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

6.0 The Findings of the Review

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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 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).

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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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).

Table 1. Timeline of the investigation into febrile reactions in young children following 2010 seasonal trivalent influenza vaccination

DateAction
08 March 2010Distribution of seasonal influenza vaccine commences in Western Australia.
19 March 2010Official launch of the seasonal influenza vaccination program in WA.
15 March 2010First febrile convulsion in Victoria. Report received by TGA on 31 March.
18 March 2010First febrile convulsion in WA. Report received by TGA on 23 March.
1 April 2010First anecdotal reports of febrile reactions and one child attending hospital received by CDCD WA Health via email.
13 April 2010CDCD 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 2010South Australia advises TGA, OHP and the jurisdictional immunisation coordinators it is receiving reports of vomiting and high fever.
20 April 2010First tranche of AEFI reports from CDCD WA Health is received by TGA.
22 April 2010National Immunisation Committee Meeting.
22 April 2010Teleconferences of TGA, ATAGI Chair, Director of NCIRS, and OHP.
22 April 2010WA Minister for Health announces suspension of the WA influenza vaccination program for children <5 years of age following advice from an expert group convened by WA Health.
23 April 2010CMO announces temporary suspension of use of all seasonal influenza vaccines in children 5 years of age and under, pending investigation of the apparent increase in febrile convulsions, and writes to all immunisation providers.
23 April 2010The Australian Health Protection Committee (AHPC) meets to discuss the temporary suspension of seasonal influenza vaccination for children 5 years of age and under. Jurisdictions agree to collect data for the investigation.
23 April 2010The TGA convenes expert scientific advisory panel to review available information.
24 - 25 April 2010ATAGI – TGA Working Group develops data collection templates for epidemiological investigation.
26 April 2010Data collection templates circulated to States and Territories through AHPC and CDNA.
27 April 2010TGA review of batch release data commences.
27 April 2010ATAGI Chair and TGA National Manager meet with WA Health.
28 April 2010AHPC meets to review an update on the AEFI investigation.
29 April 2010Laboratory analysis of field and retention samples begins through TGA.
30 April 2010AHPC meets and agrees to the continued moratorium on use of influenza vaccine for children < 5 years of age. CMO announces the continued suspension and writes to all immunisation providers.
30 April to
early May 2010
ATAGI Working Group and NCIRS continue to collate and analyse the data being provided by jurisdictions.
4 May 2010TGA meets with NCIRS to review epidemiological analyses.
4 May 2010TGA expert panel on vaccine testing convened, chaired by Prof Peter Doherty.
10 May 2010TGA reviews distribution and ADR data with vaccine sponsors.
11 May 2010TGA pharmacoepidemiology expert panel is convened by teleconference to review planned and completed epidemiological analyses and endorses the planned analyses.
13 May 2010ATAGI-TGA Working Group, NCIRS, and Department meet to review the evidence being provided by jurisdictions.
13,14 May 2010TGA undertakes GMP audit of CSL manufacturing facilities.
14 May 2010TGA expert panel on vaccine testing meets.
20 May 2010ATAGI-TGA Working Group provides interim report to the CMO.
1 June 2010CMO 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 2010TGA sends samples to NIBSC for further in vitro analyses.
2 June 2010TGA’s Advisory Committee on the Safety of Medicines (ACSOM) meets to review issues with 2010 seasonal TIV.
2 June 2010TGA issues a public report on the investigations to date.
7 June 2010TGA sends samples to CDC for in vitro and in vivo analyses.
10 June 2010ATAGI meets.
18 June and
21-23 June 2010
TGA undertakes inspection of CSL manufacturing facilities.
2 July 2010TGA issues interim report on the investigations to date.
8 July 2010ATAGI Working Group meets to consider further data on Vaxigrip from studies in New Zealand and NSW.
30 July 2010CMO 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 2010TGA updates interim report of investigation.

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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 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 safety monitoring and investigation into adverse events following 2010 seasonal influenza vaccination in young children (TGA 8 October 2010).

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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).

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.

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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.

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:

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.

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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:
  1. 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
  2. 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
  3. 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 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.

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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.

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.

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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.

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.

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