Review of the management of adverse events associated with Panvax and Fluvax

3.0 The Australian Regulatory System for Drugs and Vaccines

Page last updated: April 2015

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 well-designed 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).

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.

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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
  • 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 internationally-accepted criteria. They are then coded using standard terminology in accordance with the Medical Dictionary for Regulatory Activities (MedDRA), a document endorsed by the 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).

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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.

IIn 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.

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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 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.


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.

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