Vaccine efficacy/effectiveness None Reconciliation of issues outlined in the RMP report Table 7 summarises the OPR’s first round evaluation of the RMP, the sponsor’s responses to issues raised by the OPR and the OPR’s evaluation of the sponsor’s responses. Table 7. Reconciliation of issues outlined in the RMP report Recommendation in RMP evaluation report Sponsor’s response OPR evaluator’s comment Safety considerations may be raised by the nonclinical and clinical evaluators through the consolidated 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 Risk Management Plan, 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. The sponsor confirms that the Nonclinical and Clinical Evaluation Reports have been reviewed to ensure that the any safety considerations raised have been considered for relevance to the Risk Management Plan and addressed accordingly. This is acceptable. The reason for not calling the vaccine Fluzone Quadrivalent (as in USA) is not The sponsor is requested to clarify the reason behind not proposing a standard name for the vaccine. Fluzone Quadrivalent was initially licensed in the United States but Sanofi Pasteur is now expanding licensure to several countries in the northern and southern hemispheres. Several health authorities in southern hemisphere countries objected to the use of the trade name “Fluzone”; therefore, Sanofi Pasteur researched the use of another trade name. This is acceptable.
Since the majority of countries that will license quadrivalent influenza vaccine (QIV) are expected to use the name FluQuadri, Sanofi Pasteur proposes to continue to use the name FluQuadri for QIV in Australia, unless there is a more compelling scientific or medical rationale to change. The proposed wording in the indication might lead to incorrect administration of the vaccine. The risks are presented below; There is potential risk of administration of the whole 0.5 ml in children aged 6 months to 35 months at one time, There is potential risk of incorrect preparation, measurement and storage of the half dose, There is potential risk that the vaccine might be used in sequential patients. It is recommended that the risks mentioned above are addressed in the RMP. The sponsor has proposed a revised indication in response as follows: FluQuadri is indicated for use in adults and children 3 years and older. FluQuadri Junior is indicated for use in children aged 6 months to 35 months inclusive. Additionally the sponsor has provided the following comments: … clear instructions regarding the preparation, administration, and storage of the vaccine (which is only supplied in a single-dose syringe presentation) are provided in the proposed PI. Accordingly, it is not considered necessary to include further measures to address the above risks in the RMP. The evaluator notes the revised indication for final consideration by the Delegate. It is recommended that the Delegate may wish to replace “Immunisation Handbook” with “Australian Immunisation Handbook” in the proposed “Dose and administration” Section. The sponsor proposes to keep the wording more general in nature as the overall intention for this labelling is that it will be applicable in both This recommendation is for consideration by the Delegate.
older. There is CBER (the Centre for Biologics Evaluation and Research) guidance that the safety and immunogenicity of QIV to children 9 to 17 years of age could be inferred from the safety profiles of QIV in children 6 months to < 9 years of age and in adults 18 years of age and older. Notwithstanding this justification, it is recommended that the sponsor proposes pharmacovigilance activities for adolescents (˃ 9 years of age). Routine pharmacovigilance is proposed. consideration by the Delegate. From a RMP perspective, the proposed routine pharmacovigilance is acceptable. ACSOV advised that ‘data in aged 9 to 17 years’ should be included in the RMP as important missing information. This recommendation is endorsed by the evaluator. Important potential risks in the RMP include “Adverse Events of Special Interest” (AESI) which reflect post market experience for the Fluzone (inactivated TIV), which is not currently registered in Australia. The sponsor states in the RMP; “Based on the available information from clinical studies GRC43, QIV03 and QIV04 and supportive data from the Applicant’s trivalent formulation of Fluzone vaccine, no further risk minimization activities are deemed necessary at this point. No additional pharmacovigilance activities to assess effectiveness of risk minimization measures are ongoing or planned”. In general terms the rationale for the studies is appropriate. However, the sponsor has not provided information for any Australian specific activities. It is noted that Fluzone is currently not registered in Australia. Adverse event rates observed in the clinical trials of a vaccine also cannot be The sponsor has advised in their response that they are not planning to conduct any other observational studies beyond a pregnancy registry study in Australia. The sponsor contends that the safety profile is well characterised (according mainly to data for the trivalent formulation) and thus no additional activities are required. The sponsor’s justification is accepted from a RMP standpoint. However the acceptability of a postmarketing safety profile of the quadrivalent vaccine largely extrapolated from the trivalent vaccine is ultimately the decision of the Delegate. ACSOV advised that there should be consideration for class-wide enhanced surveillance of quadrivalent influenza vaccines particularly for the potential risk of febrile seizures.
activities, it is recommended to the Delegate that the draft PI document be revised as follows: The Delegate may wish to replace “Immunisation Handbook” with “Australian Immunisation Handbook” in the proposed Dose and administration Section As previously outlined in the response to Recommendation 4 above it is proposed to keep the wording more general in nature based on the intent that this labelling will be applicable in both Australia as well as New Zealand. This recommendation is referred to the Delegate for final consideration. ACSOV supported the RMP evaluator’s recommendation. The Delegate may wish to add “Immunisation should not be performed during a febrile or illness” under contraindication in the Australian PI in the light of an already approved Australian PI of another influenza vaccine. The sponsor agrees and has added an appropriate statement within “Contraindications” section. The proposed PI change is noted and referred to the Delegate for final consideration. The Delegate may wish to add a statement in the draft PI regarding “general advice on overdose management. The sponsor agrees and has language consistent with that included in the PIs for other licensed influenza vaccines. The proposed PI change is noted and referred to the Delegate for final consideration. The Delegate may wish to strengthen the wording in the Australian PI regarding the use of this vaccine in children below the age of 6 months (that is, FluQuadri/FluQuadri Junior are not recommended in children below the age of 6 months). The sponsor believes the age indication for FluQuadri is clearly stated in the proposed PI. Therefore, no changes are proposed to be made to this wording. The recommendation is referred to the Delegate for consideration. The Delegate may wish to add the following statement to the proposed PI for FluQuadri/ FluQuadri Junior about the potential risk of interaction with other medicines: “Influenza vaccine can impair the metabolism of warfarin, theophylline, phenytoin, phenobarbitone and carbamazepine by the hepatic The sponsor acknowledges the request to add the above advice, which would be consistent with the current Vaxigrip Australian PI; however, alternative language is proposed that is consistent with the company’s updated core The proposed PI change is noted and referred to the Delegate for final consideration. trial
P450 system. Results from studies have been variable in degree of interaction and time after vaccination for the interaction to take effect. The interaction may be idiosyncratic. Patients taking warfarin, theophylline, phenytoin, phenobarbitone or carbamazepine should be advised of the possibility of an interaction and told to look out for signs of elevated levels of medication. The immunological response may be diminished if the patient is undergoing immunosuppressant treatment”. labelling document (CCDS), which will soon be reflected in a new version of the Vaxigrip Australian PI. The proposed language is as follows: “Although inhibition of hepatic clearance of phenytoin, theophylline and warfarin has been reported after influenza vaccination, subsequent studies have not shown any evidence of undesirable effects related to this phenomenon.” The Delegate may wish to add the following statement in the proposed Australian PI the Section of “Effects on Laboratory Tests”; “Following influenza vaccination, false positive results in serology tests using the Enzyme-linked Immunosorbent Assay (ELISA) method to detect antibodies against HIV1, hepatitis C virus and especially Human virus Type I (HTLV1) have been observed. The Western Blot technique disproves the results. The transient false positive reactions could be due to the IgM response due to the vaccine”. The sponsor agrees and has added proposed wording to the “Effects on Laboratory Tests” section. The proposed PI change is noted and referred to the Delegate for final consideration. In regard to the proposed routine risk minimisation activities, it is recommended to the Delegate that the draft CMI document be revised as follows: See below See below That the draft CMI is based on the other approved influenza vaccine marketed by the same sponsor. The FluQuadri/FluQuadri Junior CMI have been updated to align with The proposed changes to the CMI are noted and referred to the
Risk minimisation activities Information has been updated according to recommendations from the RMP evaluation report (see section 5 of this advice). The evaluator has no objection to the changes and recommends to the Delegate that the updated version is implemented (see below). Suggested wording for conditions of registration RMP Implement the Core RMP (version 1.0 data lock point 15 March 2013) with Australian Specific Annex (version 1.1 dated April 2014) and any future updates as a condition of registration. VI. Overall conclusion and risk/benefit assessment The submission was summarised in the following Delegate’s overview and recommendations: Quality The quality evaluators recommend that for FluQuadri and FluQuadri Junior 60 µg HA/0.5 mL dose and 30 µg HA/0.25 mL dose, prefilled syringe without needle, with a shelf life of 12 months at 2 to 80C should be approved. The sponsor has agreed to provide target formulation values to the TGA prior to the commencement of each season. Nonclinical The sponsor provided adequate justification for the lack of nonclinical studies for FluQuadri®. There are no nonclinical objections to registration of FluQuadri® and FluQuadri Junior®. Clinical Clinical immunogenicity The three submitted studies are presented involving the different age groups, adults ≥ 18 years, adults ≥ 65 years and children 6 months to <9 years. In each of the studies, assessment of immunogenicity was the primary objective. No efficacy data was presented. Serum antibody responses to the influenza viruses were considered to correlate with protection against infection and serve as valid surrogates of vaccine efficacy. The method used to measure serum antibodies in the clinical studies was the haemagglutination inhibition (HAI) test. Assessment of immunogenicity post vaccination was uniform amongst the studies: Seroprotection was defined as an HAI antibody ≥ 40 (l/dil) at pre and postvaccination Seroconversion was defined as a pre-vaccination titre < 10 (1/dil) and a titre ≥ 40 (1/dil), or a pre-vaccination titre ≥ 10 (1/dil) and a ≥ 4 fold increase in postvaccination titre