the recent
analysis surrounding the adverse events
reports.
2. Review overseas benchmarks for reporting
of, and responses to, adverse events
associated with vaccination.
3. Identify improvements that could be
made to current Australian adverse events
reporting arrangements, with particular
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eference to improvements in transparency
and communication.
A report is to be provided by Professor Horvath to
the Parliamentary Secretary for Health and Ageing
by 28 February 2011.
2.3 Matters outside the
Terms of Reference
The following matters have not been addressed
in the Review as they are outside the Terms of
Reference:
• issues specific to WA, including the
interactions within the WA health
department and between the department
and the public health units;
• the debate in the media as to the need
for vaccination of the population, and
children in particular, with pandemic H1N1
containing vaccines; and
• the perceived conflicts of interest of experts
in providing vaccination advice and of the
TGA in post market surveillance.
2.4 Method of the Review
Professor Horvath:
• reviewed the data, documents and
communications detailed in Appendix I;
• wrote to all the Chief Health Officers in
Australia to advise them of the Review and
ask them to provide input if they wished;
• wrote to the European Medicines Agency and
the national medicines regulatory agencies
of Canada, Ireland, New Zealand (NZ), Japan,
Singapore, Switzerland, United Kingdom (UK)
and the United States of America (US), asking
for information about their adverse events
monitoring systems; and
• interviewed the key informants listed in
Appendix II. The interviews were semistructured
and covered a range of aspects,
including: how the current system works;
its strengths and weaknesses; the roles
played by key organisations; the processes
involved in identifying and managing
a safety signal; the analysis required to
identify signals; reporting arrangements;
communications between jurisdictions
and the TGA; communications with health
professionals and consumers; lessons
learned from the 2010 influenza season
experience; and views on safety monitoring
system improvements.
The Review was also informed by the outcomes
of a Meeting of Experts convened by the Chief
Medical Officer, Professor Jim Bishop AO, on
1 December 2010.
Administrative support to the Review was
provided by Dr Bronwen Harvey, Medical
Adviser with expertise in immunisation policy
and programs, and Mr Joel Willis, Departmental
Officer with experience in seasonal and pandemic
influenza vaccine programs.
2.5 Structure of the Report
The Report describes the Australian regulatory
system for drugs and vaccines (Section 3.0) and
how the post-marketing surveillance component
compares with international systems (Section
3.4). The Report then outlines the National
Immunisation Program and its governance
structures (Section 4.0). Information about influenza
and influenza vaccination is presented Section 5.0.
The Review findings on the response to the 2010
seasonal influenza vaccine adverse events and
on potential improvements to the vaccine safety
monitoring system are presented in Section 6.0 and
the Review recommendations in Section 7.0.
Introduction 3

3
THE AUSTRALIAN REGULATORY SYSTEM
FOR DRUGS AND VACCINES
3.1 Premarket assessment and
registration of vaccines
In Australia, all therapeutic goods, including
vaccines, are regulated by the Therapeutic Goods
Administration (TGA) in accordance with the
provisions of the Therapeutic Goods Act 1989
(the Act). The objective of the Act is to provide
a national framework for the regulation of
therapeutic goods in Australia, so as to ensure
their quality, safety, efficacy (where appropriate)
and timely availability. It is a requirement of the
Act that therapeutic products imported into,
supplied in, or exported from Australia be either
registered or listed in the Australian Register of
Therapeutic Goods (ARTG).
In order for a vaccine to be included in the
ARTG, a premarket evaluation of the vaccine is
undertaken by the TGA. The sponsoring company
is required to make an application with data to
support the quality, safety and efficacy of the
product for its intended use. These data are then
subject to rigorous evaluation by the TGA, which
may include seeking clarifications and further
data from the sponsor. The data requirements are
largely based on those applying in the European
Union, supplemented by Australia-specific
requirements where necessary.
The pre-market evaluation data include: the
quality and quality control aspects of the
manufacture of the vaccine; pre-clinical data
designed to assess to toxicological profile of the
vaccine, including safety when tested in animals;
and clinical trial data to support the safety and
efficacy of the vaccine in humans.
The quality control aspects of an application cover
the batch production processes to ensure that the
vaccine is produced to a consistent standard as
defined by the product specification. This quality
specification places controls on the purity and
potency of the vaccine as well as on other aspects
necessary to ensure the efficacy of the product.
Clinical trials for vaccines need to be welldesigned
with sufficient subjects representing
the target population and of sufficient duration to
demonstrate the efficacy and safety of the vaccine
for the proposed indication. All medications and
vaccines carry a potential risk of causing adverse
events in some people. In making a regulatory
decision on the registration of a vaccine, the
TGA takes into consideration the overall balance
of benefits and risks, noting that a high level of
safety is needed for vaccines which, unlike most
medications used to treat existing conditions,
are generally given to healthy people to prevent
illness and death from vaccine preventable
diseases (VPDs).
The Australian Regulatory System for Drugs and Vaccines
5

Applications for registration of a new vaccine, or
for a major extension of indications for an existing
vaccine, are generally referred by the TGA to the
Advisory Committee on Prescription Medicines,
although the decision-maker is not bound by the
Committee’s advice.
3.2 Premarket assessment and
authorisation of seasonal influenza
vaccine
Seasonal influenza vaccines present a particular
challenge for registration processes because of
the short time between the selection of the virus
strains for the seasonal influenza vaccine and the
beginning of the next influenza season. To ensure
timely availability of seasonal influenza vaccine in
Australia each year, the TGA does not require an
annual clinical trial of the vaccine. Where there
are no changes to the manufacturing process
other than the virus strain(s), the application for
registration of each season’s vaccine is processed
as a strain change, rather than as an application
for new product approval. This approach is taken
because the manufacturing process for the
vaccine varies little from year to year and there is
lengthy experience with influenza vaccination,
based on many years of safe, effective use of the
seasonal vaccine in millions of people.
The TGA approach is in keeping with other
regulators, such as the US Food and Drug
Administration (FDA). In Europe, the European
Medicines Agency (EMA) requires very small
scale studies to be conducted with the northern
hemisphere seasonal trivalent influenza vaccine
to confirm immunogenicity and gross safety.
These studies are on healthy people and include
50 people aged between 18 and 60 years and
50 people aged 60 years and over. While the
results of these studies are available to the TGA,
the small number of people involved means
the safety information obtained is very limited
and low frequency adverse events are unlikely
to be identified. Even if larger scale trials were
done, they would not be able to pick up rare
adverse events. Post-market safety monitoring
is considered by the TGA to be particularly
important for identifying new signals for seasonal
influenza vaccines.
The TGA undertakes regular audits of vaccine
manufacturing sites. TGA also performs regular
testing of seasonal influenza vaccines for endotoxin
and potency prior to releasing batches for
distribution. In a normal flu season, the first 10–20
batches are tested then approximately every tenth
batch. The TGA also reviews the manufacturing
records for each batch prior to release.
3.3 Post-market surveillance and
monitoring of vaccines
Post-marketing surveillance and monitoring of
all medicines, including vaccines, is essential.
Although drugs and vaccines are tested
extensively before they are registered for use in
Australia, even large clinical trials do not include
sufficient people to detect reactions that happen
only rarely. Post marketing surveillance and
monitoring aims to detect and respond quickly to
any safety signals.
Post-market surveillance and monitoring of
vaccines is the legal responsibility of the TGA, as
part of its legislated function of monitoring the
safety of medicines in Australia. This responsibility
is shared with:
• the vaccine manufacturers or sponsors who
make and market the vaccines, undertake
global surveillance and are legally required
to report vaccine safety issues to the TGA
(see below);
• the state and territory public health
authorities who administer the National
Immunisation Program and undertake
adverse event surveillance in their
jurisdictions; and
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• the health professionals who administer
the vaccines, whether they are provided
through funded programs or purchased
privately.
Consumers also play an important role in
reporting adverse events of concern to them.
Effective post-marketing surveillance, therefore,
relies on cooperation between the TGA, the
vaccine companies, state and territory health
authorities, health professionals and consumers.
International post-marketing surveillance
experience is also important for understanding
vaccine and drug safety and the TGA maintains
close liaison with its overseas counterparts to
share safety information.
The core of the post-market monitoring system
for vaccines is the identification, reporting,
and evaluation of adverse events following
immunisation (AEFIs). The system is managed
through the Office of Product Review of the
TGA as part of the monitoring of all adverse
drug reactions. The primary function of the AEFI
monitoring system is to detect early warning
signals and generate hypotheses about possible
new vaccine adverse events or changes in
frequency of known ones.
The monitoring of AEFI is largely through passive
surveillance, which relies on voluntary reporting
of AEFIs by state and territory health authorities,
immunisation providers, other health professionals
and consumers. AEFI reporting is mandatory for
vaccine sponsors and the Act requires sponsors to
submit reports of serious AEFIs within 15 days of
becoming aware of the event.
In all jurisdictions, other than Tasmania and
Victoria, health professionals notify serious or
unexpected AEFIs to the relevant health authority.
In Victoria, AEFIs are notified to SAEFVIC, a service
funded by the Department of Health. Reporting to
the health authority is mandated by jurisdictional
legislation except in Tasmania, South Australia and
Victoria. Health authorities and SAEFVIC forward
some or all of the reports to TGA after processing.
Each jurisdiction has its own report form and
data collection differs across the jurisdictions. In
Tasmania, health professionals report directly to
the TGA, with TGA providing a line listing of each
month’s reports and a separate report for each
case to the Tasmanian Department of Health and
Human Services about 2 weeks into the following
month. The TGA provides all jurisdictions monthly
with case details of all AEFIs reported to the TGA
that occurred in the relevant jurisdiction in the
previous month.
An important aspect of the monitoring of AEFIs
at jurisdictional level is the capacity to provide
advice to the reporting health professional
or consumer on the clinical investigation and
management of the event itself and for provision
of advice on future vaccination. Some jurisdictions
have specialised services to support the clinical
management of persons who have experienced
an AEFI.
Health professionals reporting directly to TGA
may do so by telephone, on-line or through
completing a Report of suspected adverse reaction
to medicines or vaccines (“Blue Card”) form and
submitting it by mail, fax or email.
Consumers may report adverse events to the
relevant health authority in some jurisdictions
(eg South Australia). They can also report through
their doctor, directly to the TGA, or by phoning the
Adverse Medicine Events Line a service funded
through the National Prescribing Service and
based at the Mater Hospital in Brisbane, which
forwards reports to the TGA. Information about
how consumers can make a report is available on
the TGA website.
AEFI reports received by the TGA are triaged as
serious or non-serious based on internationallyaccepted
criteria. They are then coded using
standard terminology in accordance with the
Medical Dictionary for Regulatory Activities
(MedDRA), a document endorsed by the
The Australian Regulatory System for Drugs and Vaccines
7

International Conference on Harmonisation
of Technical Requirements for Registration of
Pharmaceuticals for Human Use. Reports are
entered into the Adverse Drug Reactions System
(ADRS) database within 48 hours of receipt—in
most cases within 24 hours. Causality is assigned
using the WHO Uppsala Monitoring Centre (UMC)
causality assessment criteria (WHO UMC 2011).
All individual reports of serious AEFIs are reviewed
and entered into the database by a medical
officer. TGA medical officers also undertake a
weekly review of all reports for quality control
and for identifying clusters of reports or unusual
reports. AEFIs are reviewed separately from other
reports. Two-monthly reviews are also undertaken
of proportional reporting ratios (PRRs), a statistical
aid to finding signals within the ADRS database.
An acknowledgement is sent to each person
reporting an AEFI. Further information may
be sought from the reporter to assist in the
assessment of the event. Further information is
routinely requested for adverse events of special
interest (AESIs) involving vaccines, using clinical
follow-up templates.
TGA staff may request advice about AEFIs from
the TGA’s Advisory Committee on the Safety of
Medicines (ACSOM). If potential safety signals
are identified, the TGA may also convene an
ad-hoc expert advisory committee to augment
its in-house and statutory committee expertise
and enable TGA to rapidly undertake focused
assessment of emerging safety signals. The
TGA can also obtain expert advice from
the Australian Technical Advisory Group on
Immunisation (ATAGI) and utilise the expertise of
the National Centre for Immunisation Research
and Surveillance (NCIRS) to assist in undertaking
further investigation of safety signals.
TGA may place additional post-marketing safety
monitoring requirements on vaccine sponsors
through the risk management plans (RMPs),
required since 2009 as part of the registration
process for new vaccines or vaccines with
changed indications. These plans may include
requirements for undertaking active surveillance
or other specific post-marketing research
studies. An example is the requirement for CSL
to undertake active surveillance for Guillain Barré
Syndrome (GBS) following Panvax vaccination.
A hospital-based sentinel surveillance program
(the Paediatric Active Enhanced Disease
Surveillance, or PAEDS, program) is also in
place in Australia. The program is modelled
on the Canadian IMPACT (see 3.4 International
post-market surveillance and monitoring of
vaccines) and is coordinated through the NCIRS
in collaboration with the Australian Paediatric
Surveillance Unit (APSU). The program currently
collects data from tertiary paediatric hospitals
in four jurisdictions (New South Wales, South
Australia, Victoria, and Western Australia). AEFIs
currently under active surveillance through
this program include intussusception, varicella
(vaccine failures) and acute flaccid paralysis.
De-identified AEFI data are routinely released to
the NCIRS which undertakes a range of analyses.
NCIRS collaborates with the TGA to prepare annual
national surveillance reports, which have been
published in Communicable Diseases Intelligence
(CDI) since 2003. The TGA publishes specific
safety information on the Alerts and Advisories
section of the TGA website. Such information can
be reports on the post-marketing surveillance
experience with new vaccines—recent examples
include human papillomavirus (HPV) vaccine and
the pandemic H1N1 vaccine—or advice about a
specific issue such as the identification of porcine
circovirus (PCV) in rotavirus vaccines.
Regulatory action that TGA may take if a safety
problem is identified can include requiring
amendments to the product information or
inclusion of black box warnings, restricting the
use of vaccine to specific group, suspending the
supply of the vaccine or withdrawing the product
from the market.
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3.4 International post-market
surveillance and monitoring of
vaccines
At the global level, vaccine pharmacovigilance is
undertaken by the WHO through its Immunization,
Vaccines and Biologicals Division and the
independent Global Advisory Committee on
Vaccine Safety (GACVS). The WHO has established a
global database for the reporting of adverse events
to medicines, including vaccines. The database is
administered by the WHO Collaborating Centre for
International Drug Monitoring in Uppsala, Sweden,
also known as the Uppsala Monitoring Centre
(UMC). Australia is one of over 100 countries which
report to this database.
Pharmacovigilence of vaccines through
monitoring AEFI comprises three steps: signal
detection, hypothesis development and
hypothesis testing. In industrialised countries, the
monitoring of AEFI is typically through national
passive surveillance systems which rely on
spontaneous reporting of individual case reports
by health workers and others (Global Advisory
Committee on Vaccine Safety 2009). Additional
active surveillance is frequently implemented
when there are concerns about specific health
risks, especially with new vaccines, for example,
monitoring for GBS after use of Panvax and
monitoring for intussusception after use of
rotavirus vaccines.
Investigation of possible signals involves validation
of cases and gathering data on possible additional
cases (Global Advisory Committee on Vaccine
Safety 2009). The use of standard case definitions
allows for systematic classification of cases and
comparability of surveillance and studies in
different settings. The Brighton Collaboration is
an international partnership, largely comprised of
volunteer experts, that develops and publishes
AEFI definitions and guidelines for their use.
Twenty-four (24) definitions have been published
to date. They are endorsed by the WHO and
the UN Council for International Organizations
of Medical Sciences (CIOMS) and their use is
recommended by the FDA, the EMA, the CDC and
the European Centre for Disease Prevention and
Control (ECDC) (Brighton Collaboration 2010).
All countries considered by the Review have a
national passive AEFI surveillance system, but
there are differences in the ways the systems are
structured and administered. At the global level
and in most countries, AEFI reporting is included
in the general medicines adverse event reporting
system. In the USA and in Canada, AEFIs are
reported to a specific system for vaccines. The
USA system is called the Vaccine Adverse Event
Reporting System (VAERS). The database is held
by the Department of Health and Human Services
and jointly managed by two of the Department’s
agencies, the FDA and the CDC. In Canada, the
system is called the Canadian Adverse Events
Following Immunization Surveillance System
(CAEFISS). It is currently administered by the
Vaccine Safety Unit (VSU) of the Centre for
Immunization and Respiratory Diseases (CIPD)
of the Public Health Agency of Canada (PHAC).
The Canadian system has a specific committee,
the Advisory Committee on Causality Assessment
(ACCA), with broad-based clinical, scientific
and public health skills which regularly reviews
all case reports of severe or unexpected AEFIs
to determine whether they are related to the
administration of the vaccine.
In most countries, reporting is voluntary for health
professionals and mandatory for vaccine sponsors.
In the US, health professional reporting of certain
conditions (as listed in the Reportable Events
Table) is mandated, but health professionals are
encouraged to report any significant or unusual
adverse event. In Canada, health professional
reporting is voluntary except in a limited number
of jurisdictions which have mandated reporting
requirements. In some countries (eg New Zealand),
consumers are also encouraged to report.
The Australian Regulatory System for Drugs and Vaccines 9

In many countries, reporting is directly into the
national medicines adverse events reporting
system. In the US reports are made directly to
the VAERS system, however, in Canada reports
are made to the local, provincial and/or territorial
public health authorities, which forward the
reports to the CAEFISS.
The administration and analysis of the AEFI
database also varies. It may be
• within the regulatory agency, for example
within the Medicines and Healthcare
products Regulatory Agency (MHRA) in
the UK and the Irish Medicines Board (IMB)
in Ireland;
• within another agency of the health
authority, for example the Public Health
Agency of Canada;
• shared by the regulatory agency and
another health authority agency, for
example the FDA and CDC in the US; or
• outsourced to an independent body, such
as the UMC for WHO and the Centre for
Adverse Events Monitoring (CARM) in
New Zealand.
Regardless of the body administering the
database, close liaison between the regulator,
the vaccine program managers and the AEFI
monitoring system is maintained.
Each country has arrangements for signal
identification and investigation. Only limited details
were provided to the Review by the regulatory
agencies and most had little information about
these aspects on their websites, so it was difficult to
determine how these varied between countries.
In Canada and the US the vaccine safety
monitoring systems include additional active
surveillance activities. Canada monitors AEFIs in
children through the Immunization Monitoring
Program ACTive (IMPACT) which undertakes
active sentinel surveillance in 12 tertiary care
paediatric hospitals across Canada.
The US CDC has implemented the Vaccine Safety
Datalink (VSD) project, which uses data linkage to
analyse vaccine-related and clinical information
for more than 7 million people from eight large
managed care organisations. The VSD can also
be used for planned immunisation studies to
detect rare adverse events when new vaccines
are licensed or when a safety question arises.
A number of Priority Studies using VSD data are
currently underway. The CDC also undertakes Rapid
Cycle Analysis (RCA) in which de-identified data,
updated weekly, from the eight managed care
organisations are used for active surveillance of
AEFI for newly licensed vaccines and new vaccine
recommendations. Potential adverse events (AEs),
which are identified through premarketing studies,
early analysis from VAERS and published scientific
articles, are monitored by comparing their rate of
occurrence in people who have received a vaccine
with the rate of occurrence in a similar group
of people who have not received that vaccine.
If the rate is significantly higher, then a formal
epidemiological study is done.
In the UK, a dedicated risk management
strategy may be put in place when a major new
immunisation program is introduced. For the HPV
vaccine program, the strategy included enhanced
passive surveillance involving stimulated AE
reporting (via letters and other communications)
and conducting real time observed/expected
(O/E) analyses of pre-defined AESIs. Analyses of
any signals detected can be evaluated through
epidemiological studies using the General
Practice Research Database (GPRD), an electronic
data source with record linkage capacity, which
contains information from 590 practices in the UK
covering about 5 million patients.
Almost all countries, including Australia, had
implemented enhanced surveillance for the
H1N1 2009 vaccine. These enhancements varied
but included providing specific reporting forms/
arrangements for the H1N1 2009 vaccine;
stimulating reporting from health care providers
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and others by providing information and
reminders; and undertaking more intensive
monitoring of the passive AEFI reports. In some
countries, active surveillance systems were
used to monitor pre-defined AESIs. In the US,
this included RCA of VSD data, a similar process
applied to the Defense Medical Surveillance
System (DMSS) data and active case-finding for
GBS through the Emerging Infections Program
(EIP) (CDC 2009).
The above summarises information which was
provided in the international regulatory agencies
responses to the Review’s request for information
or obtained from the agencies’ websites. The
approach to the monitoring of vaccine safety in
each country and the EU is outlined in a Table in
Appendix III.
Comment
The Review found that, owing to the diverse
nature of health care systems and the
vaccine safety programs within them, it was
not possible to discern a common pattern
in the implementation of these programs
internationally. There were features of some
of the programs that, if modified and adopted
in our environment, would enhance current
practice whilst there were others that would
not work within the structure of the Australian
health care setting. The system in place in
Australia is, overall, in keeping with international
passive adverse events surveillance systems.
The Australian Regulatory System for Drugs and Vaccines 11

4
THE NATIONAL IMMUNIZATION PROGRAM
4.1 The National Immunisation
Program
The National Immunisation Program (NIP) is a
collaborative program between the Australian
and state and territory governments which
aims to increase national immunisation rates
for vaccines on the NIP schedule. The program,
which is implemented as the Immunise Australia
program, funds free vaccines for eligible
Australians, administers the Australian Childhood
Immunisation Register (ACIR) and communicates
information about immunisation to the general
public and health professionals.
The NIP is a broad ranging program which has
grown considerably in cost and complexity
since its establishment in 1997. The number of
diseases the program aims to protect against has
doubled and the program now includes adults as
well as children. Annual expenditure on vaccines
alone has risen from $13 million in 1996/97 to an
estimated $322.6 million in 2010/11.
Vaccines are included in the NIP only after
evaluation of their quality, safety and effectiveness
and of the cost-effectiveness of the vaccine for its
intended use in the Australian population.
4.2 Governance of the NIP
Australia has a complex series of governance
arrangements for the NIP. The Program is a
collaborative one, based on scientific evidence
and technological developments, which requires
the interaction of a large number of organisations
and bodies, whose roles are outlined below.
These arrangements have worked well in the
past, due to a high level of cooperation based on
good personal relationships, supported by formal
arrangements for cross-membership of relevant
committees.
Australian Government
The Australian Government provides national
leadership in the development, implementation
and evaluation of immunisation policy. It also
funds vaccine purchase in the NIP, provides
funds to Medicare Australia for the ACIR and the
General Practice Immunisation Incentives Scheme
(GPII) and undertakes or funds a number of
other services that support the NIP, including the
provision of parental incentives..
The Australian Government Department of
Health and Ageing (DoHA) has administrative
responsibility for the Government’s immunisation
policy and the NIP. This responsibility is carried out
by the Immunisation Branch (IB) of the Office of
Health Protection (OHP). The vaccine regulator, TGA,
The National Immunization Program
13

is an agency of the Department and works closely
with the IB on issues affecting the NIP. The CMO
provides advice to the Secretary of the Department
and the Minister for Health and Ageing on
immunisation policy and program issues.
State and territory governments
State and territory governments, through their
health authorities, are responsible for purchasing
vaccines 1 , managing the distribution of vaccines
to public and private immunisation providers,
undertaking local education and communication
activities, running school-based immunisation
programs and contributing to ACIR notification
payments. In addition to managing AEFI
surveillance in their jurisdictions, public health
officers and immunisation coordinators ensure
that there is appropriate clinical management
of AEFI cases and that local health professional,
consumer and media concerns about vaccine
safety are addressed.
The National Immunisation Committee (NIC)
The NIC oversees the development,
implementation and delivery of the NIP. The
Committee is chaired by the Assistant Secretary
of the IB and comprises all the Jurisdictional
Immunisation Coordinators (JIC) and
representatives of general practice as well as a
consumer, the National Indigenous Immunisation
and GP Immunisation Coordinators and the NCIRS.
The NIC reports to the Australian Health Protection
Committee (AHPC) via the Communicable
Diseases Network Australia (CDNA).
The Communicable Diseases Network
Australia (CDNA)
The CDNA coordinates communicable disease
surveillance, prevention and control in Australia
and provides strategic advice to governments
and other agencies. The Committee comprises
representatives of the Commonwealth, State
and Territory Government and the New Zealand
Government health departments and other
experts in communicable diseases.
The Australian Health Protection Committee
(AHPC)
The AHPC is a principal committee of the
Australian Health Ministers’ Advisory Committee
and coordinates the national approach to
preventing and responding to public health
emergencies communicable disease threats
and environmental threats to public health. The
Committee is chaired at Deputy Secretary level by
the DoHA and includes among its core members
the CMO and the State and Territory Chief Health
Officers (CHOs).
The Australian Health Ministers’ Advisory
Committee AHMAC)
The AHMAC advises the Australian Health
Ministers’ Conference (AHMC) on strategic issues
relating to the coordination of health services
across the nation and, as applicable, with New
Zealand and operates as a national forum for
planning, information sharing and innovation.
It comprises the Head (plus one other senior
officer) of each of the Australian Government,
State and Territory and New Zealand Health
Authorities and the Australian Government
Department of Veterans’ Affairs.
The Australian Health Ministers’ Council
(AHMC)
The AHMC comprises all Australian Government,
State, Territory and New Zealand Ministers with
direct responsibility for health matters and the
Australian Government Minister for Veterans’ Affairs.
1 The purchasing of vaccines is in transition to become an
Australian Government responsibility by 2014
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The Australian Technical Advisory Group on
Immunisation (ATAGI)
The ATAGI is an independent expert body that
provides technical advice to the Minister for
Health and Ageing on the medical administration
of vaccines available in Australia, including
those on the NIP. It also provides advice to the
Pharmaceutical Benefits Advisory Committee
(PBAC) on the scientific evidence on the
effectiveness and use of vaccines in Australian
populations. In developing its advice, the
ATAGI consults with other relevant committees
on matters relating to the implementation
of immunisation policies, procedures and
vaccine safety. Members include a consumer
representative and health professionals with
expertise in immunology, vaccine research,
paediatrics, infectious diseases, public health,
epidemiology, general practice and nursing.
The National Centre for Immunisation
Research and Surveillance (NCIRS)
The NCIRS, a national research centre located at the
Children’s Hospital at Westmead, Sydney, undertakes
immunisation related research and provides
technical advice to the DoHA to support delivery
of the NIP. As part of its role with DoHA, the NCIRS
provides technical support to ATAGI and its Working
Parties; undertakes epidemiological analysis and
reporting on vaccine preventable diseases, vaccine
coverage and vaccine adverse events; undertakes
program evaluations; and develops information and
printed material to support education and training
for immunisation providers.
In addition to the standing advisory committees,
DoHA may convene ad hoc committees to
provide advice in particular circumstances, for
example, the Expert Advisory Panel on Vaccine
Testing convened by TGA to advise on the
laboratory aspects of the investigation into the
Fluvax adverse events.
Other bodies with a role are the Pharmaceutical
Benefits Advisory Committee (PBAC), which
makes recommendations to the Minister for
Health and Ageing on vaccines for inclusion in the
NIP, and the National Health and Medical Research
Council (NHMRC) which endorses the Australian
Immunisation Handbook developed by ATAGI.
All of these bodies and organisations have an
interest in the safety and effectiveness of vaccines
and of the vaccination program, but currently
the governance and reporting arrangements for
vaccine safety issues are not clear.
The National Immunization Program
15

5
INFLUENZA AND THE
ROLE OF IMMUNISATION
5.1 Influenza
Influenza is a contagious disease of the respiratory
tract caused by influenza viruses which generally
circulate in the winter in temperate countries, but
year-round in tropical areas. The virus is constantly
changing. Most people who get influenza have
a self-limiting illness, lasting from a few days to
several weeks, but for some people—the elderly,
those with poor immune systems and those
with certain pre-existing chronic diseases—
influenza can be a significant disease, requiring
hospitalisation and resulting in death. Serious
disease and death can also occur in healthy adults
and children. High rates of influenza resulting
in hospitalisation occur in infants and young
children. Vaccines are available to protect against
seasonal influenza infection (see 5.8 Seasonal
influenza vaccine).
5.2 Pandemic influenza
Influenza pandemics occur when a new subtype
of influenza virus, which most people have not
previously been exposed to, emerges in humans.
The virus spreads easily and rapidly in the highly
susceptible population, infecting large numbers
of people worldwide (Australian Government
Department of Health and Ageing 2008). Some
pandemics cause severe disease and many deaths
but others are mild in the illness and death they
cause. The severity of a pandemic can change
over its course (WHO 2011).
Pandemics have occurred at irregular intervals
throughout history. During the 20th century, the
world experienced three pandemics—in 1918–19,
1957–58 and 1968–70. Pandemics have been
of varying severity. The 1918–19 pandemic was
extremely severe with at least 50 million deaths
worldwide, with an unusually high number of deaths
in young otherwise healthy people. The other two
pandemics were less severe with 2 million and
1 million deaths respectively around the world.
The timing and severity of pandemics are
unpredictable; even at the beginning of a pandemic
it is not possible to predict its overall severity.
Pandemics also have the potential to overwhelm
national health systems and cause economic and
societal disruption. A high level of preparedness
is needed globally to enable rapid and flexible
responses to reduce the impact of the pandemic.
5.3 Australia’s preparation for a
pandemic
Australia has prepared for an influenza pandemic
over the past decade, with the development of
plans for both whole of government and health
sector responses. For the 2009 H1N1 influenza
Influenza and the role of immunisation
17

pandemic (see 5.4 The 2009 H1N1 influenza
pandemic), national guidance for the health
sector response was provided by the Australian
Health Management Plan for Pandemic Influenza
2008 (AHMPPI) (Department of Health and
Ageing 2008). This document, which built on two
previous iterations and the outcomes of Exercise
Cumpston in 2006, was developed following
extensive consultation with peak bodies, advisory
groups and eminent experts in pandemic
influenza. The AHMPPI was endorsed by all
Australian Health Ministers in December 2008.
The purpose of Australia’s pandemic planning has
been to ensure that we are ready to assess the
situation, make decisions quickly and take action
whenever a pandemic occurs. Without such
planning, Australia would not have been able to
act as quickly and effectively as it did in response
to the 2009 H1N1 pandemic and the impact of
the pandemic could have been a lot more serious.
Pandemic planning and preparation is ongoing.
The AHMPPI was updated in December 2009 to
reflect the lessons learnt from the response to
the 2009 H1N1 pandemic. The updated AHMPPI
was endorsed by the Australian Health Ministers’
Council (AHMC) in October 2010. This is an interim
revision—a more comprehensive revision will be
undertaken once a formal review of the health
sector response to the 2009 H1N1 pandemic has
been finalised.
A key objective of the AHMPPI is to reduce the
transmission of the pandemic virus to decrease
the number of people who become infected.
The AHMPPI identifies the development and
widespread use of a specific customised
pandemic vaccine as the best method of
protecting individuals against infection and the
development of severe illness as well as reducing
the spread of the virus in the community.
Candidate pandemic (pre-pandemic) vaccines,
based on viral strains thought to have pandemic
potential, also have a role within the AHMPPI.
This is in keeping with World Health Organization
(WHO) advice that influenza vaccines are “one of
the most effective ways to protect people from
contracting illness during influenza epidemics and
pandemics” (WHO 2011).
Customised pandemic vaccines can only be
developed once the new pandemic viral strain
emerges. As production timelines for influenza
vaccine using a standard egg-based method
are several months long and global production
capacity is limited, the AHMPPI recommends that
arrangements be made early for future production
and purchase of customised pandemic vaccine.
To ensure the government has priority access
to pandemic influenza vaccine, the Australian
Government has put Influenza Deeds of
Agreement in place for the supply of seasonal,
candidate pre-pandemic and customised
pandemic influenza vaccines. The current
Influenza Deeds of Agreement are with both
CSL Limited and Sanofi Pasteur. They were
initially signed in 2004 following an open
tender procurement process conducted by the
Department of Health and Ageing. Interim deeds
are in place with CSL and Sanofi Pasteur in 2010
and a tender process is nearing completion for
supply after 2011. The Office of Health Protection
in the Department of Health and Ageing manages
the Influenza Deeds.
5.4 The 2009 H1N1 influenza
pandemic
The 2009 H1N1 influenza pandemic was the first
human influenza pandemic in 40 years and caused
significant human infection and mortality globally.
The pandemic (H1N1) 2009 virus combines
genetic components from swine, avian and
human influenza virus strains. This genetic form
was new and there was very little immunity in
the largely naïve Australian population, although
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there was some evidence of cross protection
against the virus in older Australians. The virus
itself has proven to be more transmissible
between humans than seasonal influenza and
spread rapidly during the pandemic. Symptoms
have been mild and generally short lived in
most cases. In many cases, however, infection
has had serious consequences. The groups most
vulnerable to poor outcomes have included
pregnant women, those with underlying medical
conditions and Indigenous Australians.
As at 5 November 2010, a total of 44,403 confirmed
cases of pandemic (H1N1) 2009 influenza had been
recorded in Australia since the first case in May
2009. Of these, 37,636 cases were reported in
2009 and 6,767 cases were reported in 2010.
A total of 213 pandemic influenza-associated
deaths had been reported, 22 of which occurred in
2010. Thirteen percent (13%) of the 2009 confirmed
cases were hospitalised and 14% of these required
admission to an intensive care unit (ICU).
In Australia and around the globe, the highest
attack rates were in school children and young
people. As with seasonal influenza, there was
also a high rate of hospitalisation among children
under the age of 5 years in Australia.
Although the pandemic was moderate overall, it
was severe in a significant number of people and
we could not be complacent about its impact
in Australia. There remained a risk that the virus
could mutate to a more virulent form and there
was also a need to guard against an anticipated
second wave of infection. Vaccination remained a
key strategy for protecting the population.
Based on expert advice on the number of
people requiring vaccination to achieve the dual
aims of protecting vulnerable individuals and
preventing transmission of the pandemic virus,
the Government purchased 21 million doses of
Pandemic H1N1 Vaccine from CSL through its
existing Deed of Agreement. This was sufficient to
vaccinate half the population should two doses
be needed to achieve immunity or the whole
population should only one dose be needed.
5.5 Pandemic H1N1 Vaccine (Panvax®)
The CSL Pandemic H1N1 Vaccine (Panvax®) was a
purified, inactivated, monovalent (single strain),
split virion (split virus) vaccine, manufactured by
the same production method as the seasonal
vaccine. The virus strain included in the vaccine
was selected by the Australian Influenza Vaccine
Committee (AIVC) based on the recommendation
of the World Health Organization.
Clinical trials of the CSL adult and paediatric
vaccine were undertaken to assess the safety and
immunogenicity of the vaccine. Clinical trials are
not normally conducted for changes in strains
in seasonal influenza vaccine (see 3.2 Premarket
assessment and authorisation of seasonal
influenza vaccine). The pandemic (H1N1) 2009
virus, however, was a novel virus and clinical
trials prior to registration were requested by the
TGA. The trials commenced in July 2009 and first
reported in September 2009, with children’s data
available at the end of November 2009. The trials
confirmed that the vaccine was immunogenic
and well tolerated, with an adverse effect profile
similar to that of seasonal influenza vaccines.
A single dose was confirmed to be sufficient
for immunity in adults and older children in
September. Children under the age of 10 years
achieved a good level of immunity after one dose
but a second dose was recommended to ensure a
sustained response.
The Therapeutic Goods Administration (TGA)
approved the registration of Panvax H1N1 pandemic
vaccine for use in adults and children 10 years and
older on 18 September 2009 and in children aged
6 months to 9 years on 3 December 2009.
Influenza and the role of immunisation
19

5.6 The National Pandemic (H1N1)
2009 Vaccination Program
The national Pandemic (H1N1) 2009 Vaccination
Program commenced in adults and children
10 years and over on 30 September 2009 and in
children aged 6 months to less than 10 years on
4 December 2009. The vaccine remained available
until the final batches reached their expiry date on
31 December 2010.
The program was delivered through general
practice and other primary care immunisation
services, hospitals, state run clinics and
workplaces. In addition, some jurisdictions ran
community based vaccination clinics, for example,
at schools on several weekends in Queensland
and at various public events (festivals) in Tasmania.
By the end of the program, 9.4 million doses of
Panvax had been distributed to immunisation
providers. The number of doses administered
is not known but, based on serosurvey and
telephone survey results, it has been estimated
that about 18% of the population of all ages and
21% of adults had been vaccinated by February
2010, noting that uptake continued until the end
of December 2010.
5.7 Pharmacovigilence arrangements
for the National Pandemic (H1N1)
2009 Vaccination Program
An intensive pharmacovigilence program,
based on EMEA recommendations (2009),
was implemented to monitor the pandemic
vaccination program. TGA’s routine
pharmacovigilance mechanisms and processes
(see 3.0 The Australian Regulatory System for
Drugs and Vaccines) were enhanced with the
establishment of a dedicated call centre within
TGA to receive telephone reports of adverse
events through the Pandemic hotline. A simplified
web reporting form was developed and made
directly accessible from the TGA website
homepage. Information materials about the
vaccination program for health professionals and
consumers encouraged the reporting of adverse
events and provided information about how to
make a report. TGA worked with international
regulatory agencies to establish agreed case
definitions and follow up tools for assessing cases
of adverse events. The agreed case definitions
and clinical follow up forms for adverse events
of special interest (AESIs) were circulated to
all jurisdictions. All AESIs, such as anaphylaxis,
convulsions or Bell’s palsy, were followed up to
determine the relationship between the event
and the use of the vaccine. The Adverse Drugs
Reaction Advisory Committee (ADRAC) undertook
weekly review of the adverse events reports until
the end of 2009. ADRAC was replaced by the
Advisory Committee on the Safety of Medicines
(ACSOM) in January 2010, after which TGA
continued regular review of the AE reports and
referred cases to ACSOM when further advice was
needed. An expert pharmacoepidemiology panel
was established to provide advice on methods of
further evaluation for any safety signals.
Additional activities included:
• CSL undertook fortnightly signal detection
and provided the TGA with monthly
simplified Periodic Safety Update Reports
(PSURs) outlining all serious adverse events
associated with the vaccine reported to CSL
in Australia and internationally.
• Where a report of exposure of pregnant
woman to the vaccine was made, CSL
followed up the case to pregnancy
outcome and reported this to TGA.
• CSL established active surveillance for
Guillain Barré Syndrome (GBS).
• TGA exchanged information about
pandemic H1N1 vaccine pharmacovigilence
activities with its international counterparts
and established a mechanism for the rapid
sharing of safety data.
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TGA published summary reports on the adverse
events data on the TGA website. The most recent
covered the period 30 September 2009 to 17
September 2010 (TGA 2010). No safety issues with
the vaccine were identified (see 6.1.2 Was there a
safety signal from the Panvax Program in 2009?).
5.8 Seasonal Influenza Vaccine
The seasonal influenza vaccines currently available
in Australia are inactived, split virion or subunit
vaccines, produced using virus strains propagated
in fertilised hens’ eggs. The process involves
various steps, including purification, inactivation
and disruption of the virus. There are some
differences in the order in which these steps are
carried out and in the chemical agents used for
the different brands of the vaccine.
Seasonal influenza vaccines are trivalent ie
they protect against three strains of influenza,
two A strains (an H1 and an H3) and a B strain.
As influenza viruses are continually subject to
antigenic change, annual adaptation of the
influenza vaccine composition is needed to
ensure the vaccine provides protection against
the virus strains likely to be circulating during the
influenza season.
Information on the circulating strains and
epidemiological trends is gathered by the WHO
Global Influenza Surveillance Network (GISN),
to which the WHO Collaborating Centre for
Reference and Research on Influenza, based at the
Victorian Infectious Diseases Reference Laboratory
in Melbourne, is an important contributor. Twice
a year the WHO organises a consultation with
representatives from the Network to review the
results of their laboratory and clinical studies and
make recommendations on the composition
of the influenza vaccine (February: northern
hemisphere; September: southern hemisphere).
The strain composition of influenza vaccines
for use in Australia is determined each year
by the TGA’s Australian Influenza Vaccine
Committee (AIVC) based on the information and
recommendations provided by the WHO. The
AIVC decision is published on the TGA website.
In some years there are no changes in strain
composition, with the same strains being used
in two consecutive years. Other years can involve
changes in one, two or all three strains. In the
2010 vaccine, all three strains changed, with the
seasonal A(H1N1) strain being replaced with
the pandemic (H1N1) 2009 strain, the H3N2
component being replaced with the Perth 16
strain and the B/Florida/4 (Yamagatta lineage)
virus being replaced with the B/Brisbane/60
(Victoria lineage) virus. The same strains were
recommended and used in the 2010/11 Northern
Hemisphere vaccine. The pandemic (H1N1) 2009
strain change was managed as a normal seasonal
influenza vaccine strain change (see 3.2 Premarket
assessment and authorisation of seasonal
influenza vaccine) and it is now considered to be
a seasonal influenza virus.
5.9 Seasonal influenza vaccination
in Australia
The Australian Immunisation Handbook (AIH)
(NHMRC 2008) strongly recommends annual
seasonal influenza vaccination for any person
≥6 months of age who is at increased risk of
severe influenza or complications from influenza
or who is likely to transmit the infection to those
at increased risk. It also recommends annual
influenza vaccination for any person ≥6 months
of age who wishes to reduce the likelihood of
becoming ill with influenza.
Influenza and the role of immunisation 21

Seasonal influenza vaccines are available free
through the National Immunisation Program
(NIP) for people who meet eligibility criteria.
In 2010, eligibility for NIP funded influenza vaccine
was broadened to cover individuals at high
risk of complications from influenza, including:
those aged 65 years and older; Aboriginal and
Torres Strait Islander people aged 15 years and
older; individuals aged 6 months and older with
conditions predisposing to severe influenza; and
pregnant women.
Seasonal influenza vaccines are also available on
the private market and some employers offer
subsidised influenza vaccination to their staff.
States and Territories provide health care worker
vaccination programs and, since 2008, WA has
been providing a seasonal influenza vaccination
program for all children aged 6 months to less
than 5 years.
Approximately 6.3 million doses of seasonal
influenza vaccine were distributed in Australia in
2010, of which 3.9 million doses were NIP funded
vaccines.
Fever is common following immunisation,
especially in young children. In most cases the
fever is mild but high fevers can occur. Febrile
convulsion is a rare but recognised adverse
event following immunisation with a number
of vaccines, including measles-mumps-rubella
(MMR), diphtheria-tetanus-whole cell pertussis
(DTPw) and, more recently, measles-mumpsrubella-varicella
(MMRV) as well as influenza
vaccines (Barlow et al 2001; CDC ACIP 2008).
A Joint ATAGI/TGA Working Group found no clear
literature-based estimate for expected rates of
influenza vaccine- attributable febrile convulsions.
They noted that the US CDC VSD project data
over the period 2005–06 to 2009–10 indicated
a rate of febrile seizures following trivalent
seasonal influenza vaccine in children 6 months
to 3 years of 0.03 per 1,000 doses on the day of
administration and 0.16 per 1,000 doses in the
1–7 days post-vaccination. They also noted that
febrile convulsions had been reported in influenza
vaccine post marketing data at a rate between
0.1 in 1,000 and 1 in 1,000 persons vaccinated
(TGA 28 September 2010; TGA 8 October 2010).
5.10 Febrile reactions and convulsions
following immunisation
Febrile convulsions are relatively common in
young children, with approximately 3% of children
having at least one between the ages of 6 months
and 6 years. Although distressing to parents and
other family members, they generally have an
excellent prognosis. Febrile convulsions occur
most commonly with high or rapidly rising fevers
caused by typical childhood infections but can be
associated with any condition that results in fever.
Influenza infection can cause high fevers and
febrile convulsions. Children with severe influenza
are at particular risk with up to 1 in 5 children
hospitalised for influenza having a febrile
convulsion in Hong Kong based studies (Chiu et al
2001; Chung and Wong 2007).
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6
THE FINDINGS OF THE REVIEW
6.1 Rates of febrile convulsions
related to previous influenza
vaccination (seasonal and pandemic)
in Australia
The Review considered whether the situation in
2010 was different to other years and whether
there was any evidence that could have predicted
the problem with the 2010 Fluvax vaccine.
6.1.1 Was there a safety signal from the use of
previous seasonal influenza vaccines in children
under 5 years of age?
There was no safety signal from the use of
seasonal influenza vaccine in WA in 2008 and
2009. Data reviewed by ATAGI as part of the
investigation of the 2010 events indicated that
there was no increase over baseline in febrile
convulsions in children less than 5 years of age
presenting to Perth emergency departments
during the 2008 and 2009 influenza vaccination
programs. A cohort study undertaken by NCIRS in
collaboration with WA as part of the investigation
showed no evidence of increased febrile
convulsions in vaccinated children in 2009
(ATAGI/TGA 13 May 2010).
6.1.2 Was there a safety signal from the Panvax
program in 2009?
The Panvax program in 2009 was a national
program established by the Commonwealth in
accordance with the agreed protocols of the
nationally adopted AHMPPI. Enhanced monitoring
and surveillance was in place, in keeping with the
requirements for a pandemic vaccine program
recommended by the WHO. No safety signals
were detected during the roll out of this program
and, specifically, no increase in febrile convulsions
was noted.
Further analysis of the rate of febrile convulsions
associated with Panvax and Panvax Junior vaccine
was undertaken by a joint TGA and Australian
Technical Advisory Group on Immunisation
(ATAGI) working group in September 2010
(ATAGI/TGA 27 September 2010). Using a range
of estimates of the number of doses of Panvax
given to young children, the Working Group
found an apparent modest increase in febrile
convulsion rate associated with the use of Panvax/
Panvax Junior in children less than 4 years of age,
compared with rates observed with seasonal
influenza vaccines in the United States. However,
the estimated rate of 7–18 (and possibly up
to 30) per 100,000 doses was within the range
specified in the Panvax Product Information and
remained within the ‘rare’ side effect range of
between 10 and 100 per 100,000 doses. It was
The findings of the Review 23

noted that the rate was at least 25-fold lower
than the estimated rate of 700 febrile convulsions
per 100,000 doses estimated to occur following
the 2010 Fluvax vaccine. The ATAGI/TGA Working
Group considered that the absolute risk of febrile
convulsion was within the acceptable range and
did not alter the indications for the use of Panvax.
A cohort study of adverse events in children
vaccinated with Panvax, Fluvax or Influvac at
three NSW hospitals from February 2010, was
coordinated by the NCIRS. This study obtained data
on fever and medical attendances retrospectively
by telephone interview of parents of children who
had been vaccinated; parents were unaware which
brand of seasonal vaccine their child had received.
In this study, the rates of fever following Panvax
(16%) were higher than the rates following Influvac
(7%) but significantly lower than for Fluvax (46%)
(TGA 24 September 2010).
6.2 The national response to the
reporting of adverse events in young
children following receipt of the 2010
seasonal influenza vaccine
6.2.1 When were the adverse events following
Fluvax immunisation first detected and what
actions were taken?
The 2010 seasonal influenza vaccination program
began in early to mid-March with a variation
in start date across jurisdictions. In WA, vaccine
delivery commenced 8 March 2010, with the
official launch of the vaccination program on
19 March 2010.
From a review of TGA logs and emails and
information provided by WA and in the Stokes
Report, a chronology of events has been
developed (Table 1).
This Review concludes that there was no safety
signal from the use of Panvax in the pandemic
H1N1 influenza vaccination program that would
have indicated a need to change the the use
of Fluvax in the subsequent seasonal influenza
vaccination program in 2010.
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Table 1. Timeline of the investigation into febrile reactions in young children following 2010 seasonal
trivalent influenza vaccination
Date
Action
08 March 2010 Distribution of seasonal influenza vaccine commences in Western Australia.
19 March 2010 Official launch of the seasonal influenza vaccination program in WA.
15 March 2010 First febrile convulsion in Victoria. Report received by TGA on 31 March.
18 March 2010 First febrile convulsion in WA. Report received by TGA on 23 March.
1 April 2010 First anecdotal reports of febrile reactions and one child attending hospital received
by CDCD WA Health via email.
13 April 2010 CDCD WA Health advises the TGA it has reports of febrile convulsions in children
and seeks information on whether TGA has received similar reports. TGA requests
documentation of the cases.
15 April 2010 South Australia advises TGA, OHP and the jurisdictional immunisation coordinators it is
receiving reports of vomiting and high fever.
20 April 2010 First tranche of AEFI reports from CDCD WA Health is received by TGA.
22 April 2010 National Immunisation Committee Meeting.
22 April 2010 Teleconferences of TGA, ATAGI Chair, Director of NCIRS, and OHP.
22 April 2010 WA Minister for Health announces suspension of the WA influenza vaccination
program for children

Date
Action
4 May 2010 TGA meets with NCIRS to review epidemiological analyses.
4 May 2010 TGA expert panel on vaccine testing convened, chaired by Prof Peter Doherty.
10 May 2010 TGA reviews distribution and ADR data with vaccine sponsors.
11 May 2010 TGA pharmacoepidemiology expert panel is convened by teleconference to review
planned and completed epidemiological analyses and endorses the planned analyses.
13 May 2010 ATAGI–TGA Working Group, NCIRS, and Department meet to review the evidence
being provided by jurisdictions.
13,14 May 2010 TGA undertakes GMP audit of CSL manufacturing facilities.
14 May 2010 TGA expert panel on vaccine testing meets.
20 May 2010 ATAGI–TGA Working Group provides interim report to the CMO.
1 June 2010 CMO announces continued temporary suspension of the use of seasonal influenza
vaccine in healthy children under 5 years of age and vaccination of at risk children with
a preference for Influvac or Vaxigrip. CMO writes to immunisation providers.
1 June 2010 TGA sends samples to NIBSC for further in vitro analyses.
2 June 2010 TGA’s Advisory Committee on the Safety of Medicines (ACSOM) meets to review issues
with 2010 seasonal TIV.
2 June 2010 TGA issues a public report on the investigations to date.
7 June 2010 TGA sends samples to CDC for in vitro and in vivo analyses.
10 June 2010 ATAGI meets.
18 June and
21–23 June 2010
TGA undertakes inspection of CSL manufacturing facilities.
2 July 2010 TGA issues interim report on the investigations to date.
8 July 2010 ATAGI Working Group meets to consider further data on Vaxigrip from studies in New
Zealand and NSW.
30 July 2010 CMO announces that seasonal influenza vaccination of children under age of 5 years
can now be resumed using Influvac and Vaxigrip in preference to Fluvax and writes to
immunisation providers.
24 September 2010 TGA updates interim report of investigation.
By 13 April 2010, TGA had received 4 reports
of febrile convulsions associated with seasonal
influenza vaccination, two from Victoria and two
from WA. The Victorian reports were received on
31 March and were of events that had occurred
on 15 and 24 March. The first febrile convulsion
following seasonal influenza vaccination in WA
occurred on 18 March. It was reported directly to
the TGA by the doctor and logged on 23 March.
The second case occurred on 26 March and a
report was received by the TGA on 13 April.
On 13 April 2010, the Communicable Disease
Control Directorate (CDCD) of WA Department of
Health emailed the TGA indicating it was receiving
a lot of calls from immunisation service providers
about children having high temperatures and
being unwell, some with seizures after the
vaccine, and seeking information about whether
other states were experiencing anything similar.
On April 14 2010 there were further email and
telephone contacts between TGA and WA and
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the TGA requested case report information from
WA. It was noted that South Australia (SA) had
contacted WA to check its experience, as SA was
also receiving increased reports of AEFI following
seasonal influenza vaccine. WA requested the TGA
to check with other states and provide an update
at the upcoming NIC meeting.
On 15 April, SA emailed the TGA and the
OHP (copied to all jurisdictions, including the
jurisdictional immunisation coordinators (JIC)),
indicating that they were receiving reports of
vomiting and high fever and mentioning that
Victoria was also receiving similar reports. SA
considered this was different to what they had
experienced with Panvax and provided a copy of
an analysis of the reports they had received as at
15 April 2010 (but no formal AEFI case reports or
notifications). The TGA responded to this email
on 16 April indicating that they had a total of
62 AEFIs (22 in patients under the age of 18 years)
following 2010 seasonal influenza vaccine, asking
that jurisdictions forward all relevant unsubmitted
reports and data on influenza vaccines
administered and proposing that the issue be
discussed at the following week’s NIC meeting.
On 15 April, the TGA received two reports of
febrile convulsions from Queensland, for events
which had occurred on 29 March and 1 April.
The first batch of reports from WA (14) were sent on
19 April and received/logged by the TGA on
20 April; these recorded events that had happened
between 18 March (this was a duplicate report of
the first WA case) and 19 April. A report from Qld
was also received that day for a febrile convulsion
that had occurred on 26 March. The first case report
of a febrile convulsion from SA was received on
22 April, having occurred on 19 April.
On 22 April, the National Immunisation
Committee (NIC) meeting was briefed on and
discussed the available TGA data and the SA and
WA concerns. Some other jurisdictions reported
noticing an increase in AEFIs. The jurisdictions
agreed to expedite the reporting of all cases
of AEFIs followings seasonal flu vaccination so
that these could be investigated by TGA. They
also agreed to provide data to TGA on vaccine
distribution, batches and emergency department
admissions to support the investigation.
Following the NIC meeting, two teleconferences
of TGA, ATAGI Chair, Director of NCIRS, and OHP,
the first of which also included WA and SA,
discussed the approach to the investigation of the
febrile convulsions, the data requirements for the
investigation and the development of information
for the public and immunisation providers.
On 21 April 2010, the WA Health Department
convened an expert group who reviewed the data
available to WA and, following a second meeting
on 22 April 2010, recommended suspension of
the WA seasonal influenza vaccination program for
well children under age 5 years. The suspension,
which did not include the at risk children being
vaccinated under the NIP, was announced by the
WA Minster for Health, the Hon Dr Kim Hames,
that afternoon in WA.
The CMO suspended the use of all influenza
vaccines for all children aged 5 years and under
nationally the following day (23 April 2010), that is,
within 3 days of TGA’s receipt of the first tranche of
reports from WA.
The suspension of the program was to enable
an investigation of the causality of the reported
events and to ascertain the nature and extent
and cause of the problem. The investigation
was multi-faceted with concurrent areas of
work to validate cases through detailed case
review, undertake epidemiological analyses,
review clinical trial and manufacturing process
data, review information on the international
experience, auditing the manufacturing
facilities and undertaking extensive laboratory
investigations. The investigation aimed to answer
a number of questions, as detailed in the TGA
document Overview of vaccine regulation and
The findings of the Review 27

safety monitoring and investigation into adverse
events following 2010 seasonal influenza vaccination
in young children (TGA 8 October 2010).
Work commenced immediately and involved the
establishment of a TGA expert scientific advisory
panel and a joint ATAGI–TGA Working Group,
supported by the ATAGI Secretariat in OHP. The
Working Group developed templates for data
collection for the epidemiological analyses and
provided them to all jurisdictions on 26 April 2010.
All jurisdictions collected and provided data on
febrile convulsion presentations to emergency
department, vaccine distribution, batch numbers
and clinical data for the validation of cases. The
NCIRS undertook the epidemiological analyses
in consultation with the ATAGI–TGA Working
Group. The TGA also established an expert
panel on vaccine testing, chaired by Professor
Peter Doherty, to advise on the laboratory
investigations. The expertise of the TGA and
its advisory committees and the AHPC all
contributed to the investigation.
Throughout the period of the investigation, the
CMO liaised regularly with state and territory
health officials, TGA, ATAGI, and general practice
and other immunisation provider organisations
to facilitate rapid exchange of clinical and
epidemiological data and dissemination of the
findings as they became available. The CMO also
held regular briefings to keep the community
informed.
Comment
It is apparent from the document review
that there had been a sense among health
professionals and parents in WA and SA that
there was something unusual about the adverse
events profile of the 2010 seasonal flu vaccine
from soon after the start of the vaccination
programs in these two jurisdictions. However,
this did not translate quickly into formal
reports with hard data suitable for confirming
the presence of a signal. At the time that the
immunisation coordinators in WA and SA were
asking for information, TGA had received a small
number (4) of reports of febrile convulsions.
The records indicate that many jurisdictions
were not forwarding reports as they were
received, but were batching them. In some
cases, an AEFI report was sent but did not
mention a febrile convulsion, which was only
identified later during the investigation.
The majority of febrile convulsion reports were
received by TGA only after the jurisdictions
had been prompted to send reports because
of the concerns being raised by WA and SA.
Almost all reports were received by TGA after
19 April 2010.
There also appeared to be some confusion
about what constitutes an AEFI report, when it
is possible to determine that there is a potential
signal, and the subsequent determination of
causality and action to be taken. The Review
considers that, while emails and phone calls
between health professionals are a way of
alerting each other to the possibility that
there is a potential problem, they do not in
themselves constitute confirmation of a signal.
Properly documented and timely case reports
are needed before a signal can be confirmed
and appropriate action be taken. Investigation
of a signal is a complex process involving
confirmation/validation of the cases, active
looking for unreported cases, estimation of
rates and further epidemiological and other
investigations (Global Advisory Committee on
Vaccine Safety 2009).
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6.2.2 Were the actions of the Commonwealth
timely and appropriate?
The Review considers that the actions of the
TGA and the CMO were appropriate, timely and
proportionate. Once data had been received by
the TGA to indicate a possible signal needing
further investigation, the CMO took action to
suspend the program. The recommendation
by the CMO to suspend the use of all seasonal
influenza vaccines pending the investigation was
discussed with the Chief Health Officers (CHOs) at
a meeting of the AHPC on the morning of 23 April
2010. This enabled jurisdictions, which implement
the NIP, to be briefed on the rationale for the
recommendation and the planned investigation.
The CHOs agreed to provide data to support the
investigation.
The decision to suspend the use of all seasonal
influenza vaccines was based on the advice from
ATAGI and TGA that, while early data on Influvac
was reassuring, there was insufficient data on the
use of vaccines other than Fluvax in Australia to be
certain that they did not have the same problem,
particularly as there was no clearly identifiable
reason to explain the increase in febrile reactions.
An important aspect of the subsequent
investigation was to specifically look at any
available data in Australia and internationally that
would be able to confirm that there was no safety
signal with the other available vaccines.
Comment
The Review considers that, overall, the
management of the adverse events associated
with Fluvax demonstrated: the identification
of a safety signal; the instigation of an
appropriate investigation and response; the
regular provision of information to keep
health professionals consumers and the media
informed; and the re-instigation of vaccination
with alternative vaccines once it had been
demonstrated that they did not have the same
increased risk of febrile reactions as Fluvax.
The investigation was extensive. The TGA
worked closely with the ATAGI and the NCIRS in
undertaking the epidemiological analyses, drew
on national and international experts to define
and explore its hypotheses and worked with
the Centers for Disease Control and Prevention
(CDC) in Atlanta on in vitro and in vivo studies
to determine the cause of the reactions. The
extent and rigour of the investigation has been
positively received internationally and has been
drawn on by other regulators and agencies
in their consideration of the use of seasonal
influenza vaccines in children.
The Review considers, however, that the
management of these events has highlighted a
number of areas in the current AEFI monitoring
arrangements in Australia that could be
improved. These are discussed in the next section.
In making a decision to suspend a vaccination
program while further investigations are
underway, there is a need to balance the
benefits and risks of taking such action. The
suspension of the program for a signal that
later turns out to be false, means that people
do not receive the protection offered by
vaccination for the period of the suspension,
and risk contracting the disease in this period.
Suspension of a program can undermine
the confidence of the public in the specific
vaccine and may result in people choosing
not to be immunised when the program
recommences. Confidence in other vaccines and
the NIP can also be undermined. However, the
identification of a possible signal of a potentially
serious safety problem needs to be promptly
investigated and suspension of the use of the
vaccine may be necessary to ensure people
are not being exposed to an unacceptable risk
while the investigation is being completed.
The findings of the Review 29

6.3 Improving the monitoring of
AEFI in Australia
Based on a consideration of the monitoring and
reporting procedures in place in Australia at
national and jurisdictional levels, the information
provided by jurisdictions, the interviews with
stakeholders and the information received about
international systems, the Review considers that
the monitoring of AEFI in Australia is in keeping
with international systems of passive adverse
events surveillance. The recent issues surrounding
the events that prompted this Review, however,
have demonstrated that improvements could be
made to make the system more robust and timely.
Areas considered for improvement have been
grouped under several headings:
• Governance arrangements
• Clarifying the objectives and processes for
AEFI monitoring
• Harmonising reporting and improving
information flows between TGA and the
jurisdictions
• Transparency and communication
• Improving the collection of vaccine
administration data
6.3.1 Governance arrangements
While the TGA has legislated responsibility
to monitor the safety of vaccines, many
organisations, committees and individuals have a
role to play in identifying, investigating and acting
upon safety signals related to vaccines in use in
Australia, particularly those used in the NIP. These
groups and their roles have been described in
the National Immunisation Program—Governance
section. The Review found, however, that there
was a lack of clarity about the relationships
between these groups and that their roles and
responsibilities in AEFI surveillance and vaccine
safety monitoring are not well understood
by jurisdictional health authorities, health
professionals and the public.
A particular issue is the differentiation between
when regulatory action for a product, which is
a legislated responsibility of the TGA, is required
and when non-regulatory action related to the
use of a vaccine in a national (or jurisdictional)
program may be indicated. The Review notes
that there are no Standard Operating Procedures
for responding to a vaccine safety issue that
does not require regulatory action but which has
possible implications for the use of a vaccine in a
vaccination program.
The Review notes that, with the increased
complexity of the NIP, governance arrangements
that were appropriate for a smaller program need
to be changed to meet the needs of the larger
program. Improved governance arrangements are
needed with the establishment of clear lines of
responsibility for managing a vaccine safety issue
and for reporting, decision making and action.
Options for achieving improved governance
identified by the Review include:
i. maintaining the current organisations and
structures but developing more robust and
clear governance and reporting through
clearly defining the roles and key areas
of responsibility of each of the existing
committees and organisations and their
relationships to each other.
or
ii. establishing and resourcing a Vaccine
Safety Committee (VSC), a new body with
responsibility for monitoring vaccine safety
in Australia. The new body could be a
subcommittee of the Therapeutic Goods
Administration (TGA) Advisory Committee
on the Safety of Medicines (ACSOM).
It should have a broad membership of
experts with knowledge of vaccines,
vaccine safety, pharmacoepidemiology and
vaccine program implementation.
or
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iii. restructuring immunisation governance
in Australia to provide a consolidated and
simpler governance pathway by creating
a new independent body to carry out
vaccine safety monitoring functions.
6.3.2 Clarifying the objectives and processes of
AEFI monitoring in Australia
The current national passive AEFI reporting
system lacks a clear articulation of its objectives
and the key principles by which it operates to
ensure a robust system. Publicly stated objectives
and principles provide a basis for the system’s
processes and procedures and for assessment
and evaluation of its performance. National
objectives need to be developed, encompassing
the monitoring of AEFI through passive reporting
as well as the more active surveillance and
investigation to be undertaken once a potential
signal is identified.
Case definitions for AEFIs are not nationally
consistent which makes the analysis and
classification of cases and identification of
signals difficult. The Review considers that the
development of agreed case definitions to be used
across all jurisdictions and the TGA is a key priority.
The Review found that it was not clear to
jurisdictions, health professionals and the public
as to what constitutes a trigger for TGA to
commence an investigation into a signal, nor what
processes and procedures are used to undertake
such an investigation. The Review notes that each
event has its own unique circumstances and that
detailed protocols cannot be developed as they
depend on the nature of the event. The Review
considers, however, that the development of
agreed triggers and protocols that outline the
processes and procedures for an investigation
would improve confidence in the system and
facilitate decision making.
The development of system objectives, case
definitions and signal identification and
investigation protocols could be undertaken by a
Working Party of experts in AEFI monitoring and
investigation and jurisdictional representatives.
6.3.3 Harmonising AEFI reporting and
improving information flows between TGA
and jurisdictions
The information considered by the Review
highlighted the different pathways for reporting
and the multiple handling of material that
results in an adverse event report to TGA and
the documentation of relevant clinical data.
There are different reporting forms, protocols
and procedures for reporting across the
jurisdictions. Data may be forwarded as it is
received or in batches after it has been analysed.
There is duplication of case reports and a lack
of consistency of case definitions. The TGA also
batches reports made directly to the organisation
before forwarding them to the jurisdictions
on a monthly basis. The TGA has improved the
information flow by establishing specific TGA
contact persons for each jurisdiction. However,
there continue to be delays in the transmission of
formal reports in both directions.
It is always a challenge to have consistent and
uniform arrangements in a health system that
is geographically spread over a large continent
and where there are divided responsibilities
between levels of Government. However, the
establishment of the National Registration and
Accreditation Scheme for health professionals and
the development of standards for the safe and
high quality delivery of health services through
the Australian Commission on Safety and Quality
in Health Care demonstrate that harmonisation
can been achieved.
The findings of the Review 31

The AEFI reporting system requires national
harmonisation and improved information flows
to ensure that relevant information is available in
‘real time’ to both the TGA and to the jurisdictions.
A consolidated reporting pathway should be
developed that is consistent nationally and is
user friendly. An agreed template/reporting
form should be developed for reporting AEFI in
all jurisdictions. Both health care professionals
and consumers should be able to make reports
using the same template and any phone reports
should be recorded on it as well. Simultaneous
reporting should occur with jurisdictions and the
TGA receiving copies of reports as they are made,
rather than in batches. Reporting of AEFIs to the
TGA by the jurisdictions and vice versa should be
standardised.
6.3.4 Transparency and Communications
The Review found there is a considerable lack
of knowledge of the AEFI surveillance system
among health professionals and consumers.
For the jurisdictions, there could be better
clarity of the processes within the TGA and the
interrelationships between TGA, the broader
Department and other bodies with roles in the
NIP. The distinction between the role of TGA as
regulator of the product (ie the vaccine) and the
role of the broader Department and the CMO
in making program decisions, in consultation
with the jurisdictions, about the use of vaccines
in the NIP is also not clear to many stakeholders.
The importance of prompt reporting of AEFIs
with accurate clinical information and sufficient
detail to enable follow up if necessary is not
well understood by many health professionals.
However, health professionals and consumers
who want to make a report are often not aware
of how to do so.
The Review also found a lack of understanding
by the community of the significance of reports
of AEFIs, when they constitute a safety signal and
when they are of sufficient concern to warrant a
suspension or cancellation of the use of a vaccine.
Informing the community of how the safety
system operates and makes decisions would
improve confidence in the system when specific
events occur.
The Review considers that an appropriate
communication strategy should be developed to
improve knowledge and awareness of the system
among stakeholders and encourage prompt
reporting.
Some health professionals and consumers felt they
were not sufficiently informed of the unfolding
events surrounding the suspension of the program
and the subsequent investigation, particularly
in the early stages before the suspension was
announced. The Review notes there are significant
challenges in determining how to communicate
with health professionals and the community
during the early stages of an investigation, when
there is a level of doubt about the significance of
the events. Jurisdictions and health professional
and consumer organisations may have to deal
with enquiries, including from the media, based on
rumours of a problem, before there a clear signal of
a potential safety issue warranting investigation has
been identified. In these situations, it is important
that there is a statement from a recognised
authority, such as the TGA or the CMO, to avoid
confusion and ensure that safety information is
available to the public.
The Review considers that a protocol for taking
program action, including informing health
professionals, consumers and the media, in the
event a possible safety signal affecting a NIP
vaccine is detected should be developed and
agreed by the DoHA and the state and territory
health authorities.
32
Review of the management of adverse events associated with Panvax and Fluvax

There was a perception among some stakeholders
that there is a lack of transparency in the
TGA vaccine surveillance processes and that
information about investigations into adverse
events associated with vaccines is slow to be
made public. Other concerns were that it is
difficult to find information on the TGA website
and current web-based reporting mechanisms
are difficult to use. Product information is difficult
to locate and consumers find the Product
Information difficult to understand and interpret.
The Review notes that the TGA is currently
undertaking a comprehensive update of its
website, to be completed early in 2011, which
is anticipated to improve the accessibility of
information.
The Review considers that issues related to
improving transparency of the TGA’s role in
vaccine safety monitoring would be best
addressed through the separate Transparency
Review of the TGA that is currently underway,
chaired by Professor Dennis Pearce AO.
A number of stakeholders indicated that they
thought Australia should make the AEFI database
available to the public, as happens in a number of
other countries. The Review considers that this is a
complex issue that requires careful consideration
and would be more appropriately addressed by
the TGA Transparency Review.
6.3.5 Improving vaccine administration data
The investigation of adverse events following Fluvax
highlighted the difficulty of obtaining accurate
and timely vaccine administration data, which is a
significant issue for the evaluation of potential AEFI
safety signals. Data on the number of vaccine doses
administered are required for the calculation of AEFI
rates and data on individual vaccination histories
are important when confirming case reports and
undertaking signal investigations.
The ACIR collects data on the vaccination status
of individual children and can be utilised for
estimating the number of doses of NIP vaccines
administered to children up to the age of 7 years.
However, there is a level of underreporting of NIP
vaccines, vaccines given outside the NIP may not
be notified to the ACIR and there are some delays
in data being sent to the ACIR, which can limit
the usefulness of ACIR data in rapidly evolving
situations such as occurred with the Fluvax
adverse events. In addition, the ACIR does not
cover vaccines given to older children and adults.
There was a particular difficulty with the collection
of influenza vaccine data by the ACIR in 2010. This
was due to a combination of factors. There were
problems with two of the desktop programs used
by general practitioners, which resulted in data
on influenza vaccines not being transmitted to or
accepted by the ACIR. In addition, ACIR was not
advised of the addition to the NIP of the Solvay
vaccine, Influvac, which impacted on the ease with
which providers could notify vaccinations with
this vaccine. All of these problems were addressed
and resolved but did impact on the timeliness and
accuracy of the seasonal influenza vaccination data
being recorded in the ACIR in 2010.
The Review notes that the experience in WA
suggested that many providers sent influenza
vaccination data to the ACIR in 2008 and 2009.
With the resolution of the problems that occurred
in 2010, providers should be able to notify
influenza vaccines in future seasons.
In the absence of vaccine administration data,
distribution data can be used for rate calculations,
but this is a crude measure as it does not indicate
how much of the vaccine was given to people
in different age groups. NCIRS used data from a
range of sources to develop estimates of vaccine
usage for the calculation of the rates of febrile
convulsions in the Fluvax investigation.
The findings of the Review 33

Comment
The Review considers that, despite its
limitations, the ACIR dataset can be very useful
in signal investigations. As a high notification
rate to ACIR of vaccines administered to children
increases the usefulness of the dataset, it is
important to encourage all immunisation
providers to notify all vaccines given to
children. The Immunisation Branch of DoHA
has advised the Review that communications
for the 2011 influenza season will encourage all
immunisation providers to notify any influenza
vaccine given to a child under the age of 7 years
to the ACIR, regardless of the funding source for
the vaccine.
Future developments in e-health provide
an opportunity to improve the capacity for
vaccine surveillance across all age groups,
including the capacity to collect data on
vaccine administration and adverse events. The
Review considers that utilising the capacity for
collecting vaccine administration and safety
monitoring data should be a key priority for
future e-health planning and development.
6.4 Other findings
6.4.1 Review of the premarket authorisation of
influenza vaccines by the TGA
As described in section 3.2 (Premarket assessment
and authorisation of seasonal influenza vaccine),
there are a number of unique features of this
process. The vaccine manufacturing process
has been well established over many decades.
Full evaluations are undertaken when there
are changes in manufacturing process (eg the
manufacture of the vaccine for H5N1) but not for
seasonal vaccines where the only change is in the
antigen composition.
The Review noted that the EMA requires annual
seasonal influenza vaccine trials in Europe,
however, they are very small, do not include
children and would not detect safety signals for
events of the frequency of the febrile convulsions
seen with Fluvax. The Review also received advice
from the WHO Collaborating Centre for Reference
and Research on Influenza in Melbourne that
there is only a limited time between the strain
selection in the southern hemisphere and the
commencement of the influenza season. To allow
time for even limited trials, earlier strain selection
would be required, which would increase the risk
of changes in the strains circulating during the
season which would limit the effectiveness of the
vaccine. The Review was advised by the TGA that
formal trials for seasonal strain changes are not
required by other regulatory agencies such as the
US FDA.
Evidence from the TGA confirms that the current
premarket authorisation and batch release
processes for seasonal influenza vaccines in
Australia are in keeping with international best
practice.
Comment
Following consideration of the detailed
information on the strain selection process and
vaccine production timeline, the Review has
concluded that even small trials of seasonal
vaccine, such as required by the EMA for use
of the vaccine in Europe, would not be feasible
with our vaccine production timelines.
34
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7
RECOMMENDATIONS OF THE REVIEW
Recommendation 1
The Governance of the Vaccine Safety System
That the Department establishes a Working Party
to consider the current governance arrangements
for monitoring and responding to vaccine safety
issues in Australia and make recommendations
for an improved system of governance for
vaccine safety monitoring. Options for achieving
improved governance recommended for
consideration by the Working Party include:
i. maintaining the current organisations and
structures but developing more robust and
clear governance and reporting through
clearly defining the roles and key areas
of responsibility of each of the existing
committees and organisations and their
relationships to each other.
or
ii. establishing and resourcing a Vaccine
Safety Committee (VSC), a new body with
responsibility for monitoring vaccine safety
in Australia. The new body could be a
subcommittee of the Therapeutic Goods
Administration (TGA) Advisory Committee
on the Safety of Medicines (ACSOM).
It should have a broad membership of
experts with knowledge of vaccines,
vaccine safety, pharmacoepidemiology and
vaccine program implementation.
or
iii. restructuring immunisation governance
in Australia to provide a consolidated and
simpler governance pathway by creating
a new independent body to carry out
vaccine safety monitoring functions.
Recommendation 2
Defining Surveillance Objectives and
Establishing Protocols and Procedures
for Managing Adverse Events Following
Immunisation
That the Department establishes a Working
Party of Experts, including state and territory
health authority representatives, to develop,
in consultation with the TGA and key national
immunisation bodies, the principles and
objectives of the Australian adverse events
following immunisation (AEFI) surveillance
system, agreed case definitions for AEFIs, agreed
triggers for when further investigation should be
undertaken and protocols and procedures for
such investigations. This Working Party will need
to evaluate the benefits of additional surveillance
mechanisms to ensure the safety of vaccines.
Recommendations of the Review
35

Recommendation 3
Improving the National System for Timely
Reporting of Adverse Events Following
Immunisation
That the Department requests the TGA to
establish a joint TGA/National Immunisation
Committee working group to develop
mechanisms for improved and timely information
flows between TGA and the jurisdictions and
agreed templates for nationally consistent
reporting of adverse events following
immunisation.
Recommendation 4
Raising Community and Health Professional
Awareness of Vaccine Safety Monitoring to
Ensure More Complete Reporting of Adverse
Events Following Immunisation
That the Department considers the development
of a communications strategy to inform
jurisdictions, health professionals and consumers
of the vaccine safety monitoring processes in
Australia.
Recommendation 5
Nationally Agreed Protocols for Program Action
and Communication
That the Department develops and agrees
with jurisdictions a protocol for taking program
action, including informing health professionals,
consumers and the media, in the event a possible
safety signal is detected affecting a National
Immunisation Program vaccine.
Recommendation 6
Transparency and the Functions of the TGA
to Ensure Better Access to Vaccine Safety
Information for Consumers and Health
Professionals
Improvements to the transparency of the TGA’s
vaccine safety monitoring processes should be
considered by the independent Transparency
Review of the TGA being chaired by Professor
Dennis Pearce.
Recommendation 7
Vaccine Usage and Safety Monitoring Data
The collection of vaccine usage and safety
monitoring data should be a key priority for future
e-health planning and development.
36
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8
REFERENCES
Australian Government Department of Health
and Ageing (2008) Australian Health
Management Plan for Pandemic Influenza
2008. Canberra, ACT.
Australian Government Department of Health and
Ageing (2009) Australian Health Management
Plan for Pandemic Influenza (Updated
December 2009).
http://www.health.gov.au/internet/panflu/
publishing.nsf/Content/B11402BB723E0B78
CA25781E000F7FBB/$File/ahmppi-2009.pdf
Accessed 4 January 2011.
Australian Government Department of Health and
Ageing (2010) Australian Influenza Surveillance
Report No. 44.
http://www.health.gov.au/internet/main/
publishing.nsf/Content/44CA16D6D75F4F13
CA2577DB007A33EC/$File/ozflu-no44-2010.
pdf
Accessed 11 January 2011.
Barlow W. Davis R. Glasser J. et al (2001) The Risk
of Seizures after Receipt of Whole-Cell Pertussis
or Measles, Mumps, and Rubella Vaccine.
N Engl J Med 2345:656–661.
Brighton Collaboration (2010)
https://brightoncollaboration.org/public/
Accessed 24 January 2011.
CDC (2009) Influenza A (H1N1) 2009 Monovalent
Vaccine Safety Monitoring: CDC Planning
Recommendations for State, Local, Tribal and
Territorial Health Officials.
http://www.cdc.gov/h1n1flu/vaccination/
safety_planning.htm
Accessed 25 August 2009
CDC ACIP (2008) Update: Recommendations from
the Advisory Committee on Immunization
Practices (ACIP) Regarding Administration
of Combination MMRV Vaccine. MMWR
—Morbidity and Mortality Weekly Report
57(10):258–260.
Chiu S. Tse C. Lau YL. Peiris M. (2001) Influenza
A infection is an important cause of febrile
seizures. Pediatrics 108(4): e63.
Chung B. Wong V. (2007) Relationship between
five common viruses and febrile seizure in
children Arch Dis Child 92:589–593.
EMEA (2009) CHMP Recommendations for the
Pharmacovigilance Plan as part of the Risk
Management Plan to be submitted with the
Marketing Authorisation Application for a
Pandemic Influenza Vaccine.
http://www.ema.europa.eu/docs/en_GB/
document_library/Report/2010/01/
WC500051739.pdf
Accessed 12 January 2011.
References
37

Global Advisory Committee on Vaccine Safety
(GAVCS) and WHO Secretariat (2009) Global
safety of vaccines: strengthening systems
for monitoring, management and the role of
GAVCS. Expert Review of Vaccines 8(6):705–716
http://www.who.int/immunization_safety/
global_committee/Global_Vaccine_Safety_
GACVS_June_09.pdf
Accessed 18 January 2011.
NHMRC (National Health and Medical Research
Council) (2008) The Australian Immunisation
Handbook 9th edition. Australian
Government Department of Health
and Ageing, Canberra ACT.
http://www.health.gov.au/internet/
immunise/publishing.nsf/Content/
Handbook-home
Accessed 7 January 2011.
NCIRS (2008) Fact Sheet—Influenza Vaccines For
Australians: Information For Immunisation
Providers
http://www.ncirs.edu.au/immunisation/factsheets/influenza-fact-sheet.pdf
Accessed 25 January 2011.
TGA (2010) Suspected adverse reactions to
Panvax® reported to the TGA 30 September
2009 to 17 September 2010.
http://www.tga.gov.au/safety/alertsmedicine-panvax-091120.htm
TGA (24 September 2010) Investigation into
febrile reactions in young children following
2010 seasonal trivalent influenza vaccination.
Status report as at 2 July 2010. Updated 24
September 2010.
http://www.tga.gov.au/safety/alertsmedicine-seasonal-flu-100702.htm
TGA (28 September 2010) Analysis of febrile
convulsions following immunisation in
children following monovalent pandemic
H1N1 vaccine (Panvax®/Panvax Junior®, CSL).
Australian Technical Advisory Group on
Immunisation (ATAGI) and Therapeutic Goods
Administration (TGA) Joint Working Group.
http://www.tga.gov.au/safety/alertsmedicine-seasonal-flu-100928.htm
TGA (8 October 2010) Overview of vaccine
regulation and safety monitoring and
investigation into adverse events following
2010 seasonal influenza vaccination in young
children.
http://www.tga.gov.au/safety/alertsmedicine-seasonal-flu-101008.htm
World Health Organization (WHO) (2011) Global
Alert and Response, Pandemic Preparedness:
What is an influenza pandemic?
http://www.who.int/csr/disease/influenza/
pandemic/en/
Accessed 7 March 2011.
World Health Organization (WHO) (2011)
Vaccines for pandemic (H1N1) 2009.
http://www.who.int/csr/disease/swineflu/
frequently_asked_questions/vaccine_
preparedness/en/
Accessed 21 January 2011.
WHO UMC (World Health Organization
Uppsala Monitoring Centre) (2011) Causality
Assessment of Suspected Adverse Reactions.
http://www.who-umc.org/DynPage.
aspx?id=22682
Accessed 24 January 2011.
38
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APPENDICES
Appendix I: Documents and other
source materials reviewed
Overview of Vaccine Regulation and Safety
Monitoring and Investigation into Adverse
Events Following 2010 Seasonal Influenza
Vaccination in Young Children—TGA—
8 October 2010
Chronology of Events Associated with Influenza
Vaccines—OHP—October 2010
Investigation into Febrile Reactions in Young
Children Following 2010 Seasonal
Trivalent Influenza Vaccination—TGA—
24 September 2010
Australian Technical Advisory Group on
Immunisation (ATAGI) Review of Seasonal
Trivalent Influenza Vaccine Adverse Events in
Children—Interim Summary Report of Joint
ATAGI/TGA Ad Hoc Working Group Meeting
and ATAGI Advice to CMO—ATAGI—
13 May 2010
ATAGI and TGA Joint Working Group—Final—
Review of Adverse Events Following
Immunisation in Children Following
Monovalent Pandemic H1N1 Vaccine (Panvax
and Panvax Junior, CSL)— ATAGI—
27 September 2010
Government of Western Australia, Department
of Health— Ministerial Review into the Public
Health Response into the Adverse Events to
the Seasonal Influenza Vaccine—Final Report
to the Minister for Health—Professor Bryant
Stokes—July 2010
Correspondence between Professor Bryant Stokes
(WA Health) and Professor Jim Bishop, CMO
regarding the Stokes Review—DoHA—
9 August 2010
Response to the West Australian (Stokes) Review
into the Handling of AEFIs following 2010
Seasonal Flu Vaccination—TGA
Correspondence between Ms Jane Halton
(Secretary, DoHA) and Kim Snowball (Director
General—WA Health)
Bonhoeffer J. et al for the Brighton Collaboration
Methods Working Group (2009) Guidelines for
collection, analysis and presentation of vaccine
safety data into surveillance systems. Vaccine
27(16):2289–2297.
Lawrence G. for the National Immunisation
Committee (2006) National Vaccine
Safety Workshop: Summary and draft
recommendations. Communicable Diseases
Intelligence 30(3):378–380.
Appendices 39

Dixon et al (2010) Lessons from the first year of
the WAIVE study investigating the protective
effect of influenza vaccine against laboratory
confirmed influenza in hospitalised children
aged 6–59 months. Influenza and Other
Respiratory Viruses 4:231–234.
Media Analysis—2010 Seasonal Influenza
Gardasil Expert Panel—Report to the National
Manager, Therapeutic Goods Administration
on the safety and efficacy of Gardasil—TGA—
February 2009.
Gold M et al (2010) Febrile Convulsions after
2010 seasonal trivalent influenza vaccine:
implications for vaccine safety surveillance in
Australia. Medical Journal of Australia 193(9):
492–493.
Email Correspondence between Office of Product
Review (TGA), WA Health and SA Health.
(April 2010)
Log, line listings and case reports of suspected
adverse events following influenza vaccination
received by the TGA 2010
Email advice from the World Health Organization
Collaborating Centre for Reference and
Research on Influenza in Melbourne (Professor
Anne Kelso) regarding yearly trivalent vaccine
strain selection and vaccine manufacture—
November 2010
40
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Appendix II: People interviewed
• Australian Technical Advisory Group on
Immunisation
– Professor Terry Nolan—Chair
• Consumers Health Forum
– Ms Carol Bennett—Chief Executive
Officer
– Ms Anna Wise— Senior Policy Manager
• CSL Limited
– Dr Darryl Maher—Senior Director
Medical and Research
– Dr Michael Greenberg—Director
Vaccines Clinical Development
– Dr Marli Watt—Head of Clinical Risk
Management
– Dr Andrew Cooper—Pharmacovigilance
Manager
• Department of Health and Ageing
– Professor Jim Bishop—Chief Medical
Officer
• National Centre for Immunisation Research
and Surveillance
– Professor Peter McIntyre—Director
• Therapeutic Goods Administration
– Dr Rohan Hammet—National Manager
– Dr Ruth Lopert—Principal Medical
Advisor
– Dr Jane Cook—Medical Officer,
Monitoring and Compliance Group
– Dr Grahame Dickson—Medical Officer,
Market Authorisation Group
– Dr Peter Bird—Assistant Secretary, Office
of Laboratories and Scientific Services
• University of Melbourne, Department of
Microbiology and Immunology
– Professor Peter Doherty, Chair, TGA
Expert Panel on Vaccine Testing
• Victorian Infectious Diseases Reference
Laboratory
– Dr Heath Kelly, Head, Epidemiology Unit
• Western Australian Department of Health
– Professor Bryant Stokes
– Dr Tarun Weeramanthri
Appendices 41

42
Appendix III: International arrangements for post-market surveillance and monitoring of vaccines
Review of the management of adverse events associated with Panvax and Fluvax
Country
Global
Regulatory Agency and
Relevant Committees
World Health Organization
(WHO)
Global Advisory
Committee on Vaccine
Safety (GAVCS)
Council of International
Organized Medical
Societies (WHO-CIOMS)
Vaccine Pharmacovigilance
(PV) Working
Group
European Union
European Medicines
Agency (EMA)
Legal basis is in EC
regulations and directives
Legislation describes
respective obligations of
marketing authorisation
holders (MAHs) and
competent authorities
(CAs) in each member
state to set up a system
to collect, collate and
evaluate information
about suspected adverse
reactions (distinguishes
between events and
reactions)
Passive AEFI Reporting
The WHO Programme
for International Drug
Monitoring (IDM)
Covers both medicines
and vaccines
104 countries participate
PV obligations apply to
all medicinal products
and legislation does not
distinguish between
vaccines and other
medicinal products
Agency responsible
for collation of AEFI
Reports and Relevant
Committees
WHO Collaborating
Centre for International
Drug Monitoring Uppsala,
Sweden (the Uppsala
Monitoring Centre or
UMC)
VigiBase = WHO Individual
Case Safety Reports
(ICSR) database = global
repository of AEFI data
Other routine
Pharmacovigilance (PV)
activities
Global capacity building,
harmonised tools,
education and training
Brighton Collaboration—
standardised definitions
of AEFIs
Vaccine Safety Blueprint
Project (with funding from
the Gates Foundation)—
supports developing
countries to develop PV
systems
Additional non-routine
activities
Safety signal
identification and
follow up
Advisory Body for
Vaccination Program
Intensive information
exchange is needed
between MAHs, CAs of
members States and the
EMA
Guidance is Vol 9A

Country
Canada
Regulatory Agency and
Relevant Committees
Passive AEFI Reporting
Agency responsible
for collation of AEFI
Reports and Relevant
Committees
Other routine
Pharmacovigilance (PV)
activities
Additional non-routine
activities
Safety signal
identification and
follow up
Advisory Body for
Vaccination Program
Health Canada
The Biologics and Genetic
Therapies Directorate
and the Marketed Health
Products Directorate
Role in registration of
products and in PV,
including recalls and
advisories
Canadian Adverse Events
Following Immunization
Surveillance System
(CAEFISS)
Specific for vaccines
(MedEffect is used for
drugs)
Voluntary (except for 4
provinces with mandatory
reporting requirements)—
health care providers
report to local, provincial
and/or territorial public
health authorities events
they feel are temporarily
associated with an
immunization
Reports are forwarded
by the provinces and
territories to the Vaccine
Safety Unit (VSU) of the
Public Health Agency
of Canada (PHAC) for
aggregation
Particular events of
interest are included in
the national reporting
form used (with
modifications) by all
Ps and T
Manufacturers are legally
required to report all
adverse events directly to
Health Canada (previously
to PHAC but now to
regulator)
Vaccine Safety Unit
(VSU) of the Centre
for Immunization and
Respiratory Diseases
(CIPD) of the Public Health
Agency of Canada (PHAC)
Advisory Committee on
Causality Assessment
(ACCA) reviews all case
reports of severe or
unexpected AEs. Uses
WHO-UMC criteria to
assess causality
Immunization Monitoring
Program ACTive
(IMPACT)—active sentinel
surveillance in 12 tertiary
care paediatric hospitals
across Canada
AEs reported from
medical practitioners
directly to Health Canada.
These data are also stored
in the AEFI database at
the PHAC
Covers AEFIs, vaccination
failures and selected
IDs. Represents over
2,000 hospital beds
and 75,000 childhood
admissions (over 90%
of all paediatric tertiary
admissions). At each
centre a nurse monitor
and chief investigator
perform active casefinding
based on regular
review of admission
records. Assisted by a
multidisciplinary network
To calculate rates,
lot specific vaccine
distribution data are
obtained from vaccine
manufacturers and used
as an approximation
of doses administered.
Limited reliability
but useful for signal
generation
If further estimates are
needed they are obtained
from vaccine coverage
studies
If signal detected, action
is taken as appropriate,
either immediate or
through additional
scientific investigation
to confirm or refute the
signal
National Advisory
Committee on
Immunization (NACI)
NACI reports to the Chief
Public Health Officer of
Canada and works with
departmental staff of the
CIDPC of the PHAC
All NACI
recommendations are
published 4 yearly in the
Canadian Immunization
Guide (CIG); updates
in the Canadian
Communicable Diseases
Report
The CIG provides
information on nature
of adverse events with
specific vaccines
Appendices 43
Data to WHO IDM
programme

44
Review of the management of adverse events associated with Panvax and Fluvax
Country
Regulatory Agency and
Relevant Committees Passive AEFI Reporting
Ireland (systems largely governed by relevant EU legislation)
Irish Medicines Board Medicines and vaccines
(IMB)
A Board appointed by
Minister for Health and
Children (the EU National
Competent Authority for
medicines in Ireland)
Role in both registration
and pharmaco-vigilance
The Advisory Committee
for Human Medicines
New Zealand
The New Zealand
Medicines and Medical
Devices Safety Authority
(Medsafe)
A business unit of the
Ministry of Health
Role in both registration
and pharmaco-vigilance
Medicines Adverse
Reactions Committee
(MARC)—a Ministerial
Advisory Committee
Voluntary—health
professionals and
consumers. HP reporting
encouraged with regular
reminders and updates
Mandatory—
pharmaceutical
companies
Medicines and Vaccines
Voluntary—health
professionals and
consumers are
encouraged to report
Reports also received
from Coroners, the
Accident Compensation
Commission and
pharmaceutical
companies
Reports of AEs can be
submitted via:
– Reporting card CARM
website (separate
online vaccine AE
reporting form)
Agency responsible
for collation of AEFI
Reports and Relevant
Committees
Irish Medicines Board
(IMB)
Medsafe contracts the
collation, review and
analysis of spontaneous
reports to the Centre
for Adverse Reactions
Monitoring (CARM) of the
New Zealand Pharmacovigilance
Centre at the
University of Otago in
Dunedin
CARM reports to Medsafe
and works with Medsafe
to analyse all information
for safety signals
No other bodies are
responsible for the
collection or review of the
case reports
Other routine
Pharmacovigilance (PV)
activities
Additional non-routine
activities
Safety signal
identification and
follow up
Advisory Body for
Vaccination Program
National Immunisation
Advisory Committee
(NIAC) of the Royal
College of Physicians of
Ireland
Health Protection
Surveillance Centre
National Immunisation
Office of the Irish Health
Service Executive
– Electronic (embedded
in GP practice patient
management systems)
– Phone to Medical
Assessors at CARM

Regulatory Agency and
Country Relevant Committees
United Kingdom
Medicines and Healthcare
products Regulatory
Agency (MHRA)
An Executive Agency of
the Department of Health
Role in both registration
and pharmaco-vigilance
Commission on Human
Medicines (CHM)
Biologicals and Vaccines
Expert Advisory Group
Pharmaco -vigilence
Expert Advisory Group
Passive AEFI Reporting
“Yellow Card” System
(both medicines and
vaccines)
Voluntary reporting health
professionals and public.
HPs are encouraged to
report. Education and
training through regional
Yellow Card centres
Mandatory—
pharmaceutical
companies
Agency responsible
for collation of AEFI
Reports and Relevant
Committees
Medicines and Healthcare
products Regulatory
Agency (MHRA)
Case reports collated into
the ADR database
Analyse using
clinical judgement
and specialised IT
software and statistical
analyses, including disproportionality
analyses
Other routine
Pharmacovigilance (PV)
activities
Evaluation of clinical and
epidemiological studies,
published medical
literature, information
from pharmaceutical
companies and other
regulatory agencies
General Practice Research
Database (GPRD)
An electronic data source
of information from over
590 practices in the UK
covering about 5 million
patients with record
linkage. Used to conduct
ad hoc evaluation and
research
Additional non-routine
activities
Risk management strategy
defined in advance of
rollout of new vaccine.
May include stimulating
reporting, and/or
conducting real-time
observed/expected (O/E)
analyses of AESIs
Active surveillance and/
or commissioned research
on a case by case basis
Safety signal
identification and
follow up
Epidemiological studies
through the GPRD system
Dedicated ‘on-line’
reporting system
implemented for
pandemic H1N1
Independent advice from
CHM and subcommittees,
EU Member States and
EMA
Information sharing with
international counterparts,
including TGA
Advisory Body for
Vaccination Program
Joint Committee
on Vaccination and
Immunisation (JCVI)—
Independent expert
advisory committee that
advises Ministers on
matters relating to the
provision of vaccination
and immunisation
services
Immunisation policy set
by Department of Health/
Health Protection Agency
(DoH/HPA)
Appendices 45

46
Review of the management of adverse events associated with Panvax and Fluvax
Regulatory Agency and
Country Relevant Committees
United States of America
Food and Drug Authority
(FDA)
Agency within the
Department of Health
and Human Services
Role in both registration
and pharmaco-vigilance
Vaccines and Related
Biological Products
Advisory Committee
Passive AEFI Reporting
Vaccine Adverse Events
Reporting System (VAERS)
Mandatory reporting of
events in the Reportable
Events Table by health
care providers. Legal
authority is the National
Childhood Vaccine Injury
Act of 1986
Health care professionals
encouraged to report any
clinically significant or
unexpected event
Anyone can report.
Consumers are advised to
seek assistance from their
health care professional in
completing the form
The primary objectives of
VAERS are to:
– Detect new, unusual,
or rare vaccine adverse
events (VAEs)
– Monitor increases in
known adverse events;
– Identify potential
patient risk factors
for particular types of
adverse events;
– Identify vaccine
lots with increased
numbers or types
of reported adverse
events; and
– Assess the safety
of newly licensed
vaccines.
Agency responsible
for collation of AEFI
Reports and Relevant
Committees
Immunization Safety
Office (ISO) of the Centers
for Disease Control and
Prevention (CDC)
Agency within the
Department of Health
and Human Services
Jointly with FDA
Both FDA and CDC review
the case data
Other routine
Pharmacovigilance (PV)
activities
Vaccine Safety Datalink
project (VSD) run by CDC
Eight large managed
care organisations—uses
data linkage to analyse
vaccine-related and
clinical information for
more than 7 million
people
Brighton Collaboration
Standardised definitions
of AEFIs
Rapid Cycle Analysis (RCA)
De-identified data,
updated weekly, from
eight managed care
organisations used for
active surveillance of
AEFI in near real time
for newly licensed
vaccines and new vaccine
recommendations.
Potential AEs—identified
through premarketing
studies, early analysis from
VAERS and published
scientific articles—are
monitored by comparing
their rate of occurrence
in people who have
received a vaccine with
the rate of occurrence in
a similar group of people
who have not received
that vaccine. If rate is
significantly higher, then
a formal epidemiological
study is done
Additional non-routine
activities
Clinical Immunization
Safety Assessment (CISA)
Network
Collaboration between
CDC (ISO) and 6 academic
centres
To investigate pathophysiologic
mechanisms
and biological risks of
AEFIs. Has a registry of
people who have had an
AEFI and a repository to
store specimens for future
studies
The VSD can also be used
for planned immunisation
studies to detect rare
adverse events when new
vaccines are licensed or
when safety question
arises. A number of
Priority Studies using
VSD data are currently
underway
Safety signal
identification and
follow up
Additional case data may
be obtained from person
reporting the event
and/or their health care
provider
Advisory Body for
Vaccination Program
Advisory Committee on
Immunization Practices
(ACIP)
Members are selected by
the Secretary of the
U. S. Department of
Health and Human
Services to provide advice
and guidance to the
Secretary, the Assistant
Secretary for Health, and
the Centers for Disease
Control and Prevention
(CDC) on the control
of vaccine-preventable
diseases
The Committee develops
written recommendations
for the routine
administration of vaccines
to children and adults in
the civilian population;
recommendations
include age for vaccine
administration, number
of doses and dosing
interval, and precautions
and contraindications. The
ACIP is the only entity in
the federal government
that makes such
recommendations
National Vaccine Program
National Vaccine
Advisory Committee
(NVAC) provides advice
on matters related to
program responsibilities
to the Director of the
National Vaccine Program
within the Department
of Health and Human
Services

www.health.gov.au
All information in this publication is correct as of May 2011
D0371 May 2011