Review of the management of adverse events associated with Panvax and Fluvax. Professor John Horvath ao mbbs fracp

Transcription

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

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

3 Review of the management of adverse events associated with Panvax and Fluvax Print ISBN Online: Publications Number: D0371 Paper-based publications Commonwealth of Australia 2011 This work is copyright. You may reproduce the whole or part of this work in unaltered form for your own personal use or, if you are part of an organisation, for internal use within your organisation, but only if you or your organisation do not use the reproduction for any commercial purpose and retain this copyright notice and all disclaimer notices as part of that reproduction. Apart from rights to use as permitted by the Copyright Act 1968 or allowed by this copyright notice, all other rights are reserved and you are not allowed to reproduce the whole or any part of this work in any way (electronic or otherwise) without first being given the specific written permission from the Commonwealth to do so. Requests and inquiries concerning reproduction and rights are to be sent to the Communications Branch, Department of Health and Ageing, GPO Box 9848, Canberra ACT 2601, or via to Internet sites Commonwealth of Australia Year This work is copyright. You may download, display, print and reproduce the whole or part of this work in unaltered form for your own personal use or, if you are part of an organisation, for internal use within your organisation, but only if you or your organisation do not use the reproduction for any commercial purpose and retain this copyright notice and all disclaimer notices as part of that reproduction. Apart from rights to use as permitted by the Copyright Act 1968 or allowed by this copyright notice, all other rights are reserved and you are not allowed to reproduce the whole or any part of this work in any way (electronic or otherwise) without first being given the specific written permission from the Commonwealth to do so. Requests and inquiries concerning reproduction and rights are to be sent to the Communications Branch, Department of Health and Ageing, GPO Box 9848, Canberra ACT 2601, or via to

4 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 Background to the Review Terms of Reference Matters outside the Terms of Reference Method of the Review Structure of the Report 3 3. THE AUSTRALIAN REGULATORY SYSTEM FOR DRUGS AND VACCINES Premarket assessment and registration of vaccines Premarket assessment and authorisation of seasonal influenza vaccine Post-market surveillance and monitoring of vaccines International post-market surveillance and monitoring of vaccines 9 4. THE NATIONAL IMMUNIZATION PROGRAM The National Immunisation Program Governance of the NIP INFLUENZA AND THE ROLE OF IMMUNISATION Influenza Pandemic influenza Australia s preparation for a pandemic The 2009 H1N1 influenza pandemic Pandemic H1N1 Vaccine (Panvax ) The National Pandemic (H1N1) 2009 Vaccination Program Pharmacovigilence arrangements for the National Pandemic (H1N1) 2009 Vaccination Program Seasonal Influenza Vaccine 21 Contents v

5 5.9 Seasonal influenza vaccination in Australia Febrile reactions and convulsions following immunisation THE FINDINGS OF THE REVIEW Rates of febrile convulsions related to previous influenza vaccination (seasonal and pandemic) in Australia Was there a safety signal from the use of previous seasonal influenza vaccines in children under 5 years of age? Was there a safety signal from the Panvax program in 2009? The national response to the reporting of adverse events in young children following receipt of the 2010 seasonal influenza vaccine When were the adverse events following Fluvax immunisation first detected and what actions were taken? Were the actions of the Commonwealth timely and appropriate? Improving the monitoring of AEFI in Australia Governance arrangements Clarifying the objectives and processes of AEFI monitoring in Australia Harmonising AEFI reporting and improving information flows between TGA and jurisdictions Transparency and Communications Improving vaccine administration data Other findings Review of the premarket authorisation of influenza vaccines by the TGA RECOMMENDATIONS OF THE REVIEW 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 vi Review of the management of adverse events associated with Panvax and Fluvax

6 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

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

8 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 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 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 Executive summary ix

9 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. x Review of the management of adverse events associated with Panvax and Fluvax

10 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

11 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. xii Review of the management of adverse events associated with Panvax and Fluvax

12 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

13 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 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 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 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 2 Review of the management of adverse events associated with Panvax and Fluvax

14 reference 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 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 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

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16 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

17 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 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 6 Review of the management of adverse events associated with Panvax and Fluvax

18 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 . 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

19 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 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. 8 Review of the management of adverse events associated with Panvax and Fluvax

20 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

21 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 H1N vaccine. These enhancements varied but included providing specific reporting forms/ arrangements for the H1N vaccine; stimulating reporting from health care providers 10 Review of the management of adverse events associated with Panvax and Fluvax

22 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

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24 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 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