Public Assessment Report. Scientific discussion. Fluarix Tetra (Influsplit Tetra) DE/H/1939/001

Transcription

1 CMDh/224/2005 February 2012 Public Assessment Report Scientific discussion Fluarix Tetra (Influsplit Tetra) Monovalent inactivated split-virion: A/H1N1 Monovalent inactivated split-virion: A/H3N2 Monovalent inactivated split-virion: B strain (Victoria lineage) Monovalent inactivated split-virion: B strain (Yamagata lineage) DE/H/1939/001 December 2014

2 This module reflects the scientific discussion for the approval of Fluarix Tetra. The procedure was finalised at For information on changes after this date please refer to the module Update (Chapter VI). Updates since the PAR from December 2013 are highlighted in yellow. Minor editorial corrections are not highlighted. PAR Scientific discussion 2/15

3 I. INTRODUCTION Based on the review of the quality, safety and efficacy data, the Member States have granted a marketing authorisation for Influsplit Tetra (DE), Fluarix Tetra (AT, CZ, EL 1, ES, IT, SK, UK), FluarixTetra (FR), α-rix Tetra (BE, LU), suspension for injection, from GlaxoSmithKline GmbH & Co. KG, Munich, Germany. The marketing authorisation application (MAA) was started on with DE, UK and FR as a decentralised procedure and positively closed on Then, Fluarix Tetra was licensed through one mutual recognition procedure in the other Member States. The product is indicated for active immunisation of adults and children from 3 years of age for the preventions of influenza disease caused by the two influenza A virus subtypes and the two influenza B virus types contained in the vaccine. A comprehensive description of the indications and posology is given in the SmPC. The marketing authorisation has been granted pursuant to Article 28 of Directive 2001/83/EC as amended. II. QUALITY ASPECTS II.1 Introduction Fluarix Tetra is a quadrivalent influenza-virus vaccine, presented as suspension for injection in prefilled syringe, containing the split surface antigens of influenza viruses type A (California/7/2009 H1N1, Perth/16/2009 H3N2) and B (Brisbane/60/2008 [Victoria lineage], Brisbane/3/2007 [Yamagata lineage]). Its Anatomical Therapeutic Classification (ATC) is J07BB02. Fluarix Tetra contains purified haemagglutinin (HA) and neuraminidase (NA) antigens from the split surface of each of the four influenza virus strains, types A and B, as recommended annually for immunisation by the World Health Organisation (WHO), Center for Biologics Evaluation and Research (CBER) and the European Union for the Northern Hemisphere. At the time of application for the marketing authorisation, a recommendation for the second B strain had not yet been established and the company included the B strain from the opposite lineage from the official recommended strain in the formulation. The influenza virus strains are individually grown in embryonated chicken eggs and inactivated by formaldehyde treatment before purification of the split surface antigens and formulation without preservatives into a sterile suspension. The potency of the vaccine is expressed as the amount of the HA protein per dose. Each 0.5 ml of the vaccine has the following composition: Active Ingredient: Purified antigen fractions of Monovalent inactivated split-virion: A/H1N1 15 µg Monovalent inactivated split-virion: A/H3N2 15 µg Monovalent inactivated split-virion: B strain (Victoria lineage) 15 µg Monovalent inactivated split-virion: B strain (Yamagata lineage) 15 µg Other ingredients: 1 Issuance of national license pending PAR Scientific discussion 3/15

4 RRR- α-tocopheryl hydrogen succinate Polysorbate 80 Octoxinol 10 Sodium chloride Disodium phosphate dodecahydrate Potassium dihydrogen phosphate Potassium chloride Magnesium chloride hexahydrate Water for injections II.2 Drug Substance The drug substance is composed of inactivated split-virus antigen of each of the four strains recommended by the WHO for inclusion in the quadrivalent influenza vaccine. Two of these strains are from A subtypes and two of B subtypes. The second B strain belongs to the opposite lineage (Yamagata/Victoria) as the strain currently recommended for trivalent composition. Manufacture A master and a working seed were prepared for each of the virus strains, received from the WHO Reference centre. The manufacturing process for the monovalent bulk is identical to the manufacturing process for the monovalent bulks of the licensed product Fluarix and can be divided into four main parts: o Propagation of the working seed in fertilized hen`s eggs, harvesting and pooling of infected allantoic fluids o Splitting of the monovalent with sodium deoxycholate o Purification of the whole virus o Inactivation of the purified monovalent split virus using sodium deoxycholate and formaldehyde, followed by ultrafiltration and sterile filtration The process is derived from the Fluarix process and is the same. Control of Materials The following starting materials used in the production of the drug substance are of biological origin: influenza seed virus, eggs and sodium deoxycholate. The testing of the virus and the eggs is the same as for Fluarix. Sufficient detailed information has been provided on the control and source of the starting materials. The genetic stability of the working seeds has been satisfactorily addressed. Process validation Critical steps of the drug substance production process have been identified and are sufficiently controlled. Process consistency has been demonstrated on at least three commercial scale batches for each subtype. Inactivation studies performed on different strains have demonstrated that the proposed inactivation method (sodium deoxycholate and formaldehyde) results in complete inactivation. Characterisation and specification The structure of the inactivated monovalent bulks was studied by transmission electron microscopy and confirmed the predominance of disrupted virus particles after splitting. The active pharmaceutical ingredients in influenza subunit vaccines are viral haemagglutinin and neuraminidase proteins. Appropriate activity and quantity tests of these proteins were conducted. All analytical methods have been appropriately validated. PAR Scientific discussion 4/15

5 The monovalent bulks are filled and stored in 10 L glass type I containers with polypropylene caps or in 50 L plastic bags. Stability 12 months of stability has been granted for all subtypes. II.3 Medicinal Product Fluarix Tetra is a quadrivalent inactivated, split virion seasonal influenza vaccine. It contains four influenza strains, two A (A/H1N1 and A/H3N2) and two B (one each of the Victoria and Yamagata lineages) strains. The selection of strains follows recommendations by the World Health Organisation who started with the season 2012/2013 with official recommendations for a fourth influenza strain. Pharmaceutical development The Fluarix Tetra drug product development is based on GSK`s licensed seasonal trivalent influenza vaccine Fluarix, taking into consideration the addition of a fourth active substance. It is formulated to a minimum HA concentration of 15 µg HA per strain per 0.5 ml dose. The same excipients are found in both vaccines. There is no excipient of human or animal origin, or novel excipient in the vaccine. Manufacture of the product The manufacturing process for the Fluarix Tetra drug product has been developed based on the Fluarix drug product manufacturing process and consists of the following steps: o Formulation of the final bulk; o Transfer of the final bulk into GSK network for filling (when filling takes place outside the formulation site); o Filling (including stoppering) and inspections of the final containers; o Transfer of the final containers into GSK network for labeling and packaging (when labeling and packaging take place outside the filling site); o Labeling and packaging of the Fluarix Tetra final product. The process uses the same starting materials, equipment and facilities as Fluarix. The development of the manufacturing process is limited to the production scale-up and to technical adjustments during the formulation process. Product specifications Compliance with the product specifications has been shown on 7 batches and 10 final container lots of pilot and commercial scale. In addition to the classical SRD method an adapted SRD method has been developed for the two influenza B strains in the quadrivalent formulation. The adapted SRD assay should eliminate problems with cross-reactivity of the B Yamagata and B Victoria antisera. For Fluarix Tetra 2013/2014, it was consensus with the CMS to use the adapted SRD assay for release and stability follow-up. Further discussions between the NCA and the company were planned to decide with each strain change whether the classical or the adapted SRD assay is the most appropriate method. After the experiences with batch release data for the first commercial production (NH 2013/2014) and the assessment of the forced degradation studies with different B strains, the company demonstrated superiority of the adapted SRD method for the involved B strains. The company will inform NCA which method will be used for batch release during the next season based on the data that GSK will generate with a new combination, if one or the other B strain will be changed. Specifications for excipients and analytical procedures are in line with the Ph. Eur. Controls of final bulks (sterility, bacterial endotoxins, α-tcs content, Octoxinol 10 content, Polysorbate 80 content, residual formaldehyde, residual Ovalbumin, ph, volume) are acceptable. Methods are either in line with Ph. Eur. or validated. The proposed shelf-life of 12 months for the Fluarix Tetra final product by storage at 2 to 8 C could be granted. PAR Scientific discussion 5/15

6 II.4 Discussion on chemical, pharmaceutical and biological aspects Not applicable. III. NON-CLINICAL ASPECTS III.1 Introduction Nonclinical evaluation of Fluarix Tetra comprises very limited pharmacological data and a dedicated reproductive and developmental toxicity study. In addition, a supportive toxicity package generated with seasonal trivalent influenza vaccine formulations with and without adjuvant AS03 is provided. III.2 Pharmacology In a clinical setting, the non-adjuvanted quadrivalent influenza vaccine produced in Dresden (D-QIV) could induce satisfactory antibody responses to each vaccine antigens in adults and children and addition of the second B strain does not cause antigenic interference. Nonclinical general toxicity studies and clinical data do not reveal clinically important adverse effects on physiological functions. Safety pharmacology study is deemed unnecessary. III.3 Pharmacokinetics A pharmacokinetic study is not required for D-QIV. III.4 Toxicology Single-dose toxicity, repeated dose toxicity and local tolerance studies were conducted in rabbits with related vaccines that are manufactured using the same manufacturing process as used for D-QIV, including Fluarix, AS03-adjuvanted trivalent influenza vaccine and AS03-adjuvanted QIV. Overall, results of these studies were consistent from study to study: apart from a transient local inflammation at injection site primarily with adjuvanted formulations and irrespective of the amount of antigen tested (60 µg and 45 µg), intramuscular administration of these vaccines did not reveal evidence of other local and systemic toxicity. Two reproductive and developmental toxicity studies were performed in CD rats, using Dresden and Quebec seasonal trivalent and quadrivalent influenza vaccines. Repeated dosing at two fifths of the full human dose per occasion, on Days -28 and -14 before pairing and then on days 3, 8, 11 and 15 of gestation and on Day 7 of lactation was well tolerated by the F0 females. Intramuscular administration of D-QIV did not adversely affect female fertility, embryo-fetal survival, growth or development, as assessed at Day 20 of gestation, or post-natal survival, growth or development of the offspring up to Day 25 of age. Relevance of the rat species and animal exposure were supported by serological data collected from these two studies. No genotoxicity and carcinogenicity studies were conducted with D-QIV. These studies are not required for D-QIV. III.5 Ecotoxicity/environmental risk assessment (ERA) Not applicable to D-QIV. PAR Scientific discussion 6/15

7 III.6 Discussion on the non-clinical aspects Nonclinical pharmacology data for D-QIV was limited and did not well predict immunogenicity of this vaccine in humans. Toxicological testing of D-QIV was restricted to reproductive and developmental toxicity study in CD rats. Although no dedicated single dose/local tolerance and repeatdose toxicity studies were conducted with D-QIV, data generated with AS03-adjuvanted trivalent influenza vaccine and QIV reflected a worst case scenario and were considered supportive. Toxicity studies with D-QIV or related vaccines did not raise any safety concerns. Collectively, nonclinical evaluation of D-QIV is considered adequate for support of initial MAA. IV. CLINICAL ASPECTS IV.1 Introduction Annual vaccination is the most effective method for the prevention of influenza disease and is currently performed with a trivalent influenza vaccine (TIV) containing two A strains (H1N1 and H3N2) and one B strain. The efficacy of the vaccine is dependent on how closely the strains included in the vaccine match the circulating virus; recommendations relative to vaccine composition are issued annually by the WHO, CBER and the European Union. From the late 1970s, influenza B viruses have diverged into two genetically distinct phylogenetic lineages on the basis of their haemagglutinin. Since the mid 1980s the two lineages, represented by the B/Victoria/2/87 and B/Yamagata/16/88 strains, have been co-circulating in varying proportions in different years and countries. As only one single B strain is included in the currently licensed trivalent seasonal influenza vaccines, each season there is a risk of mismatch between the strain recommended for inclusion in the trivalent influenza vaccines and the dominant circulating B strain, which may vary geographically. In anticipation of a possible change in recommendations, GlaxoSmithKline Biologicals has developed a seasonal quadrivalent influenza vaccine: the quadrivalent vaccine candidate (D-QIV) is a split-virion, inactivated influenza vaccine that contains, in addition to the three strains annually recommended by WHO and included in commercial Fluarix trivalent vaccine (two A-strains [currently A/H1N1 and A/H3N2], and one B- strain), a second B strain, belonging to the opposite lineage as the B strain currently recommended for trivalent vaccine (TIV) composition, and that is shown to co-circulate in the human population. D-QIV is proposed for the active immunization of adults and children from 3 years of age against influenza disease caused by influenza virus types A and B contained in the vaccine. D-QIV produced induces humoral antibodies against the haemagglutinins. These antibodies neutralise influenza viruses. IV.2 Pharmacokinetics Classic pharmacological studies cannot be performed with inactivated viral vaccines. The amount of active substance the vaccine antigen(s) - is too low in order to be monitored by approaches such as pharmacokinetic or bioavailability studies. Hence, pharmacokinetic studies were not performed in accordance with the note for guidance on clinical evaluation of vaccines (CPMP/EWP/463/97). IV.3 Pharmacodynamics Vaccine specific pharmacological aspects are addressed by investigating the relation of the amount of vaccine antigen(s) administered and the dynamics of an immune response triggered following application of one or more vaccine doses. Results are expressed as the overall amount of antigen specific antibodies induced, supplemented by investigating functionality of these antibodies. For influenza vaccines, functional antibodies are characterized by the potential to inhibit viral Haemagglutination (HI) capacity or by the potential to inhibit in vitro virus replication (virus neutralization (VN). PAR Scientific discussion 7/15

8 IV.4 Clinical efficacy Six studies as summarized in the following below as well as Table 1 are presented in this application in support of the safety and efficacy of the D-QIV vaccine. The six studies were randomized, controlled studies: Two pivotal, Phase III, studies, study D-QIV-008 and study D-QIV-003, evaluated the candidate D-QIV vaccine in adults and children from 3 years of age. Both studies included two comparator groups, one receiving the Trivalent influenza vaccine containing the strains recommended for the ongoing season, and one a second trivalent vaccine that contained a strain of the B lineage not included in the seasonal vaccine. D-QIV-003 enrolled an additional group of 6 to 35-month old children for exploratory purposes. This group received open-label D-QIV vaccine. Two supportive studies, study D-QIV-001 (Phase I/II) and study D-QIV-002 (Phase II), evaluated the candidate vaccine in adults and children from 18 months of age. These studies included a control group that received the seasonally recommended trivalent influenza vaccine. Fluarix US-007 evaluated GSK Biologicals trivalent vaccine Fluarix in 6 to 35 month old children, in comparison with another trivalent inactivated influenza vaccine, Fluzone, Sanofi Pasteur s (U.S.) trivalent seasonal influenza vaccine. This study, conducted with a full 0.5 ml vaccine dose, is supportive of the immunogenicity and safety of the 0.5 ml vaccine dose selected for D-QIV in children below the age of three years. Fluarix-US-007 is presented in this application to support the choice of the dose in children below 3 years of age (and therefore supportive for the dose selected for the exploratory arm in subjects 6-35 months in D-QIV-003, as well as for further development in that age group). Fluarix-US-006 (Phase IV) evaluated the efficacy, safety and immunogenicity of Fluarix versus placebo as control in adults from 18 to 64 years of age. Results from this study are presented in the application to provide supportive efficacy data, as well as a basis for the non-inferiority approach taken in the clinical development of the D-QIV candidate vaccine. objectives included efficacy of Fluarix over placebo, safety and reactogenicity of Fluarix, as well as descriptive immunogenicity 21 days after vaccination. These latter two studies were conducted with Fluarix and did not evaluate the candidate D-QIV vaccine. Table 1: Clinical studies that support GSK Biologicals D-QIV vaccine in adults and children Type of Identifier Adult studies Phase D-QIV- I/II 001 Phase III D-QIV- 008 Location in CTD m5.3.5 m5.3.5 Country (year) Czech Republic ( ) US, Germany, Romania, Spain, Korea, Taïwan ( ) Population Adults years Adults 18 years Objective(s) of the Immunogenicity, non-inferiority to TIV vaccine (GMT), superiority of 4th B strain (GMT) Reactogenicity and safety Immunogenicity (lot-to-lot consistency of D- QIV (GMT), noninferiority to TIV vaccine (GMT/SCR); superiority to 4 th strain (GMT/SCR), Reactogenicity and Safety Design Randomized, single-blind, single center, controlled 4 parallel groups Randomized, partially blind, controlled 5 parallel groups Test Product(s); Dosage Regimen; Route of Administration - D-QIV - Fluarix - D-QIV (LD) - TIV (LD) 1 IM dose on Day 0 D-QIV groups: - D-QIV-1 (lot 1) - D-QIV-2 (lot 2) - D-QIV-3 (lot 3) Control groups: - Fluarix - TIV-2 1 IM dose on Day 0 Number of Subjects 105 subjects per group D-QIV groups: 3036 ( 1000/ lot) Fluarix: 1010 TIV-2: 610 PAR Scientific discussion 8/15 Duration of Primary phase: 21 days Extended safety follow-up: 6 months Primary phase: 21 days Extended safety follow-up: 6 months Status; Type of Report Completed Completed Phase Fluarix- m5.3.5 Czech Adults Efficacy of Fluarix Randomized, - Fluarix lot 1 Fluarix: Primary Completed

9 Type of Identifier Location in CTD Country (year) Adult studies IV US-006 Republic, Finland ( ) Population years Objective(s) of the compared to placebo, Immunogenicity Reactogenicity and safety Design double-blind, controlled 3 parallel groups Test Product(s); Dosage Regimen; Route of Administration - Fluarix lot 2 - Placebo 1 IM dose on Day 0 Number of Subjects 5103 Placebo: 2549 Duration of phase: 21 days Followup: approx 7 months Status; Type of Report LD: alternative, low-dose investigational formulations: exploratory formulations containing 5µg HA per strain and adjuvanted with AS03; D-QIV: GSK Biologicals quadrivalent influenza candidate vaccine; TIV-2 refers to a trivalent, Fluarix formulation containing the alternative lineage B strain (as contained in D-QIV) instead of the WHO/CBER recommended strain. 1. D-QIV: GSK Biologicals quadrivalent influenza candidate vaccine; 2. TIV-2 refers to a trivalent, Fluarix formulation containing the alternative lineage B strain (as contained in D-QIV) instead of the WHO/CBER recommended strain. Target indication and posology: Proposed Indication: The vaccine is a quadrivalent vaccine indicated for active immunization of adults and children from 3 years of age against influenza disease caused by influenza virus types A and B contained in the vaccine. Proposed Posology: The vaccine should be administered as a single 0.5 ml injection. Children 3 to less than 9 years of age who have not previously been vaccinated against influenza should receive a second dose of 0.5 ml after an interval of at least 4 weeks. Concerns on the validity of serological assays (HI- and MN- assay) were raised during the first evaluation phase questioning in particular the bridging strategy as proposed by the MAA, i.e. bridging efficacy demonstrated with Fluarix in adults from years by comparing HI titers measured in this specific study (Fluarix-US-006) with HI-titers observed in any of the D-QIV studies. Specifically for children this approach was not accepted. In the response document, the MAA has provided another indirect yet more convincing bridging strategy. In this second approach efficacy demonstrated in the age group from 3 to 18 years of age using a similar QIV construct produced in the MAA s Canadian PAR Scientific discussion 9/15

10 facility (Q-QIV) was bridged to D-QIV (produced in Dresden) by comparing HI-titers from this specific Q-QIV efficacy study (Q-QIV-006; Q-QIV versus Fluarix) with HI-titers observed in comparative immunogenicity studies comparing immunogenicity for Fluarix and D-QIV. Also, the MAA provided better evidence for the validity of the HI- assay which to the opinion of the assessor still overestimates HI-titers but is sufficiently sensitive in order to detect HI- titer profiles typical for children and older individuals. Altogether, these new data justify indication and posology as proposed by the MAA. IV.5 Clinical safety The safety of Fluarix Tetra has been studied in two pivotal phase III and two supportive Phase I/II studies. In these clinical trials 4631 subjects (adults, elderly and children) received 5587 doses of D- QIV. Subjects having received the candidate vaccine were followed-up for 6 months after vaccination. Safety data have been collected as recommended in the Guideline on clinical evaluation of new vaccines (CHMP/EWP/463/97). As requested in this guideline, uncommon adverse events that occur at a frequency between 1/100 and 1/1000 vaccinated persons would have been reliably determined in these conducted studies. However, no signals for rare diseases emerged during the 6 months follow-up and no death or other SAEs have been discovered related to the vaccine. The vaccine will be indicated for active immunization of adults and children from the age of at least 3 years old against influenza disease. For that reason, it has been important to enrol enough children. Therefore, 1490 subjects of the above mentioned study participants were at the age of 6 months to 17 years. 534 of those received one dose and the other 956 children, considered unprimed, received two doses of the candidate vaccine. As no clinically relevant differences in the safety profile were observed when comparing the different age groups the extent of the data basis in children is deemed to be sufficient. A review of the available data has shown that Fluarix-Tetra is safe and well-tolerated with a safety profile similar to that of the licensed Fluarix and to the TIV-2 control vaccine. Solicited AEs: As it is the case for many vaccines, after the administration of QIV a slightly higher rate of solicited adverse events (AEs) was observed in younger adults compared with elderly ones. On the other hand, no further relevant increase of solicited AEs could be observed after the vaccination of adolescents or children at the age of at least 3 years. The only exception was fever, which occurred slightly more often in younger children compared to older ones (QIV-group, first dose only: 17 years: 1.6%; 6-17 years:6%; 3-5 years:8.9%; months: 16.4%; 6-35 months:16.2%; Table S7, S8 and S9). The occurrence of pain, the most frequently reported local AE, was similar in the adult group compared to children. Typical solicited general adverse events were headache, fatigue and muscle ache. Here again, no clinically relevant differences were found when comparing adults to children. Concerning the 3 to 5 year-old ones slightly higher incidences of drowsiness, loss of appetite and irritability occurred after vaccination with QIV compared to the trivalent vaccines. However, grade 3 reactions were rare and the median duration ranged between 1 and 3 days. Vaccination of even younger children (below 3 years) led to an increase of solicited general AEs (drowsiness, irritability, loss of appetite and fever, in particular grade 3 fever). As in this group of age only investigated in QIV-003: 6 months to 3 years in the QIV-Y(oung-arm) no control vaccine was administered and therefor the tolerance of QIV cannot be compared to another TIV. Consequently, for the time being, QIV will only be approved for children being at the age of at least 3 years. An appropriate study ( QIV-004) is currently ongoing and a variation might follow later. Unsolicited AEs: As expected, in all vaccine groups (QIV, Fluarix and TIV-2) unsolicited unrelated AEs were reported in higher occurrence in the paediatric population compared to adults. The most commonly reported PAR Scientific discussion 10/15

11 unsolicited AEs in this group of age were nasopharyngitis and upper respiratory tract infection. However, causally related AEs occurred at every age and in all vaccine groups in 1.8 to 2.6 % of the subjects. Neither vaccination of lower age groups nor the adding of an additional B strain in the QIV vaccine led to an increase of causally related unsolicited AEs. Two Doses: Among subjects receiving two doses (6 months to 5 years), there was evidence of slightly increased fever rates following administration of a second dose compared to the first one (QIV: 3 to 5 years of age: 8.9% and 11.3%, 6 to 35 months: 16.2% and 20.3%, first and second dose, respectively). Apart from that in the unprimed cohorts no increase in reactogenicity was observed concerning administration of a second dose. Use of additional medication: The percentages of subjects who used analgesic or antipyretic medication due to a reaction within 3 or 4 weeks following vaccination were mostly balanced among vaccine groups. Of course, the younger the children were the more infections appeared and consequently, the need for medication increased. Annual revaccination: If an influenza vaccination is recommended for a group of people, vaccination has to be done annually. Even if it is acknowledged that regarding this issue Fluarix data are present, up to now, no data on re-vaccination one year after initial vaccination with QIV has been available. A study on revaccination one year after initial vaccination with QIV in children 6 to 35 months has been completed in Results from this booster study (follow up of the below mentioned study D-QIV- 004) will be submitted by December Subjects at high risk for influenza and concomitant use: Only healthy individuals ( stable health ) were enrolled into the clinical studies. The use of QIV in patients having a particular risk for influenza complications (subjects with poorly controlled underlying diseases) was not investigated, but particularly those subjects would benefit from an immunisation against influenza. To investigate safety and efficacy in this special group a concomitant use study (with PPV) in subjects at risk aged 50 years and older is on-going. In addition, the Company has set up a large effectiveness study with TIV in Canada (EPI-FLU-019). With the eventual introduction of QIV, it is hoped that the study will continue to estimate the effectiveness of the Quadrivalent influenza vaccine. This study is expected to reflect the population targeted for annual influenza vaccination. For the time being the data from subjects with acute or chronic underlying medical conditions already generated with Fluarix can be considered as supportive to D-QIV. Regarding children at risk, the Company acknowledges the lack of valuable information and proposes to amend the SmPC accordingly. Regarding vaccination of pregnant women, a pregnancy registry is being established. Route of administration: The impact on safety and immunogenicity of QIV vaccine regarding the route of administration, i.e. intramuscular versus subcutaneous was not investigated. Finally, on the basis of these data, it can be concluded that the increasing antigen amount due to the additional B strain does not have any clinically relevant impact on the safety of the vaccine. For the time being the lack of specific data should be appropriately reflected in the SmPC. Pharmacovigilance system The applicant has provided documents that set out a detailed description of the system of pharmacovigilance. A statement signed by the applicant and the qualified person for PAR Scientific discussion 11/15

12 pharmacovigilance, indicating that the applicant has the services of a qualified person responsible for pharmacovigilance and the necessary means for the notification of any adverse reaction occurring either in the Community or in a third country has been provided. Assessor considers that the Pharmacovigilance system as described by the applicant fulfils the requirements and provides adequate evidence that the applicant has the services of a qualified person responsible for pharmacovigilance and has the necessary means for the notification of any adverse reaction suspected of occurring either in the Community or in a third country. Risk Management Plan The MAH has provided sufficient information to assess the appropriateness of the proposed safety specification, pharmacovigilance plan and risk minimization plan. As this quadrivalent influenza vaccine is closely related to the authorized trivalent version, for which over the last years and currently no safety concerns have been identified, the proposal from the Marketing Authorisation Holder (MAH) could be acceptable that the safety specification only relates to potential risk. Therefore, the assessor agrees, that only limited additional pharmacovigilance activities besides routine pharmacovigilance may be needed to further investigate these risks. With regard to the aspect of missing information, data concerning the exposure during pregnancy and vaccination of special patients groups at risk (e.g. immunosuppressed) are missing. The monitoring of this vaccinee population should be addressed in the respective module of the Periodic Safety Update Report (PSUR) as additional pharmacovigilance measures. Concerning the treatment of children below 3 years of age further information is expected with finalization of the clinical trial covering this age group. The observation of safety in this trial is expected to add valid information with regards to the aspect of reactogenicity in young children. Periodic Safety Update Report (PSUR) As for other seasonal flu vaccines, the PSUR cycle should be bi annually harmonised with the regulatory procedures regarding the annual update of the vaccine strains. Common renewal date The common renewal date is IV.6 Discussion on the clinical aspects Collectively, clinical evaluation of D-QIV is considered adequate for support of initial Marketing Authorisation Application. V. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION Fluarix-Tetra (D-QIV) has been investigated in a comprehensive clinical trial program lasting about 5 years and incorporating individuals from 6 months of age. The main intention was to provide evidence on the non-inferior immunogenicity of Fluarix-Tetra in comparison to Fluarix, GSK s trivalent seasonal influenza vaccine or to Fluzone, Sanofi Pasteur s seasonal influenza vaccine produced and licensed in the U.S. The concept to provide evidence on Vaccine Efficacy (VE) through immunogenicity studies is a generally accepted approach for inactivated influenza vaccines since a serological surrogate parameter a Haemagglutination Inhibition (HI) titer of 1:40 is widely considered as correlating with a 50% chance to be protected from infections with circulating influenza virus strains. Although many concerns on the validity of this serological marker have been raised in the recent past, guidance applicable to the clinical investigation of inactivated influenza vaccines entirely focuses on three serological acceptance criteria seroprotection rate, seroconversion rate and PAR Scientific discussion 12/15

13 mean titer increase to be met for two different age categories (from 18 to 60 and above 60) in order to conclude on the acceptability of a vaccine. The clinical development program carried out with Fluarix Tetra is in full compliance with applicable guidance. From the overall study results it can be concluded that Fluarix-Tetra will be at least as efficient as the trivalent comparator Fluarix as evidenced from efficacy data generated with the latter vaccine and immunogenicity data extrapolated from this specific efficacy study to all immunogenicity studies conducted with D-QIV. Moreover, given the superior immunogenicity of Fluarix-Tetra and the presence of the second B strain it can be expected that overall VE in the indicated age group (children from 36 month and adults) is higher compared to Trivalent influenza vaccines. However, since no data from a comparative efficacy study are available true VE of Fluarix-Tetra can only be estimated. Comparing immunogenicity data from efficacy study US-Fluarix-006 with immunogenicity data from various D-QIV studies suggests vaccine efficacy in adults from years of age against culture confirmed influenza in the range of 67% against matched influenza virus strains. A similar bridging approach provided by the MAA in the response document to the List of Questions resulting from the first assessment round suggests a vaccine efficacy in the range of 55% in children from 3 8 years of age and above. For this age category potential efficacy of D-QIV was bridged from an efficacy study (Q-QIV-006) using a vaccine construct (Q-QIV) produced in the MAA s Canadian facility which is comparable to D-QIV produced in the Dresden facility. In combination with a better justification of the validity of the HI- assay these bridging approaches are acceptable and provide sufficient evidence on the clinical performance of D-QIV. Moreover, serological acceptance criteria as laid down in the existing EU- guidance for influenza vaccines were fully met. No specific estimation can be given on VE in populations being at specific risk for influenza due to high age and/or underlying acute and/or chronic disease. However, in his response document the MAA has made an acceptable proposal on how these populations can best be monitored following market introduction of the Canadian counterpart (Q-QIV) of D-QIV. A review of the available safety data, as evaluated in more than 3000 adult subjects (including elderly) and in more than 915 children aged 3 years and older, has shown that Fluarix-Tetra is safe and welltolerated with a safety profile similar to that of the licensed Fluarix and to the TIV-2 control vaccine. Generally, there was no indication of clinically relevant increased reactogenicity or diminished tolerability of Fluarix-Tetra in comparison with Fluarix in any of the age groups evaluated. Slightly higher incidences of solicited AEs (fever, drowsiness, loss of appetite or irritability) occurred in younger children compared to older ones. However, this is the case for many vaccines, and has been seen in the TIV groups too. Among subjects having received two doses no relevant increase of adverse events has been observed. Taking all that into consideration, it can be concluded that the increasing antigen amount due to the additional B strain does not have any clinically relevant impact on the safety of the vaccine for children from an age of at least three years, adolescents, adults or the elderly. For children below 3 years of age, limited data are available. However, this age category is currently excluded from the age indication. Additionally, as mentioned above, safety of the vaccine in risk groups (e.g. chronically ill subjects or persons receiving immunosuppressive therapy) was not investigated. Benefits and risks in these groups will be investigated post-marketing. In essence and taking into account that this quadrivalent influenza vaccine is closely related to the authorised trivalent version, for which no significant safety concerns have been identified in the previous years, no specific safety risks can be identified. For the time being, the lack of specific data (efficacy and safety of the vaccine in risk groups, concomitant use) will be appropriately reflected in the SmPC. Post-marketing surveillance data and studies planned and designed for certain populations (e.g. toddlers and in subjects at risk) will provide additional information on the safety profile of the new product. Thus, Fluarix Tetra is concluded to have at least the same benefit-risk ratio for individuals from 3 years onwards compared to other inactivated influenza vaccines licensed in the EU. Most likely benefits will be higher (while the potential risks remain the same) due to the second Influenza B component, even in groups clinically not investigated and despite current gaps in knowledge regarding the link between serological parameters and VE or vaccine effectiveness as discussed further above. PAR Scientific discussion 13/15

14 User consultation A user consultation was not required for Fluarix Tetra, because the text is according to the Core PIL. Table 2. The following post-approval commitments have been made during the procedure. Their current status is noted as well. Description Chemical and Pharmaceutical The MAH will submit an update of the batch numbering system to be able to differentiate both B strains The MAH commits to generating HA content data by both classical and adapted SRD methods to increase experience and confirm findings for the release and stability testing of QIV final bulks and containers and to provide regular updates to the regulatory authorities. The MAH commits to justify the decision to use the adapted SRD for testing of final bulks and containers and to communicate the decision as part of each annual strain update. i) The MAH commits to assessing the cross-reactivity of B strain reagents as part of the annual SRD requalification procedure. The choice of matched reagents should be based on the suitable level of cross-reactivity. ii) The MAH commits to developing appropriate selection criteria for deciding whether the adapted SRD should be used over classical SRD. iii) The MAH commits to re-qualify new lots of B strain reagents during that season according to a method pre-agreed with regulators. The MAH commits to evaluate the risk of HA content failure (at release and over stability studies) when the final bulks and containers are formulated using monovalent bulks tested using classical SRD but tested using adapted SRD method in D-QIV vaccine. The MAH commits to demonstrating the stability indicating nature (detecting the differential degradation of one B strain over the other) using the adapted and classical SRD method for tetravalent samples, for reagents known to present different levels of cross-reactivity. This could be shown for instance by: i) checking sensitivity of the measurement by varying content of one strain whilst maintaining the content of the other ii) demonstrating sensitivity to detect a reduction in HA content during stability studies. GSK will undertake forced degradation studies to demonstrate that a reduction in HA content of either B strain could be detected in the QIV formulation using the proposed 'adapted' SRD method. Clinical The MAH commits to submit results of study D-QIV-009 (booster study: revaccination in children) The MAH commits to submit results of study D-QIV-004 (efficacy study in children 6-35 months) The MAH commits to submit results of study Zoster-004 ( Co-administration study of GSK s candidate Zoster vaccine + D-QIV) The MAH commits to submit results of study D-QIV 010 (co-administration study of D-QIV + pneumococcal vaccine, i.e in subjects at risk aged 50 years Current Status Status: fulfilled Status: fulfilled Status: fulfilled Status: fulfilled Status: fulfilled Status: fulfilled PAR Scientific discussion 14/15

15 and older) The MAH commits to submit results of study EPI-Flu-019 (Effectiveness study with GSK s Québec sourced vaccine in Canada FluLaval). Pharmacovigilance (as per Risk Management Plan) The MAH commits to submit the annual pregnancy / lactation report along with the PSUR in a timely manner. The MAH commits to submit the pregnancy / lactation final study report Labelling The MAH commits to print on outer carton label of Fluarix Tetra the wording "For use in adults and children from 3 years of age" to highlight once more the difference between Fluarix (approved for children from 6 months onwards) and Fluarix Tetra. Status: fulfilled VI. UPDATE ON THE PUBLIC ASSESSMENT REPORT Procedural Steps after the finalization of the initial procedure Date of Procedure Number Date of Approval Brief Description submission DE/H/1939/001/IB/ Introduction additional supplier for production eggs (Verbeek NL) DE/H/1939/001/II/ Extension storage of B Monobulks in Flexboy Bags to 12 months DE/H/1939/001/IA/G/004 (DE/H/xxxx/IA/033/G) Introduction Pharmacovigilance System Summary DE/H/1939/001/IB/ Update of RMP to new template version 4.0; Amendment of Part VI section DE/H/1939/001/IB/006 (DE/H/xxxx/IA/035/G) Summary of the Pharmacovigilance System DE/H/1939/001/II/ Annual Update 2013/ DE/H/1939/001/E/ Repeat Use Procedure (AT, BE; CZ, EL, ES, LU, SK, IT) DE/H/1939/001/IB/ Annual Update 2014/ DE/H/1939/001/IB/ Outsourcing of Disinfection Post-approval commitments Updates on the status of the post approval commitments have been included in Table 2 (Chapter V). PAR Scientific discussion 15/15