AusPAR Attachment 2. Extract from the Clinical Evaluation ... · Web viewAntibody responses to B/strains ... the relevant antigen just passed all three criteria while ... tion/Guidances/Vaccines/ucm091990.pdf

AusPAR Attachment 2

Extract from the Clinical Evaluation Report for Influenza Virus

30 May 2014

Therapeutic Goods Administration

Haemagglutinin H1N1, H3N2, B Victoria lineage, B Yamagata lineage

Proprietary Product Name: FluQuadri™ and FluQuadri™Junior

Sponsor: Sanofi Aventis Australia Pty Ltd

Submission PM-2013-02401-1-2 Extract from the Clinical Evaluation Report for FluQuadri™ and FluQuadri™Junior Influenza Virus Haemagglutinin H1N1, H3N2, B Victoria lineage, B Yamagata lineage

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About the Therapeutic Goods Administration (TGA) The Therapeutic Goods Administration (TGA) is part of the Australian Government

Department of Health, and is responsible for regulating medicines and medical devices.

The TGA administers the Therapeutic Goods Act 1989 (the Act), applying a risk management approach designed to ensure therapeutic goods supplied in Australia meet acceptable standards of quality, safety and efficacy (performance), when necessary.

The work of the TGA is based on applying scientific and clinical expertise to decision-making, to ensure that the benefits to consumers outweigh any risks associated with the use of medicines and medical devices.

The TGA relies on the public, healthcare professionals and industry to report problems with medicines or medical devices. TGA investigates reports received by it to determine any necessary regulatory action.

To report a problem with a medicine or medical device, please see the information on the TGA website <http://www.tga.gov.au>.

About the Extract from the Clinical Evaluation Report This document provides a more detailed evaluation of the clinical findings, extracted

from the Clinical Evaluation Report (CER) prepared by the TGA. This extract does not include sections from the CER regarding product documentation or post market activities.

The words [Information redacted], where they appear in this document, indicate that confidential information has been deleted.

For the most recent Product Information (PI), please refer to the TGA website <https://www.tga.gov.au/product-information-pi>.

Copyright© Commonwealth of Australia 2014This 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 specific written permission from the Commonwealth to do so. Requests and inquiries concerning reproduction and rights are to be sent to the TGA Copyright Officer, Therapeutic Goods Administration, PO Box 100, Woden ACT 2606 or emailed to <[email protected]>.


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mailto:[email protected]

http://www.tga.gov.au/


ContentsList of commonly used abbreviations______________________________________5

1. Clinical rationale_____________________________________________________5

2. Contents of the clinical dossier_____________________________________7

2.1. Scope of the clinical dossier___________________________________________________7

2.2. Good clinical practice__________________________________________________________7

3. Clinical efficacy_______________________________________________________8

3.1. Clinical immunogenicity_______________________________________________________8

4. Clinical safety________________________________________________________30

4.1. Adult studies__________________________________________________________________30

4.2. Paediatric study______________________________________________________________34

5. Clinical questions___________________________________________________40

5.1. Question 1____________________________________________________________________40

5.2. Question 2____________________________________________________________________40

5.3. Question 3____________________________________________________________________41

5.4. Question 4____________________________________________________________________41

5.5. Question 5____________________________________________________________________41

5.6. Question 6____________________________________________________________________41

5.7. Question 7____________________________________________________________________41

5.8. Question 8____________________________________________________________________41

5.9. Question 9____________________________________________________________________41

6. Second round evaluation of clinical data submitted in response to questions______________________________________________________________________42

6.1. Question 1____________________________________________________________________42

6.2. Question 2____________________________________________________________________42

6.3. Question 3____________________________________________________________________43

6.4. Question 4____________________________________________________________________43

6.5. Question 5____________________________________________________________________44

6.6. Question 6____________________________________________________________________44

6.7. Question 7____________________________________________________________________45

6.8. Question 8____________________________________________________________________45

6.9. Question 9____________________________________________________________________45

6.10. Summary and discussion_________________________________________________46

6.11. Conclusion_________________________________________________________________50

7. Second round benefit-risk assessment__________________________50


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7.1. Benefits_______________________________________________________________________50

7.2. Risks___________________________________________________________________________51

7.3. Balance________________________________________________________________________51

8. Second round recommendation regarding authorisation____51


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List of commonly used abbreviationsAbbreviation Meaning

ACIP Advisory Committee on Immunization Practices

AE Adverse event

AESI Adverse event of special interest

AR Adverse reaction

CBER Center for Biologics Evaluation and Research

CDC Centers for Disease Control and Prevention

CHMP Committee for Medicinal Products for Human Use

CI Confidence interval

GBS Guillain-Barré syndrome

GMT Geometric mean titer

GMTR The ratio of the post-vaccination GMT of QIV divided by the postvaccination GMT of TIV, or the geometric mean of the individual postvaccination/pre vaccination titer ratios, as appropriate

HA Hemagglutinin

HAI Hemagglutination inhibition

IM Intramuscular

PP Per-protocol

QIV Quadrivalent influenza vaccine

SAE Serious adverse event

SC Seroconversion

TIV Trivalent influenza vaccine

US United States

VRBPAC Vaccines and Related Biological Products Advisory Committee


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1. Clinical rationaleFluQuadri is identical to Fluzone Quadrivalent approved by the FDA on 7 June 2013. Fluzone QIV manufacture is based on the same process as Fluzone High-Dose. The only difference between Fluzone and Fluzone Quadrivalent relates to an increase in HA content to a total target of 60 g, based on 15 g/strain. The TIV branded Fluzone has been used in the United States μ μ(US) for over 2 decades and more than 1 billion doses have been used in the at risk population older than 6 months. Fluzone and Fluzone Quadrivalent are manufactured in the United States.

As the same manufacturing process applied for concentrates of Fluzone Quadrivalent and Fluzone, the Center for Biologics Evaluation and Research (CBER) advised that validation of the QIV final bulk formulation and mixing processes, including stability studies on consistency lots would be sufficient for US licensure of the QIV manufacturing process, and a clinical endpoint lot consistency study would not be required. Sanofi Pasteur stated that it does not consider it pertinent to provide a comparison of manufacturing in relation to Sanofi Pasteur’s influenza vaccines, FluQuadri/Fluzone and Vaxigrip.

Fluzone is not registered in Australia. The supply to Australia has been from the French site manufacturing the TIV Vaxigrip which underwent a separate development program for registration. It has been registered for use in Australia for 27 years with more that 17 million doses administered.

Sanofi Pasteur’s development of the quadrivalent vaccine is based on the following rationale. In Australia minor or major epidemics of type A or type B influenza occur most years, usually during the winter. In 2012, 44,564 cases of laboratory-confirmed influenza were reported to the country’s National Notifiable Diseases Surveillance System. It is estimated that influenza causes 3,500 deaths, about 18,000 hospitalisations, and 300,000 GP consultations each year. The highest influenza burden is seen in the elderly and in children less than 5 years of age.

Influenza A viruses include a number of subtypes, of which H1N1, H2N2 and H3N2 are known to have caused epidemics and pandemics. The epidemiology of influenza B is characterised by a major annual epidemic every 2-4 years. The burden of disease from influenza B is generally less than H3N2 but greater than H1N1.

Since 1987, two distinct lineages of influenza B have circulated worldwide, neither providing good cross-protection against the other. The ability to predict the dominant B lineage during an influenza season has been limited, resulting in mismatches between the lineage chosen for inclusion in the vaccine and the predominant lineage in circulation.

Data presented by WHO Collaborating Centre for Reference and Research on Influenza, indicates all four strains of influenza virus represented in the quadrivalent vaccine are implicated in the influenza-related morbidity observed in Australia. B strains were responsible for more than 20% of cases of influenza reported in Australia in 2004-2006 and 2011-2012, and more than 60% in 2008.

The effectiveness of the influenza vaccine in preventing or attenuating influenza illness depends in part on the age and immune competence of the recipient and on the similarity between the virus strains present in the vaccine and those circulating in the community. With a good match between vaccine and circulating strains, influenza vaccine has been shown to prevent illness in 70%–90% of healthy individuals aged less than 65 years, and to be 30%–70% effective in preventing hospitalization among community-based elderly. Among the elderly in nursing homes, influenza vaccine may be only 30%–40% efficacious in preventing influenza disease but can be 50%–60% effective in preventing hospitalization and pneumonia and 80% effective in preventing death.

During the Vaccines and Related Biological Products Advisory Committee meeting 2009, the Centers for Disease Control and Prevention (CDC) presented a model to assess the potential impact on the number of influenza cases, hospitalizations, and deaths of a quadrivalent vaccine


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compared with trivalent vaccine. Their model included 10 influenza seasons (1999-2000 to 2008-2009). The proportion of all influenza disease identified as type B varied from 0.4% to 46%. The proportion of type B isolates of a lineage not in a given year’s TIV varied from 0% to 98%. Over the 10 seasons, it was estimated that a quadrivalent vaccine would have reduced the burden of influenza disease in the US by 2.7 million cases, 21,440 hospitalizations, and 1371 deaths.

Justification for bridging results from the submitted studies, to children 9-17 years of age is based on CBER guidance that the safety and immunogenicity of QIV 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.

2. Contents of the clinical dossier

2.1. Scope of the clinical dossierThree pivotal clinical studies of safety and immunogenicity were provided:

Study GRC43 was a phase II, randomised, open-label, controlled, multi-centre clinical trial including adults 18 years of age and older, in which antibody responses to the quadrivalent influenza vaccine (QIV) were compared with those of 2009-10 trivalent influenza vaccine (TIV) and 2008-09 TIV

Study QIV03 was a phase III, randomised, active-controlled, multi-centre clinical trial including participants aged 65 years and over. Antibody responses to QIV were compared with those of 2010-2011 TIV and an investigational TIV containing the alternate B/strain

Study QIV04 was a phase III, randomised, observer-blinded, active-controlled, multi-centre clinical trial in children from 6 months to less than 9 years of in which antibody responses and safety of QIV were compared with results for of 2010-11 TIV and an investigational TIV.

2.2. Good clinical practiceThe following assurances were given.

2.2.1. Study GRC43 – adults ≥18 years

The final protocol, version 4.0, under which all participants were enrolled, was approved by the Institutional Review Board (IRB) of Duke University Health System, Chesapeake Research Review, and Quorum Review.

The trial was conducted in accordance with the South African version of the Declaration of Helsinki, and International Conference on Harmonization (ICH) Good Clinical Practice, applicable national and local requirements regarding ethical committee review, informed consent, and other statutes or regulations on the protection of rights and welfare of participants in biomedical research.

Informed consent forms contained core information but may have differed by centre depending on local regulations and IRB requirements. If the participant was unable to read and sign, informed consent form was signed and dated by an impartial witness.

2.2.2. Study QIV03 – adults ≥ 65 years

The original trial protocol used for this trial, version 1.0 (dated 02 August 2010), was approved by the Quorum Review IRB prior to the start of the trial. One protocol amendment, 13 October 2010, was issued during the trial. Participants were enrolled under protocol versions 1.0 and 2.0.


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This trial was conducted in accordance with the Edinburgh revision of the Declaration of Helsinki, Good Clinical Practice, the ICH guidelines, the applicable national and local requirements regarding ethical committee review, informed consent, and other statutes or regulations regarding the protection of the rights and welfare of human participants participating in biomedical research.

2.2.3. Study QIV04 – children 6 months to < 9 years

There were 4 protocol amendments: 03 August 2010; 07 October 2010; 20 October 2010; 28 February 2011 and final version 5.0 dated 08 July 2011. Enrolment commenced under version 3.0. Protocol versions 2.0 to 5.0 were approved by the Quorum IRB. All trial related documents and any amendments were approved by the investigational sites’ IRBs.

The trial was conducted in accordance with the revision of the Declaration of Helsinki, Good Clinical Practice, ICH guidelines, applicable national and local requirements, and other statutes or regulations regarding the protection of the rights and welfare of participants in biomedical research.

Written informed consent obtained before any study procedures were performed was signed by the child's representative. Children 7 years of age or older, based on IRB specifications, may have been asked to review and sign a study assent form.

3. Clinical efficacy

3.1. Clinical immunogenicityThe three submitted studies are presented separately due to differences in study design. The following features were common to the three studies:

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 titre ≥ 40 (l/dil) at pre- and post- vaccination

Seroconversion was defined as a pre-vaccination titre < 10 (1/dil) and a post-vaccination titre ≥ 40 (1/dil), or a pre-vaccination titre ≥ 10 (1/dil) and a ≥ 4-fold increase in post-vaccination titre

Geometric mean titre ratio (GMTR) was calculated post-vaccination (GMT QIV/ GMT TIV).

Missing or incomplete immunogenicity data were not replaced and there was no search for outliers. If there were two or more titres, the geometric mean was calculated and was used in the calculation of primary and observational immunogenicity endpoints. Missing safety data was not replaced.

Any antibody titre reported as < lower limit of quantitation (LLOQ) was converted to a value of 0.5 LLOQ to calculate the GMTs. When fold-rise was calculated, pre-vaccination values reported as < LLOQ were converted to LLOQ; post-vaccination titres reported as < LLOQ were reported as 0. If both pre and post values were < LLOQ, the fold rise was defined as 1.

3.1.1. Study GRC43


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This Phase II, open-label, controlled, three-arm, multi-centre study was conducted at four sites in the United States between 01 October and 22 December 2009. The aim was to determine of immunogenicity and safety of the Sanofi Pasteur’s prototype quadrivalent influenza vaccine compared with two seasonal trivalent vaccines. Each 0.5 mL dose contains 15 g μhaemagglutinin of the following antigens:

Investigational product:

A/Brisbane/59/2007, IVR148 (H1N1)

A/Uruguay/716/2007, NYMC X-175C (H3N2) (an A/Brisbane/10/2007-like virus)

B/Brisbane/60/2008

B/Florida/04/2006.

Comparator products

2009-2010 TIV Fluzone vaccine, adult formulation.

Each 0.5 mL dose contained 15 g haemagglutinin of:μ A/Brisbane/59/2007, IVR148 (H1N1)


B/Brisbane/60/2008.

2008-2009 TIV Fluzone vaccine, adult formulation.

Each 0.5 mL dose contains 15 g haemagglutinin of:μ A/Brisbane/59/2007, IVR148 (H1N1)


B/Florida/04/2006.

Participants were randomized to one of three groups using a pre-programmed interactive voice response system (IVRS) designed to ensure that almost equal numbers were enrolled in each vaccine group and each age stratum. Adult participants received one intramuscular dose of their assigned vaccine at Visit 1. Follow-up was approximately 21 days (window 21-28 days).

Group 1 2009-2010 TIV (TIV-1)

Group 2 2008-2009 TIV (TIV 2)

Group 3 QIV

The planned enrolment was 598 participants in ‘reasonably good health’ (219 in Group 1 (included 30 children), 189 in Group 2, and 190 in Group 3.

Children aged between 6 months and 5 years were not vaccinated with the quadrivalent vaccine; results from this group will not be discussed in this evaluation report.

3.1.1.1. Objectives

The primary objective was to describe the immunogenicity of the prototype Quadrivalent Influenza Vaccine (QIV) compared with the 2009-2010 TIV (B/Brisbane) and the 2008-2009 TIV (B/Florida) among adults. The primary endpoint was post-vaccination antibody titres for B/Brisbane and B/Florida influenza strains. Non-inferiority in terms of post vaccination GMT ratios (QIV/TIV) was demonstrated if the lower limit of the two-sided 95% CI was > 2/3 for each of the B virus strains separately.


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There was no secondary objective. Immunogenicity was evaluated as an observational objective prior to vaccination on Day 0 (Visit 1) and 21 days (window, 21- 28 days) post-final vaccination using the haemagglutination inhibition (HAI) technique. For each vaccine strain, pre- and post-GMTs were calculated. The derived endpoints were individual titre ratio of post-vaccination/pre-vaccination seroprotection rates pre-vaccination and post-vaccination and seroprotection rates. The serological assessment included an evaluation against the criteria of the Committee for Medicinal Products for human use (CPMP) included in the Note for Guidance CPMP/BWP/214/96. (Table 1).

Table1. Immunogenicity Criteria Defined by CPMP/BWP/214/96

The endpoint of the HI assay was the reciprocal of the highest serum dilution in which complete inhibition of haemagglutination occurred. Each serum sample was titrated in independent duplicates. The GMT between the two values was calculated after the release of the data to Clinical Data Management. The lower limit of quantitation (LLOQ) was set at the lowest dilution used in the assay, 1/10.

Serum samples were initially tested at Focus Diagnostics. In 2009, Sanofi Pasteur re-assessed the HAI assay using red blood cells from different avian species and varying serum-virus incubation temperature. The HAI assay revalidation was completed in 2010. The optimized conditions for the 2009-2010 and 2010-2011 QIV and TIV strains were determined to be turkey red blood cells and serum-virus incubation temperature of 37°C.

The optimized HAI assay was used in subsequent studies (QIV03 and QIV04) and therefore the GRC43 sera were retested at Sanofi Pasteur using the optimized conditions and these results are presented in this GRC43 version 2.0 Clinical Study Report presented to the TGA.

3.1.1.2. Definition of populations

Per-Protocol Analysis Set: Participants in the PP analysis set met inclusion/exclusion criteria, received an injection of study vaccine at Visit 1 in the time interval specified in the protocol, provided both pre- and post-vaccination serum specimens that were obtained at the intervals specified in the protocol and had at least one valid post-vaccination serological result.

Full Analysis Set: The FAS included all participants who received one dose of study vaccine and had a post-vaccination serological result.

Safety Analysis Set: The safety analysis set was defined as those participants who received one dose of study vaccine

Data were summarized by study group, within age group (18 to 60 years and ≥ 61 years). Analysis for the full and per protocol analysis sets were computed by randomised vaccine group. The primary immunogenicity analysis was based on the per-protocol analysis set. Safety analyses were performed on the safety analysis set and computed by vaccine received.


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3.1.1.3. Determination of samples size

The sample size of 598 participants allowed a possible attrition rate of up to 11% while providing 80.2% power to achieve both primary hypotheses and 89.5% power to achieve each hypothesis. Since both the B/Brisbane and B/Florida hypotheses needed to be met, no alpha adjustment was necessary.

3.1.1.4. Results

3.1.1.4.1. Enrollment and disposition

A total of 570 adult participants were randomized, vaccinated and completed the study. The full analysis set included 187 (98.4%) participants in the 2009-2010 TIV group, 189 (99.5%) in the 2008-2009 TIV group, and 190 (100%) in the QIV group. The per-protocol analysis set included 187 (98.4%) participants in the 2009-2010 TIV group, 188 (98.9%) in the 2008-2009 TIV group, and 190 (100.0%) in the QIV group.

3.1.1.4.2. Demographic characteristics

The mean age was 55.0 years in the 2009-2010 TIV group, 54.9 years in the 2008-2009 TIV group, and 56.7 years in the QIV group. The majority of adult participants in all groups were female (2009- 2010 TIV, 67.9%; 2008-2009 TIV, 65.3%; and QIV, 68.4%) and Caucasian (2009-2010 TIV, 86.8%; 2008-2009 TIV, 87.4%; and QIV, 91.1%). Demographics were also evenly spread in the per-protocol population.

3.1.1.4.3. Primary objective

For strain B/Brisbane, the post-vaccination GMT for QIV (101) was non-inferior to the GMT for the 2009-2010 TIV (114); GMR = 0.89 (95% CI: 0.70 – 1.12). (Table 2)

For strain B/Florida, the post-vaccination GMT for QIV (155) was non-inferior to the GMT for the 2008-2009 TIV (135); GMR = 1.15 (95% CI: 0.93 – 1.42). (Table 2).

Table 2. Study GRC43: primary objective results- - per-protocol - re-test analysis

3.1.1.4.4. Observational results

The HAI antibody responses to each influenza virus strain among adult participants were as follows. Results are recorded in the order 2009-2010 TIV, 2008-2009 TIV, and QIV, with results for QIV in bold:

A/Brisbane (A/H1N1) in 2009-2010 TIV, 2008-2009 TIV, and QIV.

Pre-vaccination GMTs: 27.5, 28.4, and 27.6, respectively; post-vaccination GMTs: 145, 157, 161

Geometric mean titre ratios pre- to post-vaccination were 4.64, 4.88, 5.14

Post-vaccination seroprotection rates: 89.8%, 92.0%, 92.6%

Seroconversion rates: 55.4%, 51.9%, 58.9%.

A/Uruguay(A/H3N2) in 2009-2010 TIV, 2008-2009 TIV, and QIV:


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Pre-vaccination GMTs: 29.9, 32.7, 38.5; post-vaccination GMTs: 302, 380, 304

Geometric mean titre ratios pre- to post-vaccination: 8.52, 9.75, 6.57

Post-vaccination seroprotection rates: 96.3%, 94.1%, 94.7%

Seroconversion rates: 69.9%, 64.2%, 62.6%.

B/Brisbane in 2009-2010 TIV (Brisbane) and QIV:

Pre-vaccination GMTs: 22.0 and 19.9; post-vaccination GMTs: 114 and 101

Geometric mean titre ratios pre/post-vaccination: 4.35 and 4.19

Post-vaccination seroprotection rates: 89.8% and 85.3%

Seroconversion rates: 55.9% and 53.2%.

B/Florida in 2008-2009 TIV (Florida) and QIV:

Pre-vaccination GMTs: 32.6 and 27.1; post-vaccination GMTs: 135 and 155

Geometric mean titre ratios pre- to post-vaccination: 3.78 and 4.98

Post-vaccination seroprotection rates: 92.6% and 92.1%

Seroconversion rates: 44.4% and 57.9%.

Results by age are summarised below.

A/Brisbane (A/H1N1))

Pre-vaccination GMTs for 2009-2010 TIV, 2008-2009 TIV, and QIV

– 28.5, 28.8, and 36.6 for 18-60 years of age

– 26.4, 28.1, and 21.0 for ≥ 61 years

Post vaccination GMTs:

– 250, 254, and 221 for 18-60 years

– 84.5, 97.6, and 118 for ≥ 61 years

Geometric mean titre ratio (95% CI)

– 7.56 (5.63; 10.2), 7.32 (5.38; 9.97), and 5.23 (4.01; 6.84) for 18-60 years

– 2.85 (2.33; 3.48), 3.23 (2.55; 4.11), and 5.04 (4.01; 6.34) for ≥ 61 years

Post-vaccination seroprotection rate (95% CI)

– 95.7% (89.4; 98.8), 98.9% (94.2; 100.0), and 96.8% (91.0; 99.3) for 18-60 years

– 84.0% (75.0; 90.8), 85.1% (76.3; 91.6), and 88.5% (80.4; 94.1) for ≥ 61 years of age

Seroconversion rates (95% CI)

– 68.8% (58.4; 78.0), 62.8% (52.2; 72.5), and 59.6% (49.0; 69.6) for 18-60 years

– 41.9% (31.8; 52.6), 40.9% (30.8; 51.5), and 58.3% (47.8; 68.3) for ≥ 61 years

A/Uruguay (A/H3N2):

Pre-vaccination GMTs

– 25.8, 26.6, and 30.8 for 18-60 years

– 34.7, 40.4, and 47.9 for ≥ 61 years

Post vaccination GMTs


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– 431, 511, and 301 for 18-60 years

– 213, 282, and 306 for ≥ 61 years of age

Geometric mean titre ratios (95% CI)

– 14.0 (9.99; 19.6), 14.9 (10.2; 21.7), and 7.60 (5.65; 10.2) for 18-60 years

– 5.19 (3.97; 6.79), 6.37 (4.52; 8.99), and 5.70 (4.32; 7.52) for ≥ 61 years

Post-vaccination seroprotection rates (95% CI)

– 96.8% (90.9; 99.3), 94.7% (88.0; 98.3), and 95.7% (89.5; 98.8) for 18-60 years;

– 95.7% (89.5; 98.8), 93.6% (86.6; 97.6), and 93.8% (86.9; 97.7) for ≥ 61 years


– 78.5% (68.8; 86.3), 74.5% (64.4; 82.9), and 67.0% (56.6; 76.4) for 18-60 years;

– 61.3% (50.6; 71.2), 53.8% (43.1; 64.2), and 58.3% (47.8; 68.3) for ≥ 61 years

B/Brisbane:

Pre-vaccination GMTs

– 19.6 and 21.5 for 18-60 years

– 24.8 and 18.3, respectively for ≥ 61 years

Post-vaccination GMTs

– 159 and 132 for 18-60 years

– 82.4 and 78.3 for ≥ 61 years


– 6.79 (5.27; 8.75) and 5.16 (4.05; 6.58) for 18-60 years

– 79 (2.28; 3.40) and 3.41 (2.81; 4.15) for ≥ 61 years


– 95.7% (89.4; 98.8) and 89.4% (81.3; 94.8) for 18-60 years

– 84.0% (75.0; 90.8) and 81.3% (72.0; 88.5) for ≥ 61 years


– 71.0% (60.6; 79.9) and 59.6% (49.0; 69.6) for 18-60 years

– 40.9% (30.8; 51.5) and 46.9% (36.6; 57.3), for ≥ 61 years

B/Florida in 2008-2009 TIV and QIV:

Pre-vaccination GMTs:

– 28.5 and 31.1 for 18-60 years; 37.3 and 23.6 for ≥ 61 years

Post-vaccination GMTs:

– 179 and 210 for 18-60 years

– 101 and 115 for ≥ 61 years


– 5.47 (4.11; 7.28) and 6.02 (4.67; 7.76) for 18-60 years

– 2.61 (2.15; 3.15) and 4.13 (3.34; 5.11) for ≥ 61 years


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– 96.8% (91.0; 99.3) and 94.7% (88.0; 98.3), for 18-60 years

– 88.3% (80.0; 94.0) and 89.6% (81.7; 94.9), for ≥ 61 years


– 55.3% (44.7; 65.6) and 59.6% (49.0; 69.6) for 18-60 years;

– 33.3% (23.9; 43.9) and 56.3% (45.7; 66.4) for ≥ 61 years

The QIV vaccine met all three CPMP criteria for all four vaccine strains.

Although not a study objective, results for A/Brisbane and A/Uruguay, for the QIV group compared to the pooled TIV groups were submitted. Non-inferioriority in terms described for B strain viruses was shown: GMR = 0.90 (95% CI: 0.70 – 1.15).

3.1.1.5. Sponsor’s conclusion

The retesting by the optimized HAI assay gave results not materially different to those described in the GRC43 clinical study report previously submitted to CBER. The QIV formulation of influenza vaccine induced antibody responses that were non inferior to those of the 2009-2010 TIV and the 2008-2009 TIV with respect to each A strain and each included B strain. In addition, QIV met the CHMP criteria for each strain for both adult age groups. The data indicate that the addition of an alternate lineage B strain into the vaccine formulation did not adversely affect the immunogenicity profile of QIV compared to the currently licensed TIV vaccine.

3.1.1.6. Evaluator comment

The reviewer is not in a position to comment on similarity or otherwise of the results presented in this submission and the initial testing submitted to CBER.

The primary objective was met in protocol defined terms and the vaccine would have passed the criteria necessary for registration as a seasonal vaccine based on CPMP/BWP/214/96 criteria.

Because the description of the study vaccine included gelatine and there is no mention of animal products in the Module 121 application form or in the proposed Product Information, it is unclear whether the prototype vaccine manufacture was exactly the same as the vaccine proposed for registration in Australia.

3.1.2. Study QIV03

QIV03 was a Phase III, randomized, four-arm, active-controlled, multi-centre trial of safety and immunogenicity of Sanofi Pasteur’s quadrivalent influenza vaccine, conducted in 12 sites in the United Sates between 8th October and 22nd December 2010. The study was designed to determine immunogenicity and safety of Sanofi Pasteur’s QIV in adults aged ≥ 65 years, compared to the licensed 2010-2011 TIV containing the primary B strain, and investigational TIV containing the alternate B strain.

The study included men and women, free from immune deficiency conditions and without chronic illness which may have been compromised by vaccination.

Vaccine antigen content is summarised below.

3.1.2.1. Investigational product

Each 0.5 mL dose of vaccine contains 15 g haemagglutinin each of:μ A/California/07/2009 (H1N1)

A/Victoria/210/2009 (H3N2)

B/Brisbane/60/2008


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B/Florida/04/2006.

Comparator products

Licensed 2010-2011 TIV, No Preservative (Fluzone®).



B/Brisbane/60/2008

Investigational TIV with alternate B strain, No Preservative.



B/Florida/04/2006.

Participants were randomized 1:1:1 to one of three groups. Individuals in these groups were blinded to group assignment. One intramuscular dose of vaccine was administered at Visit 1.

The study groups and the planned enrolment are shown below:

Group 1: Investigational Quadrivalent Influenza Vaccine: N=225

Group 2: Investigational Trivalent Influenza Vaccine: N=225

Group 3: Licensed 2010-2011 Trivalent Influenza Vaccine: N=225

Group 4: Licensed 2010-2011 Trivalent Influenza Vaccine: N=64 participants aged 18 – 64. This group is not included in further discussion as no equivalently aged group received the QIV.

3.1.2.2. Objectives

The primary objective was to demonstrate non-inferiority of antibody responses to QIV compared with licensed 2010-2011 TIV and investigational TIV assessed by GMTRs for each virus strain. The primary endpoint was HI GMTs for each of the four virus strains 21-28 days post-vaccination. Data from the two TIVs were pooled for each of the A strains. Comparison for the B strains was done between QIV and the TIV with the corresponding B strain.

Non-inferiority in terms of post vaccination GMT ratios (QIV/TIV) was be demonstrated if the lower limit of the two-sided 95% CI was > 0.66 for each of the four virus strains separately.

There were no secondary objectives. There were 3 observational immunogenicity objectives:

1. To demonstrate non-inferiority of QIV seroconversion rates compared with the licensed and investigational TIVs. Non-inferiority was shown if the lower limit of the 95% CI for the difference in seroconversion rates (QIV - TIV) was > - 10% for each of the four virus strains.

2. To demonstrate superiority of post-vaccination GMTRs and seroconversion rates for QIV compared to TIV for each B strain in QIV not contained in the TIV. Superiority of response was shown if the LL of the 95% CI of the GMTR (QIV/TIV) was > 1.5 and if the LL of the 95% CI of the difference of seroconversion rated (QIV – TIV) was > 10%.

3. To describe GMTs, GMTRs, seroconversion rates, and seroprotection rates induced by QIV and the TIVs. Immunogenicity parameters with 95% CI were calculated pre- and post-vaccination.


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3.1.2.3. Definition of populations

The per-protocol set results were used for the primary analysis, the result of which was confirmed using the full analysis set.Analysis using these populations were based on the randomised group Participants were excluded from the PP Analysis Set for the following reasons:

Participant did not meet all protocol-specified inclusion/exclusion criteria, did not receive vaccine

Participant received a vaccine other than the one that he/she was randomized to receive

Preparation and/or administration of vaccine was not done as per protocol

Participant did not receive vaccine in the proper time window

Participant did not provide a post-dose serology sample in the proper time window

Participant received a protocol-restricted therapy/medication/vaccine

Participant’s serology sample did not produce a valid test result.

The FAS consisted of all vaccinated participants with a dose of study or control vaccine and had a valid post-vaccination serology result.

The Safety Analysis Set included all participants who received the study or control vaccine. The safety analyses were conducted according to the vaccine received.

3.1.2.4. Determination of sample size

Allowing for 5% attrition, the sample size of 675 participants, 225 per group, provided 90.3% power to achieve the primary hypothesis. The hypothesis in all four strains needed to be met and no adjustment for alpha was made.

3.1.2.5. Blinding and randomisation

Participants were randomly assigned via an IVRS. Assignment to Groups 1, 2, and 3 were blinded. Lot numbers were used to identify the vaccines for the purposes of randomization, treatment, and the recording of treatment administered. The lot number codes associated with each vaccine were assigned by an Industrial Operations planner and retained by a representative of the Sponsor’s Quality Assurance Department. These individuals did not disclose the vaccines associated with the lot numbers or discuss the treatment assignment of any participant with any other person until the final unblinding of the trial. All other individuals involved in the conduct of the study remained blinded. There were no instances of code breaking in this study.

3.1.2.6. Protocol amendments

The first study protocol used for the trial, version 1.0, (02 August 2010), was approved by the IRB prior to the start of the trial. There was one protocol amendment; protocol version (13 October 2010: 5 days after commencement of the study). The key changes were:

Added exclusion criterion: the receipt of any influenza vaccine since 01 August 2010.

Added the collection of vital signs before and after vaccination at Visit 1.

As per CBER request, seroconversion rates were added to the superiority observational objective.

Clarified code-breaking procedures at the request of health authorities.

Changed reporting of concomitant medications from “30-day follow-up” to “Visit 1 to visit 2”.


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3.1.2.7. Results

3.1.2.7.1. Enrolment and disposition

A total of 675 participants, 225 participants per vaccine group, received one dose of study vaccine and were included in the Safety Analysis Set.

The FAS included 223 (99.1%) participants in the QIV group, 220 (97.8%) in the 2010-2011 TIV group, and 224 (99.6%) in the investigational TIV group. The PP Analysis Set included 220 (97.8%) participants in the QIV group, 219 (97.3%) in the 2010-2011 TIV group, and 221 (98.2%) in the investigational TIV group.

Fifteen participants (QIV, 5 [2.2%]; 2010-2011 TIV, 6 [2.7%]; and investigational TIV, 4 [1.8%]) had one or more of the following protocol violations.

3.1.2.7.2. Demographic and baseline characteristics

Demographic characteristics were similar in all three vaccine groups.

The mean age was 72.4 to 72.8. Just over half of each group was female (QIV, 57.3% [129/225]; 2010-2011 TIV, 56.0% [126/225]; and investigational TIV, 53.8% [121/225]). The majority were Caucasian (QIV, 87.6% [197/225]; 2010-2011 TIV, 89.8% [202/225]; investigational TIV, 91.1% [205/225]). The demographics of the FAS and in the PP Analysis Set were similar.


Non-inferiority of GMT ratios was demonstrated for each strain in QIV

A/California, the post-vaccination GMTR QIV (231)/ pooled TIV (270); GMTR = 0.85 (95% CI: 0.67 – 1.09)

A/Victoria, post-vaccination GMTR QIV (501)/ pooled TIV (324) = 1.55 (95% CI: 1.25 – 1.92)

B/Brisbane, the post-vaccination GMTR QIV (73.8)/2010-2011 TIV (57.9) = 1.27 (95% CI: 1.05 – 1.55)

B/Florida, the post-vaccination GMTR QIV (61.1)/investigational TIV (54.8) = 1.11 (95% CI: 0.90 – 1.37).

Table 3. Study QIV03 Primary analysis - comparison of GMTs against A Strains after QIV with those after TIV - per-protocol analysis set


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Table 4. Study QIV03 Primary analysis - comparison GMTs against B Strains after QIV with those after TIV with corresponding B Strain - per-protocol analysis set

3.1.2.7.4. Observational objectives

Non-inferiority was shown for the two B strains and for strain A/Victoria/210/2009 (A(H3N2). Non-inferiority was not demonstrated for strain A/California.

A/California seroconversion rates were 65.91% (145/220) and 69.77% (307/440) for the QIV and pooled TIV groups, respectively. The difference was -3.86 (95% CI -11.50, 3.56)

A/Victoria/210/2009 (A/H3N2), the difference in seroconversion rates for QIV (69.09% [152/220]) minus the pooled TIV (59.32% [261/440]) was 9.77 (95% CI: 1.96, 17.20)

B/Brisbane/60/2008, the difference in seroconversion rates for QIV (28.64% [63/220]) minus the 2010-2011 TIV (18.72% [41/219]) was 9.91 (95% CI: 1.96 – 17.70)

B/Florida/04/2006, the difference in seroconversion rates for QIV (33.18% [73/220]) minus the investigational TIV (31.22% [69/221]) was = 1.96 (95% CI: - 6.73 – 10.60).

Superiority was demonstrated for B/Florida but was not shown for B/Brisbane in the predefined terms of GMT ratio (QIV/TIV) = > 1.5

B/Brisbane. GMTR QIV 73.8/TIV 42.2 = 1.75 (95% CI 1.43, 2.14).

B/Florida: GMTR QIV61.1/TIV 28.5 = 2.14 (95% CI: 1.74 – 2.65)

Superiority was demonstrated for QIV as the lower limit of the two-sided 95% CI of the difference of the seroconversion rates (QIV minus TIV) was > 10% for each B strain in QIV compared with the corresponding B strain not contained in each TIV.

B/Brisbane: QIV (28.64% [63/220]) - investigational TIV (8.60% [19/221]) = 20.04 (95% CI: 12.90 – 27.00)

B/Florida: QIV (33.18% [73/220]) - 2010-2011 TIV (9.13% [20/219]) = 24.05 (95% CI: 16.60 – 31.20).

Antibody responses are summarised below are respectively for QIV (in bold), 2010-2011 TIV (B/Brisbane), and investigational TIV (B/Florida).

A/California

Pre-vaccination GMTs: 21.7, 24.8, and 21.1; post-vaccination GMTs: 231, 269, and 271

GMTRs: 8.81, 9.18, and 10.6

Seroconversion rates: 65.9%, 66.7%, and 72.9%

Post-vaccination seroprotection rates: 91.4%, 91.3%, and 91.9%.

A/Victoria


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Pre-vaccination GMTs: 52.3, 48.3, and 42.3; post-vaccination GMTs: 501, 291, and 360

GMTRs: 8.72, 5.65, and 7.73


Post-vaccination seroprotection rates: 100.0%, 95.4%, and 95.9%.

B/Brisbane

Pre-vaccination GMTs: 27.1, 29.0, and 28.5; post-vaccination GMTs: 73.8, 57.9, and 42.2

GMTRs: 2.46, 1.83, and 1.34


Post-vaccination seroprotection rates: 77.7%, 71.7%, and 60.2.

B/Florida

Pre-vaccination GMTs: 20.2, 18.7, and 19.7; post-vaccination GMTs: 61.1, 28.5, and 54.8

GMTRs: 2.65, 1.40, and 2.47


Post-vaccination seroprotection rates: 73.2%, 46.1, and 67.4%.

3.1.2.8. Sponsor’s conclusion - immunogenicity

This study demonstrated that the QIV formulation of influenza vaccine induced GMT responses that were non-inferior to those of the licensed 2010- 2011 TIV and the investigational TIV with respect to all four strains contained in the vaccine.

For the observational objectives, the seroconversion rates after QIV were non-inferior to the control TIVs with respect to all strains except A/H1N1. In addition, when comparing antibody responses to each B strain in QIV with those induced by the TIV that did not contain the corresponding B strain, the seroconversion rates after QIV were superior for each B strain in QIV; superiority was not demonstrated for B/Brisbane as assessed by GMT ratio.

Failure to meet the non-inferiority criterion for the seroconversion rate to A/H1N1 was marginal and is not expected to adversely affect clinical protection against A/H1N1 because the seroprotection rate to this strain was approximately 91% for each vaccine, including QIV.

Failure to meet the superiority criterion for the GMT ratio to B/Brisbane is not expected to adversely affect clinical protection against B/Brisbane because the post-vaccination GMT and seroconversion rate to this strain was non-inferior in QIV compared with the 2010-2011 TIV containing the same strain.

The data indicate that the addition of an alternate-lineage B strain into the vaccine formulation did not adversely affect the safety or immunogenicity profile of QIV compared to the currently licensed TIV vaccine.


The applicant’s reasoning regarding failure to meet the criteria for non-inferiority of seroconversion rate to A/H1N1 and superiority of GMT ratio for B/Brisbane are accepted. However, the findings are in keeping with the previously well documented muted antibody responses to influenza vaccination in the elderly, and without direct evidence of efficacy, translation of the results into predictions of efficacy is hypothetical.

There was no protocol defined yardstick for evaluation of GMTs, GMTRs, seroconversion and seroprotection rates. However, the guideline CPMP/BWP/214/96 was current at the time of this study and is considered relevant to the Australian setting. Applying the CPMP criteria, each vaccine met each criterion in response to A/California and A/Victoria. Antibody responses to


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B/strains were less vigorous than to A/strains. According to the Guideline, the geometric mean increase criterion was met the QIV but by neither of the TIVs. No vaccine passed the seroconversion criterion. Each of the vaccines passed the seroprotection criterion including the vaccine that did not contain B/Brisbane.

Results for B/Florida were better for the QIV than the TIVs. According to CPMP criteria, the QIV and the TIV containing the relevant antigen just passed all three criteria while the TIV without B/Florida passed none of the criteria.

3.1.3. Study QIV04

3.1.3.1. Design

QIV04 was a Phase III, randomized, observer-blind, active-controlled, 3-arm multicenter trial, comparing safety and immunogenicity of Sanofi Pasteur’s quadrivalent influenza vaccine with the seasonal TIV and an investigations TIV administered to children in 2 age strata, 6 to < 36 months and 3 to < 9 years of age. It was conducted at 69 investigative sites in the United States between November 2010 and January 2012.

Children in ‘reasonably good health’ were randomized into one of the three groups described below using a pre-programmed IVRS. Enrolment was stratified by age at each site to ensure that approximately 50% of participants at each site were 6 months to < 36 months of age.

Group 1: 2010-2011 TIV (N=800 participants)

Group 2: Investigational TIV (N=800 participants)

Group 3: QIV (N=3340 participants).

Children 6 to < 36 months of age were administered 0.25-mL doses. Children 3 to < 9 years of age were administered 0.5-mL doses. The 0.25 mL doses of each vaccine contained 7.5 g HA of μeach antigen. The 0.5-mL doses contained 15 g HA of each antigen. The QIV and TIV vaccines μwere similarly formulated. Study vaccines included the following antigens.

Investigational product

A/California/07/2009 (H1N1)


B/Brisbane/60/2008 (primary B strain)

B/Florida/04/2006 (alternate B strain).

Comparator products

Licensed 2010-2011 TIV



B/Brisbane/60/2008.

Investigational TIV



B/Florida/04/2006.

Participants received their assigned vaccine at Visit 1. Previously unvaccinated participants received a second dose of the assigned vaccine at Visit 2, Day 28 (window, 28-35 days). The vaccine was administered intramuscularly into the anterolateral muscle of the thigh or the deltoid muscle.


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Blood specimens for immunogenicity assay were obtained prior to the first vaccination and 28 – 35 days following the final vaccination.

3.1.3.2. Objectives

The primary objective was to assess non-inferiority of QIV antibody responses compared with 2010-2011 TIV and investigational TIV assessed by GMT ratios and seroconversion rates after the final vaccination within each age group (6 to < 36 months and 3 to < 9 years of age) and overall. Primary endpoints were HAI GMTs for each of the four virus strains 28-35 days after the final vaccination and seroconversion rates.

For comparison of QIV to TIV for immune responses to the A/H1N1 and A/H3N2 strains, Groups 1 and 2 were pooled to form a single control TIV group. For comparison of QIV to TIV for the primary and alternate B strains, antibody responses to QIV were compared with that of the TIV containing the corresponding B strain.

Non-inferiority of GMT ratios was demonstrated if the lower limit of the two-sided 95% CI of the GMTR (QIV/TIV) post vaccination was > 0.66 for each of the four virus strains separately within each age group and overall.

Non-inferiority of seroconversion rates was demonstrated if the lower limit of the two-sided 95% CI for the difference in seroconversion (QIV – TIV) was > - 10% for each of the four virus strains within each age group and overall.

The primary immunogenicity analyses was performed on the per-protocol analysis set, and confirmed on the full analysis set.

The secondary objective was to demonstrate superiority of GMT ratios and seroconversion rates to each B strain in QIV compared with responses to the TIV not containing the corresponding B strain. Endpoints were post-vaccination HAI GMTs and seroconversion rates for each B strain:

Superiority was demonstrated for GMT ratios if the lower limit of the two sided 95% CI of post vaccination GMTRs (QIV/TIV) was > 1.5 for each B strain in QIV compared with the corresponding B strain not contained in each TIV.

Superiority was demonstrated for seroconversion rates if the lower limit of the two-sided 95% CI of the difference (QIV – TIV) in post-vaccination seroconversion was > 10% for each B strain in QIV compared with the corresponding B strain not contained in each TIV.

Observational immunogenicity objectives were to document GMTs, GMT ratios, seroconversion rates, and seroprotection rates overall and for those requiring one dose and two doses.

Missing data was not replaced. No test or search for outliers was performed. For the calculation of GMTs and seroprotection, any pre-vaccination or post-vaccination titre reported as < LLOQ (lower limit of quantitation) was converted to a value of 0.5 LLOQ. For the calculation of fold rise and GMTR, any pre-vaccination value reported as < LLOQ will be converted to LLOQ, and any post-vaccination titre reported as < LLOQ was converted to a titre of 0.5 LLOQ when either the numerator or the denominator is < LLOQ. If both the numerator and denominator are < LLOQ, then both will be converted in the same way so that the fold rise is defined as 1.Any titre reported as > upper limit of quantitation (ULOQ) will be converted to ULOQ.

3.1.3.3. Sample size and power calculation

With 3340 participants receiving QIV (3000 evaluable), a sample size of 800 participants (720 evaluable) in each TIV group was calculated to yield 95% overall power to demonstrate non-inferiority for all 4 strains between QIV and TIV, and 90% power to demonstrate non-inferiority separately within each age group (6 to ≤ 35 months and 3 to < 9 years of age).

For superiority comparisons, 3340 antibody responses to each B strain in QIV compared with 800 antibody responses to TIV not containing the corresponding B strains yielded at least 99%


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power separately within each age-group (6 to ≤ 35 months and 3 to < 9 years of age) and overall.

Since hypotheses in all four strains needed to be met, no alpha adjustment was necessary.

3.1.3.4. Blinding and randomisation

The study was performed in an observer-blinded fashion: Investigators and study staff who conducted safety assessments and participants were blinded. Unblinded qualified study staff members not involved with safety evaluation and other trial procedures prepared and administered the vaccine. Storage and preparation of the product was separate from the place where the injection was performed. The Investigator and study staff responsible for safety assessment were not present during vaccination.

The randomization schedule and labels were provided by the IVRS, and the codes associated with each study vaccine were assigned by an Industrial Operations planner and were retained by a representative of the Sponsor’s Quality Assurance Department. These individuals did not disclose the vaccines or discuss the treatment assignment of any participant with any other person until the final unblinding of the trial, except in the event of emergency.

3.1.3.5. Protocol amendments

The final protocol for this trial was version 5.0, dated 08 July 2011. Enrolment started under version 3.0 dated 20 October 2010. The only change considered to have possible impact on study objectives was included in protocol version 4 relating to use of 0.5 mL prefilled single vials rather than 0.25 mL prefilled syringes for use in children 6 months to < 36 months, which resulted in reliance on staff accuracy in measurement.

3.1.3.6. Results

3.1.3.6.1. Enrolment and disposition

In total 4363 (100.0%) participants were randomized, and 4013 (92.0%) completed the study. Fifteen (0.3%) were randomized but not vaccinated.

A total of 4348 (99.7%) randomized participants were included in the Safety Analysis Set: 2893 [99.7%] in the QIV group, 734 [99.7%] in the 2010-2011 TIV group, and 721 [99.4%] in the investigational TIV group.

The FAS included 2597 (89.5%) children randomized to the QIV group, 656 (89.1%) to the 2010-2011 TIV group, and 663 (91.4%) to the investigational TIV group.

The PP Analysis Set included 2339 (80.6%) children in the QIV group, 582 (79.1%) in the 2010-2011 TIV group, and 599 (82.6%) in the investigational TIV group. A total of 396 participants in the FAS were excluded from the PP Analysis Set (258 [8.9%] QIV, 74 [10.1%] 2010-2011 TIV, 64 [8.8%] investigational TIV).

A total of 843 (19.3%) participants had 1 or more protocol deviations: QIV, 563 (19.4%); 2010-2011 TIV, 154 (20.9%); investigational TIV, 126 (17.4%) participants. The most common protocol deviations were post-dose serology sample not provided in the proper time window; at least 1 inclusion criterion not met/at least 1 exclusion criterion met and vaccination not completed/incorrect number of doses.

Among the QIV, 2010-2011 TIV, and investigational TIV groups, 24.8%, 21.9%, and 25.0% of participants, respectively, received 1 dose of vaccine, and 74.9%, 77.9%, and 74.5%, respectively, received 2 doses of vaccine.

The majority of participants, 3866 [88.6%] were contacted at the 6-month follow-up (QIV, 2553 [88.0%] ; 2010-2011 TIV, 659 [89.5%], investigational TIV, 654 [90.2%]).


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3.1.3.6.2. Demographic and baseline characteristics

Males and females were equally distributed among vaccine groups, with a total of 2210 males and 2153 females. The mean ages were 49.8 months for QIV group, 49.6 months for the 2010-2011 TIV group, and 49.6 months for the investigational TIV group. The majority were Caucasian (QIV, 1693 [58.3%]; 2010-2011 TIV, 433 [58.8%]; investigational TIV, 417 [57.5%]) or Black (QIV, 595 [20.5%]; 2010-2011 TIV, 147 [20.0%]; investigational TIV, 139 [19.2%]).


Non-inferiority was shown for all strains for each age strata and overall. (Table 5 to Table 10)

6 months to < 9 years

A/California/07/2009 GMTQIV/GMT Pooled TIV = 1.03 (95% CI: 0.93 – 1.14)

A/Victoria/210/200 GMTQIV/GMTPooled TIV = 0.99 (95% CI: 0.91 – 1.08)

B/Brisbane/60/2008 GMTQIV/GMT2010-2011 TIV = 1.34 (95% CI: 1.20 – 1.50)

B/Florida/04/2006 GMTQIV/GMT Investigational TIV = 1.06 (95% CI: 0.94 – 1.18).

6 months to < 36

A/California/07/2009 GMTQIV/GMTPooled TIV = 1.05 (95% CI: 0.89 – 1.23)



B/Florida/04/2006 GMTQIV/GMT Investigational TIV = 1.10 (95% CI: 0.94 – 1.28).

3 years to < 9 years

A/California/07/2009 GMTQIV/GMTPooled TIV = 1.02 (95% CI: 0.90 – 1.16)



B/Florida/04/2006 GMTQIV/GMTInvestigational TIV = 1.02 (95% CI: 0.89 – 1.17).

Table 5. Study QIV 04 primary analysis A Strains - all age groups - per-protocol analysis set


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Table 6. Study QIV04 primary analysis A Strains - 6 months to < 36 months - per-protocol analysis set

Table 7. Study QIV04 primary analysis A Strains - 3 years to < 9 years - per-protocol analysis set

Table 8. Study QIV04 primary analysis B Strains - all age groups - per-protocol analysis set

Table 9. Study QIV04 primary analysis B Strains - 6 months to < 36 months - per-protocol analysis set


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Table 10. Study QIV04 primary analysis B Strains – 3years to < 9 years - per-protocol analysis set

Secondary objective

Overall and for each age group, superiority was demonstrated. (Table 11 to Table 13)


B/Brisbane/60/2008 GMTQIV/GMTInvestigational TIV = 4.42 (95% CI: 3.94 – 4.97)

B/Florida/04/2006 GMTQIV/GMT2010-2011 TIV = 3.79 (95% CI: 3.39 – 4.23).

6 months to < 36



3 years to < 9 years



Table 11. Study QIV04 secondary objective analysis - all age groups - per-protocol analysis set

Table 12. Study QIV04 secondary objective analysis - 6 months to < 36 months - per-protocol analysis set


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Table 13. Study QIV04 secondary objective analysis - 3 years to < 9 years - per-protocol analysis set

3.1.3.6.4. Observational objectives 6 months to < 9 years

The HAI antibody results for each influenza virus strain among participants 6 months to < 9 years of age are shown below in the order QIV (in bold), 2010-2011 TIV (B/Brisbane), and investigational TIV (B/Florida) respectively.

A/California/07/2009 (A/H1N1):

GMTs pre-vaccination: 40.4, 40.3, and 43.4; post-vaccination: 1124, 1207, and 998

Geometric mean titre ratios pre/post-vaccination were 21.1, 22.9, and 17.5

Seroconversion rates were 92.4%, 93.3%, and 89.6%, respectively

Post-vaccination seroprotection rates were 98.6%, 98.6%, and 98.0%.

A/Victoria/210/2009 (A/H3N2):





B/Brisbane/60/2008:

GMTs pre-vaccination: 8.21, 8.52, and 8.76; post-vaccination: 86.1, 64.3, and 19.5


Seroconversion rates were 71.8%, 61.1%, and 20.0%


B/Florida/04/2006:


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Geometric mean titre ratios pre/post-vaccination were 5.11, 1.68, and 4.81, respectively


Post-vaccination seroprotection rates were 71.6%, 29.1%, and 69.6%, respectively.

3.1.3.6.5. HAI antibody responses 6 to < 36 months

Results below are presented for QIV, 2010-2011 TIV (B/Brisbane), and investigational TIV (B/Florida) respectively.

A/California (AH1N1)

GMTs pre-vaccination: 25.7, 25.6 and 31.3; post-vaccination 747, 224 and 645

Geometric mean titre ratios pre/post vaccination: 20.0, 21.6 and 14.4

Seroconversion rates: 90.9%, 91.5% and 87.2%

Post-vaccination seroprotection rate: 97.7%, 98.2% and 97.5%.

A/Victoria (AH3N2)

GMTs pre-vaccination: 9.19, 9.52 and 10.1; post-vaccination: 526, 558 and 583

Geometric mean titre rations pre/post vaccination: 34.5, 35.5 and 34.4


Post-vaccination seroprotection rates: 99.9%, 98.7% and 99.6%.

B/Brisbane

GMTs pre-vaccination: 6.41, 6.56 and 6.62; post-vaccination: 72.8, 54.7 and 12.0

Geometric mean titre ratios pre/post-vaccination: 6.34, 4.77 and 1.48

Seroconversion rates (95% CIs): 72.0% (69.0, 74.8), 64.9% (58.3, 71.1) and 14.7% (10.5, 19.8)

Post-vaccination seroprotection: 75.5% (72.7, 78.2), 68.9% (62.4, 74.9) and 22.4% (17.4, 28.2).

B/Florida



Seroconversion rates (95% CIs): 57.7% (54.2, 60.6), 6.7% (3.8, 10.8) and 53.5% (47.0, 59.8)

Post-vaccination seroprotection rates: 58.0% (54.8, 61.2), 8.4% (5.2, 12.9) and 55.1% (48.6, 61.4).

3.1.3.6.6. HAI antibody responses – 3 to < 9 years of age


A/California (H1N1)





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A/Victoria (H3N2)



Seroconversion rates: 83%, 76.1% and 81.6%


B/Brisbane

GMTs pre-vaccination: 9.73, 10.1 and 10.6: post-vaccination: 96.6, 71.2 and 27.3


Seroconversion: (95% CI): 71.7% (69.2, 74.0), 58.7 (53.4, 63.9) and 23.7 (19.4, 28.5)

Post-vaccination seroprotection: 80.7 (78.5, 82.8), 73.9% (69.0, 78.4) and 41.5% (36.3, 46.9).

B/Florida



Seroconversion (95% CIs): 71.9% (69.5, 74.3), 25.0% (20.6, 29.8) and 71.4% (66.4, 76.0)

Post-vaccination seroprotection: 80.9% (78.7, 82.9), 42.1% (36.9, 47.5) and 79.6% (75.0, 83.7).

3.1.3.6.7. Antibody responses after one dose


A/California (A/H1N1)


Geometric mean titre ratios pre/post-vaccination: 16.2, 17.2, and 14.9, respectively

Seroconversion rates: 87.1%, 85.1%, and 85.8%, respectively

Post-vaccination seroprotection: 97.6%, 97.4%, and 98.6%, respectively.

A/Victoria (A/H3N2)


Geometric mean titre ratios pre- to post-vaccination were 14.7, 9.22, and 14.2


Post-vaccination seroprotection: 98.8%, 97.3%, and 97.9%.

B/Brisbane



Seroconversion (95% CI) were 59.0% (54.6, 63.3), 50.4% (40.9, 60.0), and 17.0% (11.2, 24.3)

Post-vaccination seroprotection: 66.9% (62.6, 70.9), 63.7% (54.1, 72.6), and 39.0% (30.9, 47.6).


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B/Florida/



Seroconversion (95% CI) 61.4% (57.0, 65.6), 23.9% (16.4, 32.8), and 59.6% (51.0, 67.7)

Post-vaccination seroprotection 68.6% (64.6, 72.6), 40.7% (31.6, 50.4), and 69.5% (61.2, 77.0).

3.1.3.6.8. Antibody responses after two doses


A/California (A/H1N1)





A/Victoria (A/H3N2)





B/Brisbane



Seroconversion (95% CI): 75.4% (73.3; 77.3), 63.7% (59.1; 68.0), and 21.0% (17.3; 25.0)

Post-vaccination seroprotection: 81.9% (80.0; 83.6), 73.9% (69.7; 77.9), and 32.1% (27.8; 36.6).

B/Florida



Seroconversion (95% CI): 67.4% (65.2, 69.5), 16.5% (13.2, 20.1), and 65.4% (60.9; 69.8)

Post-vaccination seroprotection: 72.4% (70.3; 74.5), 26.3% (22.3; 30.5), and 69.6% (65.1; 73.8).

3.1.3.7. Sponsors conclusion

This study demonstrated that the QIV formulation of influenza vaccine induced antibody responses that were non-inferior to those of the licensed 2010-2011 TIV and the investigational TIV with respect to all 4 strains contained in the vaccine overall and among each of the 2 age groups. When comparing antibody responses to each B strain in QIV with those induced by the TIV that did not contain the corresponding B strain the GMT ratios and SC rates after QIV were superior for each B strain in QIV.

Post-vaccination HAI antibody responses to strain A/H1N1 and strain A/H3N2 were comparable among the vaccine groups. Post-vaccination antibody responses to the B1 and B2


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strains were similar between QIV and 2010-2011 TIV groups, and between QIV and investigational TIV groups, respectively.


Reverse cumulative curves illustrate that the participants in both age strata and overall had a greater response to the A strains than the B strains. Children aged 3 to < 9 years had greater responses to all antigens than those aged 6 months to < 36 months. Those children who received two doses had greater response than those who received one dose. The age range of those who received 2 doses is uncertain. An efficacy study would be ideal especially for the youngest children.

It is accepted that the antibody response appears at least as good for the quadrivalent vaccine as the trivalent vaccine.

4. Clinical safetyAssessment of safety was an observational objective in each of the three studies. No hypothesis was tested. Missing data was not replaced. Unless otherwise specified, in the account of safety in this report, percentages were for participants per group, not events.

4.1. Adult studiesGRC43 was a Phase II study including adults aged ≥ 18 years, 190 participants randomised to each of three groups: Group 1: 2009-2010 TIV, Group 2: 2008-2009 TIV and Group 3: QIV.

QIV03 was a Phase III trial including adults aged ≥ 65 years. Participants were randomised to one of four groups. Group 1: QIV: N = 225, Group 2: Investigational TIV: N = 225, Group 3: 2010-2011 TIV: N = 225, Group 4: 2010-2011 TIV: N = 64 aged 18 – 64.

In these two studies, each individual was administered one intramuscular dose of vaccine at Visit 1.

Solicited local adverse reactions were collected from Day 0 to 3, and solicited systemic reactions from Day 0 to 7. Participants recorded the graded intensity level of pain and measured reactions of redness and swelling. The classification as Grade 1, 2, or 3 was assigned by the statistician.

In each study, participants were reminded to fill in the diary card, by phone call 8 – 10 days after vaccination. Safety data was collected at Visit 2, Day 21 to 28. This was originally not the plan for Study GRC43, in which adverse event were to have been reviewed at the time of the phone call. The change in conduct of the study may have resulted in less precise recording of adverse events.

Unsolicited adverse events were reported within the 20 minutes post vaccination and throughout the study period by system organ class, intensity, number of days of occurrence, and relatedness to the vaccine

Solicited injection site reactions (induration, erythema, ecchymosis, pain and swelling in GRC43; pain, erythema and swelling in QIV03) and solicited systemic reactions (fever, shivering (GRC43), malaise, headache, and myalgia) were collected daily from Day 0 to Day 3 in GRC42, Day 0 to 7 in QIV03, and categorized as Grade 1, Grade 2, or Grade 3 as specified in the protocol

Unsolicited adverse events were recorded in Diary Cards between Visits 1 and 2 according to intensity and the action taken, seriousness and relatedness to vaccination assessed by the investigator


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The following events of special interest were separately reported in Study QIV03, but were not recorded in Study GRC43: Guillain- Barré syndrome, Bell’s palsy, encephalitis/myelitis, optic neuritis, Stevens-Johnson syndrome, toxic epidermal necrolysis. Febrile seizures were also included for children.

Safety results for the adult studies are summarised in tables which also include combined study results for participants aged ≥ 65 years.

4.1.1. Study GRC43

There were no reports of unsolicited adverse events in the 20 minutes after vaccination. There were no deaths reported, no serious adverse events considered related to vaccination and no discontinuations due to vaccination.

Solicited injection site reactions

QIV 91 (47.9%)

2009-2010 TIV 101 (53.2%)

2008-2009 TIV V 84 (44.2%)

Solicited injection site reactions in all vaccine groups generally started within 2 days after the vaccination and typically lasted for 1 or 2 days after onset. Pain was the most frequently reported solicited injection site reaction. Frequencies were generally higher for individuals 18-60 years of age than for those ≥ 61 years.

Grade 3 solicited injection site reactions were reported by 1/190 (pain) in the 2009-2010 TIV group, 0/190 of the 2008-2009 TIV group and 1/190 (pain) of the QIV group.

Solicited systemic reactions

QIV 64 (33.7%)

2009-2010 TIV 73 (38.4%)

2008-2009 TIV 55 (28.9%)

The most frequently reported solicited systemic reactions in all vaccine groups were myalgia, headache, and malaise. Frequencies were generally higher for those aged 18-60 years than for participants aged ≥ 61 years.

Grade 3 solicited systemic reactions were reported by 2/190 (headache; malaise) of the 2009-2010 TIV group, 1/190 (malaise) of the 2008-2009 TIV group and 2/190 (headache; malaise) of the QIV group.

Unsolicited adverse events

QIV 34 (17.9%)

2009-2010 TIV

45 (23.7%)

2008-2009 TIV

47 (24.7%)


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The majority of unsolicited non-serious adverse events in all vaccine groups were Grade 1 or 2 in intensity.

In the QIV group, Grade 3 non-serious events were reported for hypoacusis, upper abdominal pain, nausea, vomiting, chills, bronchitis, laryngitis, tooth infection, musculoskeletal pain, musculoskeletal stiffness, cough, and oropharyngeal pain; these events were experienced by seven (3.7%) participants.

In the 2009-2010 TIV group, Grade 3 events were reported for chills, pyrexia, bacterial bronchitis, gout, arthralgia, back pain, musculoskeletal pain, myalgia, pain in extremity, cough, oropharyngeal pain, respiratory tract congestion, wheezing, and hyperhidrosis, reported by seven (3.7%) participants.

In the 2008- 2009 TIV group, Grade 3 events were reported for vertigo, upper abdominal pain, nausea, vomiting, fatigue, influenza like illness, nasopharyngitis, streptococcal pharyngitis, tooth infection, back pain, myalgia, and cough reported by 12 (6.3%) participants.

Overall, the frequencies of adult participants who reported at least one unsolicited non-serious adverse events in the subset of participants 18-60 years of age were higher than in participants. 61 years of age in the 2009-2010 TIV and QIV groups, but lower in the 2008-2009 TIV group.

Unsolicited adverse reactions

QIV 10 (5.3%)

2009-2010 TIV 12 (6.3%)

2008-2009 TIV 13 (6.8%)

The majority of unsolicited non-serious adverse reactions were Grade 1 or 2 in intensity. Grade 3 reactions were reported only in the 2008-2009 TIV and QIV groups.

In the 2008-2009 TIV group, Grade 3 non-serious reactions were reported for abdominal pain, influenza-like illness, and cough reported by three (1.6%) participants.

In the QIV group, Grade 3 non-serious reactions were reported for bronchitis, laryngitis, cough, and oropharyngeal pain, reported by two (1.1%) participants.

Serious adverse events were reported by two individuals but were considered unrelated to study vaccine. One suffered unspecified gastrointestinal bleeding 26 days after vaccination. The other experienced benign paroxysmal positional vertigo and unspecified chest pain 12 days after vaccination.

4.1.2. Study QIV03

There were no reports of the unsolicited adverse events in the 20 minutes after vaccination; there were no deaths, serious adverse event considered vaccine related, grade 3 unsolicited adverse reactions in any vaccine group or events of special interest. One participant in the 2010-2011 TIV group discontinued due to the adverse event, injection site pruritus and diarrhoea considered related to study vaccine.

Solicited injection site reaction

QIV 33.5% (75/224)

2010-2011 TIV 29.5% (66/224)

Investigational TIV 24.0% (54/225)


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Solicited injection site reaction

Pain was the most frequently reported solicited injection site reaction within 7 days after vaccine injection in all vaccine groups, typically starting within 3 days of vaccination and resolving within 1 to 3 days. Grade 3 solicited injection site reactions were reported by 2/224 (pain) in the QIV group. No participants in either of the TIV groups reported grade 3 reactions.


QIV 24.6% (55/224)

2010-2011 TIV 24.1% (54/224)


Myalgia was the most frequently reported solicited systemic reaction within 7 days after vaccine injection in all vaccine groups, followed by headache and malaise. Grade 3 solicited systemic reactions were reported by 1/224 of the QIV group, 0/224 of the 2010-2011 TIV group (fever, headache, malaise, myalgia) and 3/225 of the investigational TIV group (one each of fever, headache and myalgia, two of malaise).


QIV 12.4% (28/225)

2010-2011 TIV 10.7% (24/225)


The most commonly reported unsolicited non-serious adverse events were oropharyngeal pain (3 [1.3%]) and rhinorrhoea (3 [1.3%]) for the QIV group, injection site induration (3 [1.3%]) and oropharyngeal pain (3 [1.3%]) for the 2010-2011 TIV group, and headache (3 [1.3%]) for the investigational TIV group. The majority were Grade 1 or 2 in intensity.

In the QIV group, Grade 3 unsolicited non-serious AEs were reported for asthenia, upper respiratory tract infection, tibia fracture, and skin and subcutaneous tissue disorders; these events were experienced by 4 (1.8%) participants. In the 2010-2011 TIV group, Grade 3 unsolicited non-serious AEs were reported for nasopharyngitis, sinusitis, rhinorrhoea, and sneezing; these events were experienced by 2 (0.9%) participants. In the investigational TIV group there were no reports of Grade 3 unsolicited non-serious AEs.


QIV 2.7% (6/225)

2010-2011 TIV 2.7% (6/225)

Investigational TIV

1.8% (4/225)


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Unsolicited adverse reactions in the QIV group: diarrhoea (1), injection site haematoma (1), injection site induration (2), injection site pruritus (1), cough (1) and post-nasal drip (1) In the 2010-2011 TIV group: diarrhoea, injection site haematoma (1) injection site induration (3) injection site pain (1), injection site pruritus (1), Nasopharyngitis (1). In the Investigational TIV group: injection site haematoma (2), injection site pruritus (1).

Serious Adverse Events were recorded by 2 participants in the 2010-2011 TIV group (detached retina; cellulitis secondary to cat bite), and one in the Investigational TIV group (malignant melanoma). Neither report was considered related to vaccination.

4.2. Paediatric study4.2.1. Study QIV04

Study QIV04 was a phase III randomised trial including children 6 months to < 9 years of age stratified into two age groups: 6 months to < 36 months of age and 3 years to < 9 years. Children 6 to < 36 months of age were administered 0.25-mL doses containing 7.5 g HA of each antigen. μChildren 3 to < 9 years of age were administered 0.5-mL doses containing contains 15 g HA or μeach antigen. Previously vaccinated children received one intramuscular dose of vaccine. Previously unvaccinated children received two doses of the assigned vaccine the same volume as the first vaccination, 28 to 35 days after first vaccination.

Study groups and numbers included were: Group 1: Licensed 2010-2011; N = 734, Group 2: Investigational TIV; N = 721, Group 3: QIV; N = 2892.

Safety assessment included documentation of:

Immediate adverse events within 20 minutes post vaccination

Solicited injection site reactions from days 0 to 3 post vaccination

Solicited systemic reactions from days 0 to 7 post vaccination

Non-serious and adverse events and relatedness assessed by the investigator between Visits 1 and 2 for those receiving one dose and between Visits 1 and 3 (28 – 35 days after visit 2) for those receiving 2 doses

Serious adverse events from Day 1 for 6 months after the final vaccination.

Discontinuations due to adverse events

Adverse events of special interest as for Study QIV03 with addition of febrile convulsions.

Events recorded differed by age for developmental reasons.

Parents/guardians were to measure body temperature once per day, preferably in the evening. Temperature was also to be measured at the time of any apparent fever. The highest observed daily temperature and the route of measurement were to be recorded. The preferred route for this trial was rectal for participants 6 months to ≤ 23 months of age and oral/axillary for participants 24 months of age or older. Tympanic thermometers were not to be used.

For all systemic reactions but fever, participants or parents/guardians recorded the graded intensity level in the diary card. For fever, they recorded the body temperature, and the classification as Grade 1, 2, or 3 was assigned by the statistician.

For the subjective reaction of pain due to injection site reactions, participants or parents/guardians recorded the graded intensity level. For the measurable reactions of redness and swelling, they recorded the size of the reaction; classification as Grade 1, 2, or 3 was assigned by the statistician.


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4.2.1.1. Results 6 to < 36 months

Immediate unsolicited adverse events

QIV 7 (0.6%)

2010-2011 TIV 2 (0.6%)

Investigational TIV 2 (0.6%)

All immediate unsolicited events were considered vaccine related. The most frequently reported were irritability (QIV, 3 [0.2%]; 2010-2011 TIV, 2 [0.6%]; investigational TIV, 1 [0.3%]), and somnolence (QIV, 3 [0.2%]; 2010-2011 TIV, 1 [0.3%]; investigational TIV, 0 [0.0%]).


QIV 720 (62.6%)

2010-2011 TIV 165 (57.1%)


Tenderness was assessed in participants aged 6 months to ≤ 23 months and pain was assessed in participants 24 months to < 36 months; erythema and swelling were collected for all participants aged 6 months to < 36 months.

The most frequently reported were pain (QIV, 297 [57.0%] of participants; 2010-2011 TIV, 68 [52.3%]; investigational TIV, 75 [50.3%]) and tenderness (QIV, 340 [54.1%]; 2010-2011 TIV, 77 [48.4%]; and investigational TIV, 72 [49.7%]. Most reactions started between Day 0 and Day 3 and lasted from 1 to 3 days.

Grade 3 solicited injection site reactions

QIV 20 (1.7%)

2010-2011 TIV 4 (1.4%)


The most common grade 3 solicited injection site reactions were pain: QIV group: 5 [1.0%]; 2010-2011 TIV group: 1 [0.8%]; investigational TIV group; 4 [2.7%], tenderness QIV group: 12 [1.9%]; 2010-2011 TIV group: 3 [1.9%], erythema QIV group: 2 [0.2%] and swelling QIV group: 2 [0.2%]. There were no reports of Grade 3 erythema or swelling in the 2010-2011 TIV group and there were no reports of Grade 3 tenderness, erythema, or swelling in the investigational TIV group.


QIV 682 (59.2%)

2010-2011 TIV 175 (60.6%)

Investigational 157 (53.4%)


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TIV

Grade 3 solicited systemic reactions

QIV 84 (7.3%)

2010-2011 TIV 16 (5.5%)

Investigational TIV

21 (7.1%)

Vomiting, abnormal crying, drowsiness, loss of appetite, and irritability were collected for children 6 months to ≤ 23 months of age. Headache, malaise, and myalgia were collected for those 24 months to < 36 months of age; fever was collected for all children 6 months to < 36 months of age.

The most commonly reported solicited systemic reactions were irritability (QIV, 339 [54.0%]; 2010-2011 TIV, 84 [52.8%]; and investigational TIV, 77 [53.5%]), and malaise (QIV, 197 [38.1%]; 2010-2011 TIV, 45 [35.2%]; and investigational TIV, 48 [32.4%]). Most solicited systemic reactions started between Day 0 and Day 3 and lasted from 1 to 3 days.

For children 6 months to < 36 months Grade 3 events were reported as shown in Table 14. For those less than 23 months, abnormal crying and irritability were the most common. For those 24 to < 36 months, malaise was the most common grade 3 event. Difficulty in assessing a young child’s subjective findings is acknowledged. For fever, the method of measurement may have differed. Preferred method was stated in the protocol, but may not have been used by the parents.

Table 14. Grade three solicited systemic adverse events in children 6 months to < 36 months.

QIV N = 148 2010 – 2011 TIV N = 310

Investigational TIV

Fever1,2 24/1148 (2.1%) 5/288 (1.7%) 6/293 (2%)

Vomiting2 6/628 (1.0%) 1/159 (0.6%) 0/144 (0%)

Crying abnormal2 21/628 (3.3%) 3/159 (1.9%( 3/144 (2.1%)

Drowsiness 2 8/628 (1.3%) 1/159 (0.6%) 1/144 (0.7%)

Headache1 3/517 (0.6%) 0/128 (0%) 0/148 (0%)

Appetite lost2 11/628 (1.8%) 3/159 (1.9%) 1/144 (0.7%)

Malaise1 24/517 (4.6%) 2/128 (1.6%) 4/148 (2.7%)

Myalgia1 10/517 (1.9%) 2/128 (1.6%) 4/148 (2.7%

Irritability2 20/628 (3.2%) 5/159 (3.1%) 4/144 (2.8%)


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QIV N = 148 2010 – 2011 TIV N = 310

Investigational TIV

1: assessed in children 24 - < 36 months; 2: assessed in children ≤ 23 months of age

Unsolicited non-serious adverse event

QIV 678 (55.4%)

2010-2011 TIV 175 (56.5%)


The most commonly reported unsolicited non-serious AEs were cough (160 [13.1%]) and pyrexia (123 [10.1%]) for the QIV group, cough (37 [11.9%]) and upper respiratory tract infection (33 [10.6%]) for the 2010-2011 TIV group, and cough (39 [12.7%]) and pyrexia (33 [10.7%]) for the investigational TIV group.

Unsolicited non-serious adverse reactions

QIV 76 (6.2%)

2010-2011 TIV 15 (4.8%)


The most commonly reported unsolicited non-serious adverse reactions were injection site haematoma for the QIV group (23 [1.9%]), injection site haematoma and rhinitis for the 2010-2011 TIV group (each 3 [1.0%]), and diarrhoea for the investigational TIV group (5 [1.6%]). The majority were Grade 1 or 2 in intensity; Grade 3 reactions were reported in the QIV: 6 [0.5%] and investigational TIV groups: 2 [0.6%].

Adverse events leading to study discontinuation

QIV 4 (0.3%)

2010-2011 TIV 3 (1.0%)


Serious adverse event in 6 month follow-up

QIV 30 (2.5%):

2010-2011 TIV 4 (1.3%)


In the QIV group one serious adverse event was considered vaccine related (croup). No event was considered vaccine related in the 2010 – 2011 TIV group. In the Investigational TIV group one SAE was considered vaccine related, a febrile seizure occurring 8 hours post-vaccination.


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There was one death by drowning in the 2010-2011 TIV group considered unrelated to vaccination.

4.2.1.2. Results – 3 to < 9 Years

Unsolicited immediate adverse events

QIV 5 (0.3%)

2010-2011 TIV 0 (0.0%)


All unsolicited immediate adverse events were considered vaccine related. There were single reports of dizziness, pre-syncope, somnolence, irritability, cough, decreased appetite and systolic blood pressure increased.


QIV 1118 (70.2%)

2010-2011 TIV 294 (71.7%)


Pain was the most commonly reported solicited injection site reaction (QIV 1061 [66.6%] participants; 2010-2011 TIV, 265 [64.6%]; investigational TIV, 254 [63.8%)]. Most solicited injection site reaction started between Day 0 and Day 3 and lasted from 1 to 3 days.

Grade 3 solicited injection site reactions were reported for pain (QIV, 33 [2.1%] participants; 2010-2011 TIV, 8 [2.0%]; investigational TIV, 11 [2.8%]); erythema (QIV, 29 [1.8%]; 2010-2011 TIV, 5 [1.2%]; investigational TIV, 7 [1.8%]), and swelling (QIV, 22 [1.4%]; 2010-2011 TIV, 5 [1.2%]; investigational TIV, 7 [1.8%]).


QIV 847 (53.2%)

2010-2011 TIV 201 (48.9%)


Except for fever, onset of solicited systemic reactions was usually between Day 0 and Day 3. The percentages of participants with fever between Days 0 and 3 vs. Days 4 and 7 were: QIV group (4.5% vs. 2.5%), 2010-2011 TIV group (3.7% vs. 3.4%), and investigational TIV group (3.5% vs. 4.0%), respectively. Most reactions lasted from 1 to 3 days.

Grade 3 reactions were reported for fever (QIV, 34 [2.1%] participants; 2010-2011 TIV, 5 [1.2%]; investigational TIV, 3 [0.8%]); headache (QIV, 35 [2.2%]; 2010-2011 TIV, 11 [2.7%]; investigational TIV, 8 [2.0%]), malaise (QIV, 87 [5.5%]; 2010-2011 TIV, 23 [5.6%]; investigational TIV, 20 [5.0%]), and myalgia (QIV, 52 [3.3%]; 2010-2011 TIV, 11 [2.7%]; investigational TIV, 11 [2.8%]).


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QIV 687 (41.2%)

2010-2011 TIV 177 (41.7%)



QIV 100 (6.0%)

2010-2011 TIV 35 (8.3%)


The most commonly reported unsolicited non-serious adverse reactions were injection site haematoma for the QIV group 23 [1.9%], injection site haematoma and rhinitis for the 2010-2011 TIV group: each 3 [1.0%], and diarrhoea for the investigational TIV group, 5 [1.6%]. The majority were Grade 1 or Grade 2 in intensity. Grade 3 reactions were reported in the QIV 6 [0.5%] and investigational TIV groups (2 [0.6%].

Adverse events leading to study discontinuation

QIV 6 (0.4%)

2010-2011 TIV 0 (0.0%)


Serious adverse events in 6 month follow-up

QIV 11 (0.7%)

2010-2011 TIV 3 (0.7%)


One serious adverse event in the 2010-2011 TIV group was considered vaccine related (febrile seizure) No events in the other two groups were considered related.

4.2.1.3. Adverse events of special interest – 6 months to < 9 years

Febrile seizures were the only adverse events of special interest reported during the six month follow-up. There were 13 participants with 14 reports of febrile seizures.

In the 6 month to < 36 month age group, 7 (0.6%) participants in the QIV group, 1 (0.3%) in the 2010-2011 TIV group, and 2 (0.6%) in the investigational TIV group experienced at least 1 febrile seizure. In the 3 year to < 9 year age group, 1 (0.1%) in the QIV group, 1 (0.2%) in the 2010-2011 TIV group, and 1 (0.2%) in the investigational TIV group experienced at least 1 febrile seizure.

Two of these events occurred within 24 hours of vaccination, 1 each in the 6 month to < 36 month group and the 3 year to < 9 year group, and were considered related to vaccination. Of


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the remaining events, 1 occurred 5 days post vaccination, 5 occurred 7 to 28 days post-vaccination, and 6 occurred after more than 56 days post-vaccination.

Among the 14 reports, 13 were associated with ongoing infections or suspected infections, 5 had a history of febrile seizures or family history of febrile seizures, and 9 had body temperature reported above 101.5°F (38.6°C). Most participants recovered the same day or the next day with treatment of ibuprofen and/or acetaminophen and/or antibiotics.

One child in the QIV group aged between 6 and < 36 months who experienced a febrile convulsion considered unrelated to vaccination, was discontinued from study by her parent on day 12 due to a non-serious adverse event (fever on Day 3).

Based on the overall safety evaluation in this study, no new concerns of febrile seizures were identified by the investigators.

4.2.1.4. Sponsor’s conclusion

In the adults studies, the safety profile for QIV was similar to the currently licensed 2010-2011 TIV vaccine Fluzone and the investigational TIV. No safety concerns were identified.

In the paediatric study, solicited injection site and systemic reactions, unsolicited AEs, and SAEs were reported at similar rates between the QIV group and the 2 control TIV groups. The safety data from study QIV04 did not raise any safety concerns for QIV. Overall, the safety data demonstrated that the addition of the alternate-lineage B strain to existing TIV did not alter the reactogenicity and tolerability profiles of the vaccine. It was reassuring that rates of fever and febrile seizures were not higher among children administered QIV compared with those among children administered the control TIVs.


The findings, as presented in the dossier, accord with the applicant’s conclusion.

5. Clinical questions

5.1. Question 1Are the vaccines used in Studies GRC43, QIV03 and QIV04 exactly the same as the vaccine proposed for registration? The description of QIV in the three submitted studies includes mention of gelatine. The draft product information does not mention gelatine, the expert in Module 2.5 states that the product does not contain gelatine and the Module 1 Application Form states that there is no component of animal origin.

5.2. Question 2Explanation has briefly been given as to why lot-to-lot consistency study was not required by CBER. Explanation as to why such study would not be required for Australian purposes is requested, given that Fluzone is not registered in Australia.

5.3. Question 3In each of the studies, no justification for choice of the non-inferiority and superiority margins could be located. Please include justification in response to the Round 1 Clinical Evaluation Report.


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5.4. Question 4In Study QIV04 protocol version 5, the observational safety objectives included collection and analysis of clinical information on the number of all-cause hospitalizations, emergency room visits, and unscheduled physician visits during the 6 months following the final vaccination. Information regarding the incidence of influenza and influenza like illness in participants who sought medical help in the 6 months following vaccination is of interest.

The following statement was included in Module 2.5 in a footnote: “The observational objectives for Studies QIV03 and QIV04 incorrectly stated that Sanofi Pasteur would descriptively analyze hospitalizations, emergency room visits, and unscheduled physician visits. Rather, hospitalizations, emergency room visits, and unscheduled physician visits were collected and analyzed as unsolicited AEs, AESIs, and SAEs”.

Reports of Influenza like illness and influenza are spread throughout numerous tables. It was difficult to get an overall picture of the incidence of these from the multiple locations. Please collate and present the incidences between visit 1 and end of 6 month follow-up, and timing in relation to vaccination. If possible, report the strain of influenza virus causing illness.

5.5. Question 5Please explain why the proposed tradename is FluQuadri rather than Fluzone Quadrivalent. In a mobile world, standard naming is considered to be preferable.

5.6. Question 6Currently The Australian Immunisation Schedule recommends influenza vaccination for infants from 6 months of age. Please provide information on the numbers of infants aged between 3 and 6 months included in QIV04, the immunogenicity as safety results and adverse event profiles in that age range.

5.7. Question 7Please justify the statement in the Product Information: “If GBS has occurred within 6 weeks of previous influenza vaccination, the decision to give FluQuadri/FluQuadri Junior should be based on careful consideration of the potential benefits and risks.”

5.8. Question 8The applicant is requested to respond to the reviewer’s comments in the Product Information Section.

5.9. Question 9Sanofi Pasteur is requested to respond to the reviewer’s comment in the CMI Section.


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6. Second round evaluation of clinical data submitted in response to questions

6.1. Question 16.1.1. S31 response

The quadrivalent inactivated influenza vaccine (QIV) used in Studies QIV03 and QIV04 did not contain gelatin and were manufactured using the QIV process proposed for registration (ie, using validated and licensed process for US-registered Fluzone Quadrivalent influenza vaccine). The QIV used in Study GRC43 contained gelatin and was manufactured identically as the comparator trivalent influenza vaccines used in each of the three studies (ie, using validated and licensed processes for US-registered trivalent Fluzone vaccine).

6.1.2. Evaluator’s comment

Response accepted.


Fluzone influenza virus vaccines have been licensed since 16 September 1947 (international birth date) and have a well-documented and robust manufacturing process.

Lot-to-lot consistency has previously been demonstrated during the clinical development of US-registered Fluzone High-Dose and Fluzone Intradermal vaccines for immunogenicity. In addition, the safety profiles among the lots evaluated during the clinical development of Fluzone High-Dose vaccine were similar as were the safety profiles among the lots evaluated during the clinical development of Fluzone Intradermal vaccine.

The clinical consistency of Fluzone vaccines, including FluQuadri, is further supported by process, formulation, and filling validations for all Sanofi Pasteur influenza product lines. These validations help ensure manufacturing consistency. Indeed, the manufacture of Fluzone vaccines consistently meets all critical quality attributes in testing. Manufacturing consistency is further confirmed by results of annual stability testing of representative vaccine lots over a product’s lifespan. Sanofi Pasteur’s well-controlled and cGMP- compliant production of influenza vaccines has permitted some health authorities to confidently release influenza vaccines at the final bulk stage given the proven purity, safety, and potency of the final products over their approved lifespan.

Moreover, multiple annual studies of Fluzone vaccines have demonstrated that these vaccines are safe and immunogenic. In addition, studies have demonstrated that Fluzone vaccines provide substantial protection against influenza infection and illness.

Although Fluzone vaccines have not been previously registered in Australia, approximately 1 billion doses of Fluzone vaccines have been distributed worldwide during the past two decades. As documented in the most recent Periodic Benefit-Risk Evaluation Report, the favorable benefit-risk profile of Fluzone vaccines has remained constant. Moreover, there has not been any evidence to suggest that Fluzone vaccines would perform any differently in the Australian population.

All these points taken together provide strong rationale why FluQuadri could be registered without clinical lot to lot consistency in Australia.


Accepted.


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The non-inferiority margins used in Studies GRC43, QIV03, and QIV04 were based on CBER guidance, which is provided in the document entitled, Guidance for Industry: Clinical Data Needed to Support the Licensure of Seasonal Inactivated Influenza Vaccines, available at <http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInforma tion/Guidances/Vaccines/ucm091990.pdf>.

Recommendations for the co-primary endpoints include the following:

“The upper bound of the two-sided 95% CI of the ratio [of] the GMTs (GMTU.S. licensed vaccine/GMTnew

vaccine) should not exceed 1.5.” (The corollary of this is a lower bound of the two-sided 95% CI of the ratio of the GMTs [GMTQIV/GMTTIV] that exceeds 0.66.)

“The upper bound of the two-sided 95% CI [of] the difference between the seroconversion rates (SeroconversionU.S. licensed vaccine – Seroconversionnew vaccine) should not exceed 10 percentage points.” (The corollary of this is a lower bound of the two-sided 95% CI of the difference between the seroconversion rates (SeroconversionQIV - SeroconversionTIV) that exceeds -10 percentage points.).

6.3.1.1. Superiority margins

CBER recommended that Sanofi Pasteur evaluate superiority of B-strain responses induced by QIV compared with TIV that does not contain the corresponding B strain as secondary and observational objectives in Studies QIV04 and QIV03, respectively.

CBER required that the following margins be used to demonstrate superiority of B-strain responses induced by QIV compared with TIV (i.e., “to exclude non-inferiority of the TIV to the QIV” as per the agency’s comments pertaining to Sanofi Pasteur’s development plans for QIV):

The lower bound of the two-sided 95% CI of the ratio of GMTs for the B strains (GMTQIV/GMTTIV) should exceed 1.5.


Response accepted.


The incidences of influenza and influenza-like illness in QIV04 have been collated and appear in the table below. These events were captured as unsolicited adverse events during the 28 (window, 28-35) days following vaccination. The 6-month safety follow-up in QIV04 was established to capture serious adverse events (SAE) only. There were no cases of influenza or influenza-like illness reported as SAEs during the 6-month follow-up period. Information regarding the influenza strain causing illness was not systematically collected.


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http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInforma%20tion/Guidances/Vaccines/ucm091990.pdf

http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInforma%20tion/Guidances/Vaccines/ucm091990.pdf


Table 15. The incidences of influenza and influenza-like illness in QIV04


Response accepted. Systematic collection of such efficacy information would have been desirable.


Fluzone Quadrivalent was initially licensed in the United States, but Sanofi Pasteur is now seeking to expand licensure of the vaccine 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.

Therefore, since the majority of the countries that will license 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.


Accepted.


Infants younger than 6 months of age were not eligible for inclusion in QIV04. Accordingly, data regarding the immunogenicity and safety of QIV in this age group are not available. Please refer to the inclusion and exclusion criteria found in the QIV04 Clinical Study Report.


Response accepted.


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Sanofi Pasteur proposes that no changes to the statement regarding GBS are made. The justification is that the text, as written, is consistent with our core labeling document, as well as the language that has been approved by FDA for the reference product, Fluzone Quadrivalent. The GBS statement is also consistent with labeling language used for other manufacturers’ influenza vaccines that are registered in Australia.

According to the US Advisory Committee on Immunization Practices recommendations (MMWR 2013;62(RR07);1-43), “As a precaution, persons who are not at high risk for severe influenza complications…and who are known to have experienced GBS within 6 weeks of influenza vaccination generally should not be vaccinated. As an alternative, physicians might consider using influenza antiviral chemoprophylaxis for these persons. However, the benefits of influenza vaccination might outweigh the risks for certain persons who have a history of GBS and who also are at high risk for severe complications from influenza.”

According to Sejvar et al. (Vaccine 2011;29:599–612), “While duration of surveillance for potential development of GBS following an antecedent event is arbitrary, based upon available epidemiologic data, the Working Group suggests that a duration of 6 weeks following any identified antecedent event would represent a reasonable period of surveillance, beyond which biological plausibility of an association with an identifiable antigenic stimulus (e.g., infectious illness, vaccination) declines. The evidence for the most appropriate time interval is limited, largely based on certain studies of the 1976–1977 influenza vaccine.”


It is accepted that the evidence is limited. It is accepted that the Australian Product Information of two other influenza vaccines include the same information as proposed for this quadrivalent vaccine though the advice is at variance with Sanofi Pasteur’s TGA approved Vaxigrip Product Information. However, as the precedent has been set, it appears there are no grounds for objection.


The Sponsor’s response was included in Appendix 21 of the S31 response.


The replies to the responses are included in Part B2. The responses are accepted.


The responses are included in Part B2.


There is no objection to the revised Consumer Medicine Information.

1Not included with this AusPAR.2 Not included in this AusPAR.


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6.10. Summary and discussion Sanofi Pasteur has applied to register the new chemical entity, FluQuadri, an inactivated split virion influenza vaccine suspension for injection, 0.5mL pre-filled syringe and 0.25 mL pre-filled syringe. The vaccine includes two, recommended A strains, the recommended B strain, and a second B strain of the complementary B lineage. The intended use is from 3 months3 of age, based on official recommendations and dosed as for the trivalent vaccine.

Sanofi Pasteur’s quadrivalent vaccine is an extension of the trivalent influenza vaccine, Fluzone, which is manufactured and licensed in the United States. Antigen production for the quadrivalent vaccine is the same as the manufacturing process for Fluzone trivalent influenza vaccines.

In essence the development rationale was that, while annual influenza vaccination is the most effective method of prevention of influenza to date, the current influenza vaccination schedule includes only one of the two influenza B phylogenetic lineages with resultant risk of mismatch with the dominant circulating B strain. Modelling suggests that inclusion of two B/strains may reduce mortality and morbidity due to influenza caused by the B/strain not included in the seasonal trivalent vaccine.

In support of the application, three active-controlled, randomised studies undertaken in the United States were supplied. GRC43 a phase II open-label study included adults ≥ 18 years, QIV03 and QIV, phase III partially blind studies, included respectively, adults ≥ 65 years and children from 3 months4 to < 9 years.

The applicant argued that immunogenicity of QIV could be inferred from demonstration of the safety and immunogenicity profiles of QIV in children 6 months to < 9 years of age and in adults 18 years of age and older. This is accepted.

The objectives of the three studies are summarised below. With regard to immunogencity, there was a consistent approach to definition, measurement of antibodies and statistical analysis between studies.

Table 16. Study objectives

Study GRC43 Study QIV03 Study QIV04

Non-inferiority GMT Primary (B/strains assessed)

Primary (A and B strains)

Primary (A and B strains)

Non-inferiority Seroconversion

N/A Observational Primary

Superiority GMT N/A Observational Secondary

Superiority Seroconversion

N/A Observational Secondary

Antibody Responses Observational Observational Observational

CPMP criteria Observational N/A N/A

Safety Observational Observational Observational

3 Erratum: 6 months4 Erratum: 6 months


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6.10.1. Study GRC43

The participants aged ≥ 18 years were randomised to one of three groups of 190 and received one 0.5 mL intramuscular dose of vaccine as follows.

Group 1 2009-2010 licensed TIV

Group 2 2008-2009 licensed TIV

Group 3 Candidate quadrivalent

The per-protocol population included between 98.4 to 100% of randomised participants. Demographics were evenly spread. Mean ages were 55.0 – 56.7 years. Females accounted for approximately 2/3; Caucasian accounted for 87.4%; to 91.1%.

The primary objective was met. Non-inferiority in terms of GMT was shown for both B strains. The quadrivalent vaccine met each of the 3 CPMP criteria for each age group. A generally greater antibody response to vaccination was reported in individuals 18 to 60 years of age compared to those age ≥ 61 years.

There were no unexpected safety findings and no new safety signal detected. There were no reports of immediate reactions, serious adverse reactions including deaths, no events of special interest and no discontinuations occurred. Solicited injection site reactions and systemic reactions were no more common in the QIV group than in the TIV groups. Grade 3 solicited symptoms and non-serious grade 3 unsolicited adverse reactions were infrequent in all groups.

6.10.2. Study QIV03

Participants aged ≥ 65 years were randomised to one of three groups of 225 and received one intramuscular dose of assigned vaccine as follows:

Group 1 Quadrivalent vaccine

Group 2 Investigational TIV with alternate B/strain

Group 3 2010 – 2011 licensed TIV

The per-protocol population included between 97.3 to 98.2% of randomised participants. Demographics were similar across groups, the mean age of the three groups was approximately 72 years, approximately 90% were Caucasian.

The primary objective was met. Non-inferiority in terms of GMT was shown for all four strains. Observational objectives, non-inferiority in terms of seroconversion and superiority in terms of GMT and seroconversion were met with the exception of superiority of QIV GMTR for B/Brisbane.

Pre-vaccination GMTs were measurable for each strain with increase in antibody levels post-vaccination for all four virus strains. Responses for B strains were at lower levels than for A strains.

There was no protocol defined yardstick for evaluation of antibody responses. The guideline, CPMP/BWP/214/96 which has been adopted in Australia, was current at the time of this study and is considered relevant to the Australian setting. Assessment against CPMP/BWP/214/96 criteria is as follows:

A/California: Each vaccine passed each criterion

A/Victoria: Each vaccine passed each criterion


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B/Florida: The QIV and the TIV containing the relevant antigen just passed all three criteria while the TIV without B/Florida passed none of the criteria

B/Brisbane: The geometric mean increase criterion was passed by QIV but by neither of the TIV vaccines. No vaccine passed the seroconversion criterion. Each of the vaccines passed the seroprotection criterion including the vaccine which did not contain B/Brisbane.

No unexpected safety findings were reported and there was no new safety signal reported. No serious adverse event was considered vaccine related. There were no reports of death, no reports of adverse events of special interest or no immediate reactions were reported. Solicited injection site reactions were more common in the QIV group; incidences of solicited systemic reactions were similar for QIV and the 2010 – 2011 TIV group. Grade 3 solicited and unsolicited reactions were infrequent.

6.10.3. Study QIV04

Participants were randomised to one of three groups as shown below. Enrolment was stratified by age: 3 to < 36 months and 3 to < 9 years of age.

Group 1 2010 – 2011 TIV N = 800

Group 2 Investigational TIV N = 800

Group 3 QIV N = 3340

In total 4363 were randomized; 15 (0.3%) were randomized but not vaccinated; 4013 (92.0%) completed the study. The per-protocol population included 80.6% in the QIV group, 79.1% in the 2010-2011 TIV group, and 82.6% in the investigational TIV.

Demographic characteristics were evenly spread. A total of 2210 males and 2153 females enrolled. The mean ages were between 49.6 and 49.8 months. The majority were Caucasian QIV, 58.3%; 2010-2011 TIV, 58.8%; investigational TIV, 57.5%, or Black 20.5%; 2010-2011 TIV 20.0%; investigational TIV 19.2%.

The primary objectives were met. Non-inferiority of QIV GMTs and seroconversion rates was shown for each strain for each age group and overall. The secondary objectives were met. Superiority of QIV was shown for each strain overall and for both age groups for post-vaccination GMTs and seroconversion rates.

Pre-vaccination GMTs were measurable for each strain with increase in antibody levels demonstrated for all four virus strains post-vaccination. Children in both age strata had a greater response to the A strains than the B strains. Children aged 3 to < 9 years had greater responses to all antigens than those aged 6 months to < 36 months. Those children who received two doses had greater response than those who received one dose.

As with Study QIV03, there was no protocol defined measure for assessment of responses. According to CPMP/BWP/214/96, there are no criteria for children; however, the results are discussed here in relation to adult criteria.


A/California: All adult criteria met by each vaccine

A/Victoria: All adult criteria met by each vaccine

B/Brisbane: All adult criteria met by QIV and TIV (Brisbane), no criteria met by TIV (Florida)


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B/Florida: All adult criteria met by QIV, GMTR and seroconversion adult criteria met by TIV (Florida) and seroprotection rate elderly criterion met by TIV (Florida) No criteria met by TIV (Brisbane).

6 to < 36 months

A/California: These results passed as the criteria 18 to 60 year old adults

A/Victoria: These results passed all the criteria for 18 to 60 year old adults

B/Brisbane: All criteria passed by QIV for adults for QIV and none were passed for the TIV not including B/Brisbane. The TIV containing B/Brisbane passed the adult criteria for GMTR and seroconversion rate and passed the elderly criterion for seroprotection.

B/Florida: QIV and TIV (Florida) passed GMTR and seroconversion criteria. The seroprotection criteria for adults and the elderly were failed by all three vaccines.

Results for B/Florida over all age strata were also borderline appearing to be attributable to the results for the youngest participants. However, results for QIV were if anything marginally better than those for TIVs.

3 to < 9 years

A/California: Result met all adult criteria

A/Victoria: Results met all adult criteria

B/Brisbane: All adult criteria were met for QIV, GMTR and seroprotection criteria were met by TIV (Brisbane), GMTR elderly criterion was met by TIV (Florida). The seroprotection criterion for both adults and the elderly was not met by TIV (Florida)

B/Florida: All adult criteria were met by QIV and TIV (Florida). TIV (Brisbane) met elderly criterion for GMTR, but failed both seroconversion and seroprotection criteria for adults and the elderly.

One dose

A/California: All adult criteria met by each vaccine

A/Victoria: All adult criteria met by each vaccine

B/Brisbane: QIV vaccine met 2 adult criteria, GMTR and seroconversion and passed elderly criterion for seroprotection. TIV (Brisbane) passed GMTR and seroconversion adult criteria and elderly criterion for seroprotection. TIV (Florida) passed none of the criteria

B/Florida: Both QIV and TIV (Florida) passed adult criteria for GMTR and seroconversion and passed elderly criteria for seroprotection. TIV (Brisbane) passed none of the criteria.

Two doses - all ages

A/California: All adult criteria passed for each vaccine

A/Victoria: all adult criteria passed for each vaccine

B/Brisbane: All adult criteria passed for QIV and TIV (Brisbane). TIV (Florida) failed all three criteria

B/Florida: QIV passed all adult criteria, TIV (Florida) passed adult criteria for GMTR and seroconversion rate and passed elderly criterion for seroprotection. TIV (Brisbane) passed none of the criteria.

In relation to the safety objective, there were no unexpected safety findings and the safety profile of the quadrivalent vaccine was similar to that of the trivalent vaccines.

Immediate reactions were documented in 0.6% of participants in each group


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Solicited local reactions were more common in the QIV group than the TIV groups for children aged 3 to < 36 months; however significance of this was not tested. Otherwise there was no consistent difference apparent in solicited symptoms reported. Grade 3 reactions solicited local reactions were reported by < 2% of each group. Grade 3 solicited systemic reactions were reported by similar percentages of participants in the QIV and investigational TIV groups

Unsolicited adverse reactions were reported by similar percentages

Discontinuation due to adverse event was reported for 0.3% of the QIV group, 1% or the 2010 – 2011 TIV group and 0% of the investigational TIV group

A serious adverse event considered vaccine related within the 6-month follow-up period was reported for 1 child in the QIV group (croup) and one in the investigational TIV group (febrile convulsion). There were none reported in the 2010-2011 TIV group

One death (drowning) was unrelated to vaccination

Febrile convulsions were the only events of special interest reported. There were 14 reports of febrile seizures involving 13 participants (8 in the QIV group, 2 for the 2010-2011 TIV group and 3 in the investigational TIV group). Two occurred within 24 hours of vaccination and were considered vaccine related: one child vaccinated with the 2010 – 2011 TIV one with the investigational TIV.

The only change to the conduct of the study considered to have possible impact on study objectives was included in protocol version 4 relating to use of 0.5 mL prefilled single vials rather than 0.25 mL prefilled syringes for use in children 6 months to < 36 months, which resulted in reliance on staff accuracy in measurement and thus had the potential to impact the results of the study.

Assessment of safety in the youngest children was complicated by developmental language difficulty. Subjective assessment of adverse events for very young children can be difficult particularly for the youngest children.

6.11. ConclusionThe immunogenicity and safety results of the three studies support the application. Efficacy is inferred; however, future study of efficacy is recommended.

7. Second round benefit-risk assessment

7.1. BenefitsInfluenza is a highly contagious, acute viral respiratory disease with epidemic potential, affecting all age groups but with particular risk for complications including death in the very young, older adults and individuals with underlying health problems. Influenza may also extract an economic toll due to time lost from work, and increased use of medical facilities.

To date, vaccination has proven the most effective form of prevention against influenza. Theoretically, inclusion of two B/strains may increase vaccine efficacy and reduce the potential for mismatch between vaccine and circulating B strains.

Sanofi Pasteur’s trivalent influenza vaccine, Fluzone, manufactured similarly to the candidate QIV, has long a long history of safe use in the United States.


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The reported adverse reactions were predominantly of low grade severity and short duration. The safety profile of QIV reported in the three submitted studies was similar to that of the trivalent comparators. No new safety signal was reported.

7.2. RisksAdverse reactions were common. The numbers, by age strata included in the studies may have been too small to fully determine the safety profile of QIV with respect to rare events.

The antibody response to B/strains appeared considerably less than that for A/strains and response to each was less for children < 3 years of age and for adults ≥ 65 years, i.e. those at greatest risk of influenza morbidity and mortality. Efficacy for B/strains remains to be tested. There is a risk that the added antigen will not result in increased efficacy in these individuals.

The price of the quadrivalent vaccine to the consumer in comparison to the trivalent vaccine is unknown. Added cost would be required to be offset by added efficacy.

7.3. BalanceThe balance is considered to lie on the side of potential benefit.

8. Second round recommendation regarding authorisation

Registration of FluQuadri is recommended for the indication proposed.

An efficacy study is recommended with particular attention to efficacy in children less than 3 years of age and adults ≥ 65 years.


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Therapeutic Goods AdministrationPO Box 100 Woden ACT 2606 Australia

Email: [email protected] Phone: 1800 020 653 Fax: 02 6232 8605http://www.tga.gov.au

http://www.tga.gov.au/

mailto:[email protected]

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