Australian Public Assessment Report for purified antigen fractions of inactivated split virion A/Indonesia/05/2005 (H5N1), as03 adjuvanted

V. Pharmacovigilance findings

Risk management plan

The sponsor submitted an EU-Risk Management Plan (RMP) Version 11 (dated July 2013) with an Australian Specific Annex (ASA) dated 4 February 2014.

Safety specification

The sponsor provided a summary of ongoing safety concerns which are shown at Table 14.

Table 14: Ongoing safety concerns.

Reviewer comment

The ongoing safety concerns are identical to those previously accepted for Pandemrix H5N1 pandemic influenza vaccine. Notwithstanding the evaluation of the nonclinical and clinical aspects of the Safety Specification, the above summary of the Ongoing Safety Concerns is considered acceptable.

Pharmacovigilance plan

The proposed pharmacovigilance plan, based on the relevant European Union guideline that has been formally adopted in Australia,¹⁶ is almost identical to what was previously accepted for Pandemrix H5N1 pandemic influenza vaccine.

The ASA also states:

As a routine pharmacovigilance measure, all targeted follow up questionnaires referred to in the EU-RMP will be implemented in Australia.

and

GSK has committed to discuss with TGA the requirements of an Australian-specific postmarketing cohort study, should this vaccine be first used in Australia in a pandemic situation.

Details of the latter commitment are provided in the ASA under the heading ‘Commitment regarding TGA’s request for post marketing cohort study as detailed in the new RMP format’.

The ASA does not provide the details of the qualified person responsible for pharmacovigilance (PRP) within the sponsor company, who has been nominated as the person responsible for the implementation of the RMP activities within Australia.

Reviewer comment

The following statement in ‘Organisational Structure’ of the ASA should be updated to refer to the current ‘Australian requirements and recommendations for pharmacovigilance responsibilities of sponsors of medicines’ and acknowledge that the ‘Drug Safety and Evaluation Branch’ per se no longer exists within the TGA:

The Pharmacovigilance team is responsible for compliance with the appropriate regulatory guidelines: Australian Guideline for Pharmacovigilance Responsibilities of Sponsors of Registered Medicines Regulated by Drug Safety and Evaluation Branch

Section 2.4 ‘Other Pharmacovigilance Activities Referenced in the EU-RMP’ of the ASA should be corrected to make reference to Annex 7 of the EU-RMP version 11 dated July 2013, rather than “Annex 7 of the EU RMP v10 dated July 2013”. In addition, this section states in regard to the important potential risk: ‘Solid organ transplant rejection’: “(please note that a targeted follow up questionnaire for this newly added potential risk is currently in the process of being developed; final version to be submitted to TGA in February 2014).” However, this questionnaire was submitted to the TGA in the sponsor’s correspondence dated 5 March 2014 with an assurance that it would be included within the next version of the EU-RMP. As it does not appear to have been included in the EU-RMP version 11 dated July 2013, the sponsor should attach a copy of this questionnaire to an updated ASA.

Risk minimisation activities

The sponsor appears to have concluded that routine risk minimisation activities will be applied to all the specified ongoing safety concerns, except for the important potential risks: ‘Autoimmune hepatitis’, ‘Bell’s palsy’, ‘Demyelinating disorders’, ‘Increased concentrations of hepatic enzymes’ & ‘Solid organ transplant rejection’ for which no risk minimisation activities are proposed. Furthermore additional risk minimisation activities are proposed for the important potential risks: ‘Medical errors/misidentification of vaccine’, ‘Contamination of the multi-dose vials’ & ‘Coring of the rubber stopper on the antigen vial’ in the form of educational materials for healthcare professionals.

Reviewer comment

The sponsor’s conclusion remains similar to what was previously accepted for Pandemrix H5N1 pandemic influenza vaccine, and at this time continues to be acceptable.

Reconciliation of issues outlined in the RMP report

The following section summarises the first round evaluation of the RMP, the sponsor’s responses to issues raised, and the evaluation of the sponsor’s responses.

Recommendation #1 in RMP evaluation report

Safety considerations may be raised by the nonclinical and clinical evaluators through the consolidated Section 31 request and/or the nonclinical and clinical evaluation reports respectively. It is important to ensure that the information provided in response to these includes a consideration of the relevance for the RMP, and any specific information needed to address this issue in the RMP. For any safety considerations so raised, the sponsor should provide information that is relevant and necessary to address the issue in the RMP.

Sponsor response

The sponsor states it has considered the consolidated Section 31 request and the nonclinical and clinical evaluation reports and determined that no changes are required to the RMP.

Evaluator’s comment

This response would appear contrary to the CER statement: “The Safety Specification in the draft EU RMP Version 11 (dated 19 May 2013) and the Australian Specific Annex (dated 4 February 2014) are not entirely satisfactory and should be revised, …” (see Section 2: ‘Comments on the safety specification of the RMP’). Specifically, the following issues are outstanding:

The proposed indications in the updated ASA have not been revised in accordance with the current version of the PI submitted with the sponsor’s correspondence dated 29 October 2014. The sponsor should correct this oversight in a revised ASA before this application is approved.

Based on the clinical evaluation report, the important potential risks: ‘Uveitis’ & ‘Polymyalgia rheumatica/temporal arteritis’ should be included as new ongoing safety concerns. Consideration must be given as to what pharmacovigilance and risk minimisation activities will be proposed for these new ongoing safety concerns and only the ASA need be revised accordingly before this application is approved.

The clinical evaluation report has stated that heightened safety surveillance in the paediatric population will be necessary as there are limited safety and immunogenicity data in this population. The proposed PI agrees that experience in children is limited and Table 2: ‘Specific safety concerns where the wording in the EU SmPC as a risk management measure differs in meaning to the Australian PI’ of the updated ASA states: “Prepandrix is not proposed for use in children in Australia.” Consequently the sponsor should include the missing information: ‘Safety data in the paediatric population’ as a new ongoing safety concern. Consideration must be given as to what pharmacovigilance and risk minimisation activities will be proposed for this new ongoing safety concern and only the ASA need be revised accordingly before this application is approved.

Recommendation #2 in RMP evaluation report

The following statement in Section 2.1.1: ‘Organisational Structure’ of the ASA should be updated to refer to the current ‘Australian requirements and recommendations for pharmacovigilance responsibilities of sponsors of medicines’ and acknowledge that the ‘Drug Safety and Evaluation Branch’ per se no longer exists within the TGA:

The Pharmacovigilance team is responsible for compliance with the appropriate regulatory guidelines: - Australian Guideline for Pharmacovigilance Responsibilities of Sponsors of Registered Medicines Regulated by Drug Safety and Evaluation Branch

Sponsor response

The ASA has been updated accordingly.

Evaluator’s comment

This is acceptable.

Recommendation #3 in RMP evaluation report

Section 2.4: ‘Other Pharmacovigilance Activities Referenced in the EU-RMP’ of the ASA should be corrected to make reference to Annex 7 of the EU-RMP version 11 dated July 2013, rather than “Annex 7 of the EU RMP v10 dated July 2013”. In addition this section states in regard to the important potential risk: ‘Solid organ transplant rejection’: “(please note that a targeted follow up questionnaire for this newly added potential risk is currently in the process of being developed; final version to be submitted to TGA in February 2014).” However, this questionnaire was submitted to the TGA in the sponsor’s correspondence dated 5 March 2014 with an assurance that it would be included within the next version of the EU-RMP. As it does not appear to have been included in the EU-RMP version 11 dated July 2013, the sponsor should attach a copy of this questionnaire to an updated ASA.

Sponsor response

The ASA has been updated accordingly. The reference to the EU-RMP has been corrected. The targeted follow up questionnaire for ‘Solid organ transplant rejection’ has been added to the ASA.

Evaluator’s comment

This is acceptable.

Recommendation #4 in RMP evaluation report

Table 2: ‘Specific safety concerns where the wording in the EU SmPC as a risk management measure differs in meaning to the Australian PI’ of the ASA should be amended to compare the actual content and wording of the EU SmPC and the proposed Australian PI for all of the specified ongoing safety concerns. The TGA can then validate the sponsor’s assertion that there are no material differences between the routine risk minimisation activities undertaken in Europe compared to Australia. Upon receipt of such information recommendations to the Delegate in regard to the proposed routine risk minimisation activities can then be made.

Sponsor response

The sponsor has stated: “The ASA has been updated accordingly.”

Evaluator’s comment

It appears the sponsor has only done so for ‘Use in the paediatric and elderly populations’. The RMP Questions and Answers (Version 1.3, October 2012) as found on the TGA website state: “The ASA should identify any differences between the EU-RMP and the local implementation of risk management activities, for example: any differences between the risk minimisation activities undertaken as reflected in the content of the EU SmPC and the proposed Australian PI, and the reasons for the difference.” Consequently, it is reiterated that the ASA should be revised to include a risk minimisation activities table detailing all planned risk minimisation measures in the Australian context and the EU-RMP context. This table should include a comparison of the actual content and wording of the EU SmPC and the proposed Australian PI and CMI for all of the specified ongoing safety concerns and missing information to identify and provide reasons for any observed differences, particularly where it appears the EU SmPC is more restrictive. Given the differences foreshadowed above between the summary of ongoing safety concerns for Australia and the EU, the ASA should be so revised before this application is approved.

Recommendation #5 in RMP evaluation report

The sponsor should provide a table summarising the pharmacovigilance and risk minimisation activities for all of the specified ongoing safety concerns proposed for Australia in the ASA.

Sponsor response

The sponsor states: “All of the concerns identified in the EU-RMP are relevant for patients in Australia and therefore all of the planned pharmacovigilance actions proposed in the EU-RMP will be implemented in Australia. Consequently, it is unnecessary to provide a separate ‘Summary of the Risk Management Plan in Australia’ in a revised ASA.”

Evaluator’s comment

Given the differences foreshadowed above between the summary of ongoing safety concerns for Australia and the EU, this response is considered unacceptable. Consequently, it is reiterated that the sponsor provide a table summarising the pharmacovigilance and risk minimisation activities for all of the specified ongoing safety concerns and missing information proposed for Australia in the ASA before this application is approved.

Summary of recommendations

It is considered that the sponsor’s response to the TGA Section 31 request has not adequately addressed all of the issues identified in the RMP evaluation report.

Outstanding issues

Issues in relation to the RMP

The sponsor was asked to respond to safety considerations raised by the nonclinical and clinical evaluators through the consolidated Section 31 request and/or the nonclinical and clinical evaluation reports, respectively, in the context of relevance to the RMP. The sponsor states it has considered the consolidated Section 31 request and the nonclinical and clinical evaluation reports and determined that no changes are required to the RMP. This would appear contrary to the CER statement: “The Safety Specification in the draft EU Risk Management Plan Version 11 (dated 19 May 2013) and the Australian Specific Annex (dated 4 February 2014) are not entirely satisfactory and should be revised, …” (see Section 2: ‘Comments on the safety specification of the RMP’). Specifically, the following issues are outstanding:

The proposed indications in the updated ASA have not been revised in accordance with the current version of the PI submitted with the sponsor’s correspondence dated 29 October 2014. The sponsor should correct this oversight in a revised ASA before this application is approved.

Based on the clinical evaluation report, the important potential risks: ‘Uveitis’ & ‘Polymyalgia rheumatica/temporal arteritis’ should be included as new ongoing safety concerns. Consideration must be given as to what pharmacovigilance and risk minimisation activities will be proposed for these new ongoing safety concerns and only the ASA need be revised accordingly before this application is approved.

The clinical evaluation report has stated that heightened safety surveillance in the paediatric population will be necessary as there are limited safety and immunogenicity data in this population. The proposed PI agrees that experience in children is limited and Table 2: ‘Specific safety concerns where the wording in the EU SmPC as a risk management measure differs in meaning to the Australian PI’ of the updated ASA states: “Prepandrix is not proposed for use in children in Australia.” Consequently the sponsor should include the missing information: ‘Safety data in the paediatric population’ as a new ongoing safety concern. Consideration must be given as to what pharmacovigilance and risk minimisation activities will be proposed for this new ongoing safety concern and only the ASA need be revised accordingly before this application is approved.

The sponsor was asked to amend Table 2: ‘Specific safety concerns where the wording in the EU SmPC as a risk management measure differs in meaning to the Australian PI’ of the ASA to compare the actual content and wording of the EU SmPC and the proposed Australian PI for all of the specified ongoing safety concerns in order to validate the sponsor’s assertion that there are no material differences between the routine risk minimisation activities undertaken in Europe compared to Australia. The sponsor has stated: “The ASA has been updated accordingly.” However, it appears the sponsor has only done so for ‘Use in the paediatric and elderly populations’. The RMP Questions and Answers (Version 1.3, October 2012) as found on the TGA website state: “The ASA should identify any differences between the EU-RMP and the local implementation of risk management activities, for example: any differences between the risk minimisation activities undertaken as reflected in the content of the EU SmPC and the proposed Australian PI, and the reasons for the difference.” Consequently, it is reiterated that the ASA should be revised to include a risk minimisation activities table detailing all planned risk minimisation measures in the Australian context and the EU-RMP context. This table should include a comparison of the actual content and wording of the EU SmPC and the proposed Australian PI and CMI for all of the specified ongoing safety concerns and missing information to identify and provide reasons for any observed differences, particularly where it appears the EU SmPC is more restrictive. Given the differences foreshadowed above between the summary of ongoing safety concerns for Australia and the EU, the ASA should be so revised before this application is approved.

The sponsor was asked to provide a table summarising the pharmacovigilance and risk minimisation activities for all of the specified ongoing safety concerns proposed for Australia in the ASA. The sponsor states:

All of the concerns identified in the EU-RMP are relevant for patients in Australia and therefore all of the planned pharmacovigilance actions proposed in the EU-RMP will be implemented in Australia. Consequently, it is unnecessary to provide a separate ‘Summary of the Risk Management Plan in Australia’ in a revised ASA.

Given the differences foreshadowed above between the summary of ongoing safety concerns for Australia and the EU, this response is considered unacceptable. Consequently, it is reiterated that the sponsor provide a table summarising the pharmacovigilance and risk minimisation activities for all of the specified ongoing safety concerns and missing information proposed for Australia in the ASA before this application is approved.

Advice from the Advisory Committee on the Safety of Vaccines (ACSOV)

ACSOV advice was not sought.

Comments on the safety specification of the RMP

Clinical evaluation report

The paediatric clinical development covered children from 6 months to 17 years and demonstrated that two doses three weeks apart (using half the adult dose) was immunogenic with adult CHMP criteria being achieved. There was also strong booster response. It was found that the full adult dose led to increased reactogencity and, given the high rate of fevers with the adjuvanted vaccine, the benefit-risk balance is therefore in favour of the half strength dose. As there are no paediatric dosage instructions in the draft PI the Sponsor has been asked to clarify this issue.

With the number of children with grade 3 fever it was reassuring to find no reported cases of febrile convulsions, nonetheless the sponsor has been asked to confirm that this is the case. In addition, this risk of fever has not been adequately covered in the draft PI. The overall safety of the vaccine in the paediatric population has been based on relatively small numbers. There were two pIMDs identified, autoimmune hepatitis and uveitis, although the former was believed to predate vaccination and the latter resolved with treatment. There were no integrated data on the paediatric population presented and the sponsor should provide further information to justify the safety of the product in children.

Overall, it is not clear if the indication for the vaccine seeks to cover children as there is a lack of dosage instructions, inadequate coverage of paediatric clinical trial immunogenicity and safety data in the PI, a CMI which includes no instructions relating to children and inconsistencies in the RMP. These issues all need to be addressed before an assessment of benefit-risk in this population can be undertaken.

In summary, the evaluator finds that the benefit-risk balance of prepandemrix given the proposed usage, is favourable for adults subject to satisfactory responses to questions and comments. The evaluator finds that there are a number of issues still to be addressed regarding the paediatric population and so the benefit-risk balance in this group is currently unfavourable.

The Safety Specification in the draft EU RMP Version 11 (dated 19 May 2013) and the ASA (dated 4 February 2014) are not entirely satisfactory and should be revised, having regard to the comments below.

It is noted that there is a commitment to conducting post-marketing active safety surveillance using a pandemic cohort. Risk minimisation activities have addressed the risk of coring the rubber stopper of the antigen vial, medication errors and contamination of the multiple dose vials.

The sponsor concludes from the analysis of the 2011 ISS, that there is not good evidence for an increased risk of potentially immune mediated diseases with AS03 adjuvanted vaccines. Some pIMDs are listed in the safety specification and others are not. The evaluator recommends broader surveillance of such conditions, for example uveitis and polymyalgia rheumatica/temporal arteritis.

The issue of risk management in the paediatric population is not clear as the RMP states that there are no data in children less than 3 and 10 to 17 years which is clearly not the case. Given the smaller paediatric database, heightened safety surveillance in this population will be necessary.

Nonclinical evaluation report

Results and conclusions drawn from the nonclinical program for Prepandemrix detailed in the sponsor’s draft RMP (Section 1.1) are in general concordance with those of the nonclinical evaluator.

Suggested wording for conditions of registration

RMP

At this time no wording can be provided, as it is recommended that an acceptably revised ASA be submitted before this application is approved.

PSUR

Medicines Authorisation Branch to provide wording.

Key changes to RMP

In their response to Section 31 requests, the sponsor provided an updated ASA (dated 28 October 2014). Key changes from the versions evaluated at Round 1 are summarised below in Table 15.

Table 15: Key changes between RMPs.

ASA

Change of tradename from PREPANDEMRIX to PREPANDRIX. Details in Section 2.2.1: ‘Database’ have been amended. Section 2.2.2.2: ‘Pregnancy Reports’ has been included. Corrections made to Section 2.4: ‘Other Pharmacovigilance Activities Referenced in the EU-RMP’ and the targeted follow up questionnaire for ‘Solid organ transplant rejection’ has been added as Attachment 1. Details in Table 2: ‘Specific safety concerns where the wording in the EU SmPC as a risk management measure differs in meaning to the Australian PI’ have been amended.