Afluria, suspension for injection

Transcription

1 Public Assessment Report Scientific discussion Afluria, suspension for injection Influenza vaccine (split virion, inactivated) Mutual Recognition Procedure SE/H/0485/01/E01 Report date: 28 June 2007 This module reflects the scientific discussion for the approval of Afluria. The procedure was finalised at 4 April For information on changes after this date please refer to the module Update.

2 TABLE OF CONTENTS I. INTRODUCTION...3 II. QUALITY ASPECTS...3 II.1 INTRODUCTION...3 II.2 DRUG SUBSTANCE...3 II.3 MEDICINAL PRODUCT...3 III. NON-CLINICAL ASPECTS...4 III.1 PHARMACOLOGY...4 III.2 PHARMACOKINETICS...4 III.3 TOXICOLOGY...4 III.4 ECOTOXICITY/ENVIRONMENTAL RISK ASSESSMENT...4 III.5 DISCUSSION ON THE NON-CLINICAL ASPECTS...4 IV. CLINICAL ASPECTS...5 IV.1 INTRODUCTION...5 IV.2 PHARMACOKINETICS...5 IV.3 PHARMACODYNAMICS...5 IV.4 CLINICAL EFFICACY...5 IV.5 CLINICAL SAFETY...14 V. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION...17 Page 2 (17)

3 I. INTRODUCTION The application for marketing authorisation of Afluria /Enzira (Influenza Vaccine CSL) was submitted as a mutual recognition procedure (MRP), repeat use, first wave. The concerned member states were Germany and Ireland. The vaccine was nationally approved in Sweden on 29 October The first MRP was initiated 2004 with a repeat-use MRP in 2006 and the vaccine is currently licensed in United Kingdom, Finland, Norway, Denmark, The Netherlands, Belgium, Luxembourg, Sweden, Germany and Ireland. The indication is prophylaxis of influenza, especially in those who run an increased risk of associated complications. II. QUALITY ASPECTS II.1 Introduction The vaccine is a β-propiolactone-inactivated, taurodeoxycholate-split virion vaccine, propagated in embryonated eggs, supplied in a single-dose 0.5 ml, pre-filled syringe. The dose of 0.5 ml contains 15 µg haemagglutinin H1N1 strain, 15 µg haemagglutinin H3N2 strain, 15 µg haemagglutinin B strain. The product contains influenza virus antigens from the strains recommended by the WHO for the Northern Hemisphere and approved by the EU for the winter season. The vaccine is free of thiomersal, and conforms to the European Pharmacopoeia. II.2 Drug Substance The drug substance is the Monovalent Pooled Harvest (MPH). It is an aqueous suspension of inactivated and disrupted influenza virus. The vaccine strains are obtained from approved laboratories each year, and will be consistent with the WHO recommendation and approved by the appropriate National Control Agency for the northern hemisphere. A Working Seed Lot is prepared from the strains by culturing in eggs. For production of the MPH, the Working Seed Lot is inoculated in eggs. After incubation, the allantoic fluid is harvested and concentrated by sucrose gradient centrifugation. The virus is then inactivated by beta-propiolactone and disrupted by treatment with sodium taurodeoxycholate. The disrupted virus is then further purified, concentrated and sterile filtered, yielding the MPH. Specifications for the MPH include a test for absence of live virus, sterility, endotoxins, and haemagglutinin (HA) content. The MPH can be stored at 2-8 ºC for 12 months. The drug substance specification includes relevant tests and the limits for impurities/degradation products have been justified. The analytical methods applied are suitably described and validated. Stability studies under ICH conditions have been conducted and the data provided are sufficient to confirm the shelf-life. II.3 Medicinal Product CSL Influenza Vaccine is a sterile, aqueous suspension of a mixture of three approved influenza virus type A or B strains. The vaccine does not contain any adjuvant or preservative. Each year, influenza viral strains for use in composition of the vaccine are recommended by the World Health Organisation (WHO). The vaccine is manufactured by mixing the MPHs of the different strains and adjusting the HA concentration. This Final Bulk is then filled into 1 ml glass syringes. The manufacturing process has been sufficiently described and critical steps identified. Results from the process validation studies confirm that the process is under control and ensure both batch to batch reproducibility and compliance with the product specification. The tests and limits in the specification are considered appropriate to control the quality of the finished product in relation to its intended purpose. Stability studies under ICH conditions have been performed and data presented support the shelf life claimed in the SPC; 12 months when stored at 2-8 ºC. Page 3 (17)

4 The only materials of animal or human origin contained in or used in the manufacturing of the vaccine are cholic acid (used in the manufacture of sodium taurodeoxycholate), influenza virus strains of human origin, and hen s eggs. Cholic acid is derived from bovine bile, and a TSE Certificate of Suitability from EDQM is provided for this substance. The influenza strains and the hen s eggs fall outside the scope of the CPMP guideline Note for guidance on minimising the risk of transmitting animal spongiform encephalopathy agents.... Satisfactory reduction of viruses has been demonstrated for the production process. The conclusions of the viral risk assessments are found acceptable. III. NON-CLINICAL ASPECTS III.1 Pharmacology The vaccine induces antibodies to the neuraminidase and haemagglutinin surface antigens of influenza virus. Animal models of influenza virus infection exist, e.g. the ferret, but such studies would be considered questionable in the present case. There is a well-demonstrated relationship between human serum antibody titre and protection against infection. III.2 Pharmacokinetics Not applicable. III.3 Toxicology No standard single dose or repeated dose toxicity studies with the vaccine have been conducted. This is considered acceptable. The vaccine is formulated in isotonic phosphate buffered saline, excipients that have a long history of safe use. The levels of potential impurities are controlled and monitored and overall comply with appropriate guidelines and European Pharmacopoeial requirements. Although no preclinical studies are available the potential for general toxicity of the vaccine is not considered a cause for concern in view of the known active ingredients and excipients in the vaccine. Animal reproductive studies have not been conducted. There are, however, general recommendations for use in pregnancy and lactation based on limited clinical data and a risk/benefit analysis. No studies on local tolerance have been submitted. The vaccine may be administered intramuscularly or as a deep subcutaneous injection, but must not be administered intravascularly. The removal of thiomersal from the vaccine has not adversely changed local tolerability. III.4 Ecotoxicity/environmental risk assessment Not applicable. III.5 Discussion on the non-clinical aspects The constituents of the vaccine, the virus subunits and excipients are well-characterised and while the antigenic variation requires that the strains used in manufacture are novel and determined each year, the manufacturing procedure is unchanged. The safety will then be determined by quality control during manufacture together with clinical efficacy studies. Page 4 (17)

5 IV. CLINICAL ASPECTS IV.1 Introduction CSL s influenza vaccine (containing 0.01% w/v thiomersal) was first registered in Australia and New Zealand (as Fluvax ), in the mid-l960 s. The original authorisation of Fluvax was approved in Europe via the Mutual Recognition Procedure with Sweden being the RMS on 19 June 1997 and subsequently in the Netherlands, Denmark and Finland. Renewal of the Marketing was granted in these countries in The thiomersal-containing vaccine is no longer registered in the EU. The thiomersal-free formulation of CSL Influenza Vaccine was registered in Sweden on 29 th October 2004, under the trade name Afluria. Subsequently, the vaccine was registered via a Mutual Recognition Procedure (MRP) in the United Kingdom under the trade name Enzira and a generic name and in Denmark, The Netherlands, Belgium, Norway, Finland and Luxembourg under the trade name Afluria. A repeat-use MRP was successfully concluded on 4 th April 2007, with new CMS, Germany and Ireland, granting approval for licensure of Afluria / Enzira vaccine. CSL Influenza vaccine is indicated for any person to prevent falling ill with influenza although it has been specifically recommended for individuals who are in certain high-risk groups and for all people over the age of 65 years. Like many conventional vaccines with a long story of use, formal controlled vaccine efficacy studies have never been conducted. However, each year since l982, CSL Limited has conducted a clinical study in healthy adult ( 18 and < 60 years) and/or older adult ( 60 years) populations. More recently, CSL has conducted a paediatric study in children 6 months to < 9 years of age and a comparator study against an EU-licensed influenza vaccine in healthy adult and older adult populations. IV.2 Pharmacokinetics Not applicable IV.3 Pharmacodynamics Not applicable IV.4 Clinical Efficacy The clinical overview provides a critical evaluation of the clinical studies conducted to evaluate the impact of reducing or eliminating the thiomersal content of the CSL influenza vaccine. It was proposed that the criteria defined in the CHMP Note for Guidance 1 (i.e. seroprotection. seroconversion and sufficient increase in GMP) based upon in vivo tests should be sufficiently robust to assess the potential impact of the proposed changes and that clinical protection studies would not be required to establish efficacy. Safety and tolerability were also assessed consistent with the CPMP/BWP/214/96. Underpinning this thesis was the premise that the preservative free (thiomersal-reduced) and thiomersal free vaccines were essentially similar to the originally approved Fluvax (0.1% w/v thiomersal) in terms of safety (tolerability) and immunogenicity parameters (as a surrogate for efficacy). The documentation submitted for the first round MRP to seek registration of the thiomersal-free vaccine formulation included a number of studies conducted in Australia. The trials conducted in young, healthy adults aged 18 to < 60 years were generally double blind, randomised, parallel group and usually placebo controlled. Trials conducted in healthy, older adults aged 60 and usually 75 years were Phase IV, open label, uncontrolled studies with generally 60 to 70 participants. 1 CHMP Note for Guidance on Harmonisation of Requirements for Influenza Vaccines, CPMP/BWP/214/96 Page 5 (17)

6 Four of the studies were carried out with preservative free vaccines (two studies with thiomersal-reduced vaccine and two studies with thiomersal-free vaccine) during the period October 2000 to April These studies were pivotal to the registration of the thiomersal-free vaccine formulation. Additionally, nine studies of the immunogenicity and tolerability of thiomersal-containing (0.01%) CSL Influenza Vaccine conducted during the period April l992 to June 2001 were submitted as supportive information together with 10 Phase IV open-label studies with thiomersal-containing (0.01% w/v) CSL Influenza Vaccine conducted during the period April 1992 to April The trials typically enrolled around 100 subjects per treatment arm and were not statistically powered to compare the vaccines in the trials. The studies conducted with CSL Influenza Vaccine containing 0.01% thiomersal were included as supporting data and for comparison with the thiomersal free CSL Influenza Vaccine. Subsequent to the registration of the thiomersal-free vaccine formulation in Europe in the first MRP round, a paediatric study (a post-approval commitment for the Swedish licence) and a comparator study against another EU-licensed influenza vaccine were conducted. Summary of Clinical Efficacy Data from First Round MRP The thiomersal-free formulation of CSL Influenza Vaccine was registered in Sweden in October 2004, and subsequently via an MRP in the United Kingdom, Denmark, The Netherlands, Belgium, Norway, Finland and Luxembourg. The trade name Afluria is applied for all EU countries except the United Kingdom, where the trade name is Enzira. Four studies were carried out with the preservative free influenza vaccine formulation that is considered to be relevant for the present application and have accordingly been assessed. Two of the studies were undertaken in order to confirm that a reduction in the level of thiomersal should have no impact on the immunogenicity and safety profile of CSL s influenza vaccine: CSLCT-FLU-99-68: a double-blind randomised parallel group study to evaluate the immunogenicity and tolerability of thiomersal reduced influenza vaccine in a healthy adult population: 18 to 60 years CSLCT-FLU-02-85: a double-blind randomised single centre parallel group study to evaluate the immunogenicity and safety of two formulations of a preservative free influenza vaccine in a healthy older adult population: 60 to < 65 years, and the other two were the first clinical studies in which the thiomersal-free vaccine was clinically tested: CSLCT-FLU-02-86: a single site open label study to evaluate the immunogenicity and safety of Fluvax in healthy adults: 18 to < 60 years and in healthy older adults: 60 years of age for the 2003 influenza season CSLCT-FLU-03-95: a single site, open label study to evaluate the immunogenicity and safety of thiomersal-free Fluvax in healthy adults: 18 to < 60 years and in healthy older adults: 60 and < 65 years of age for the 2004 influenza season. The CHMP immunogenicity criteria (as per the Note for Guidance on Harmonisation of requirements for Influenza Vaccines CPMP/BWP/214/96) were applied to these studies. For each strain in adult subjects aged between 18 and 60 years, at least one of the serological assessments should meet the indicated requirements: 1. number of seroconversions or significant increase in anti HA antibody titre should be >40% 2. mean geometric increase > the proportion of subjects achieving a HI titre 40 should be >70% For each strain in older adult subjects aged over 60 years at least one of the serological assessments should meet the indicated requirements: Page 6 (17)

7 1. number of seroconversions or significant increase in anti HA antibody titre should be >30% 2. mean geometric increase > the proportion of subjects achieving a HI titre 40 should be >60% The thiomersal-reduced and thiomersal free inactivated influenza vaccine satisfied the CHMP criteria for immunogenicity for influenza vaccine irrespective of the formulation tested. The study undertaken in older adult subjects (CSLCT-FLU-02-85) demonstrated that the vaccine was well tolerated, irrespective of the level of HA present in the vaccine. Two formulations were tested representing the range of HA content that may occur for any two lots of vaccine. Moreover, the reduction and removal of thiomersal in the manufacturing process did not seem to prevent acceptable immunogenicity of the vaccine as tested in older adult subjects. The available clinical data demonstrated that the thiomersal free vaccine satisfies the CHMP criteria for influenza virus vaccines (CPMP/BWP/214/96) in healthy adults and healthy older adult populations. Efficacy in special groups At the time of national approval in Sweden, no data was available from clinical studies conducted in children; however, the vaccine which was previously licensed in Europe (Fluvax vaccine 0.01% w/v thiomersal) was indicated for use in children over 6 months of age. No controlled clinical studies had been conducted in infants, young children or young adolescents (aged less than 18 years), however, post marketing surveillance data is suggestive of the safe use of the vaccine in this population. No data was available to determine if the immune response in persons undergoing immunosuppressive treatments or who are immunocompromised are diminished. Nor have any controlled studies been conducted in pregnant or lactating women with the CSL inactivated influenza vaccine. Paediatric population: No efficacy or safety data were primarily available from clinical studies of the use of the thiomersal free CSL Influenza Vaccine but the recorded experience, empiric use and literature reports was considered to support a recommendation of administration of the Influenza Vaccine CSL in the population aged >36 months to 18 years. The vaccine which was previously licensed in Europe (Fluvax 0.01% w/v thiomersal) was indicated for use in children over 6 months of age. This lower age limit is consistent with the indication for the thiomersal-free formulation currently available in Australia and for other similar inactivated influenza vaccines currently licensed within the EEU, Canada and the USA. The body of experience from the use of Fluvax (0.01% w/v thiomersal and thiomersal-free) in Australia and similar inactivated influenza virus vaccines was considered to be adequate to support this indication. Available data from the literature for trivalent inactivated influenza vaccines had shown an adequate immune response in children with a high frequency of seroconversion and seroprotection. As a post-licensure commitment to the Swedish MPA and a post-approval commitment given during the first round Mutual Recognition Procedure SE/H/0485/001, the Company agreed to evaluate the safety, tolerability and immunogenicity of CSL s influenza vaccine in a paediatric population. Page 7 (17)

8 Update of Clinical Efficacy Documentation for Repeat-Use MRP Subsequent to the first MRP round for registration of the thiomersal-free vaccine formulation in Europe, two studies have been conducted to meet registration requirements. A paediatric study was conducted as a post-licensure commitment. Also, a comparator study against an EU-licensed influenza vaccine was conducted as a registration study for Afluria /Enzira vaccine: CSLCT-FLU-04-05: an open-label, multi-centre, phase III study to evaluate the safety, tolerability and immunogenicity of CSL s influenza vaccine in a paediatric population ( 6 months to < 9 years of age). CSLCT-NHF-05-11: a phase IV, randomised, observer-blind study to evaluate immunogenicity and tolerability of CSL s Enzira vaccine against an EU-licensed comparator vaccine in healthy adults (aged 18 and < 60 years) and older adults ( 60 years). Study CSLCT-FLU This study was commenced in March 2005, during the Southern Hemisphere influenza season to support the paediatric indication of CSL Influenza Vaccine. The design was an open-label, multi-centre phase III study to evaluate the safety, tolerability and immunogenicity of CSL s influenza vaccine in a paediatric population ( 6 months < 9 years of age). Only individuals who had not previously been vaccinated against influenza were enrolled. At the first stage (primary vaccination) of this study each subjects was given two doses of thiomersal-free inactivated influenza vaccine thirty days apart followed by a booster dose given at 12 months. Serum samples were taken at Day 0, at days post each vaccination and prior to the booster dose. Immunogenicity was evaluated using the CHMP assessment criteria with the endpoint for younger adults (aged 18 and < 60 years) applied. This CHMP guideline does not specifically cover the assessment of influenza vaccines in children but the assessment criteria were deemed acceptable by the CSL s Reference Member State (RMS). The influenza virus strain composition of the vaccine was consistent with the recommendation of the WHO and Australian Influenza Vaccine Committee (AIVC) for the Southern Hemisphere season 2005: Influenza A/H1N1 (A/New Caledonia/20/99), Influenza A/H3N2 (A/Wellington/1/2004 and Influenza B (B/Jiangsu/10/2003). One group of 151 children aged 6 months to < 3 years (Group A) and another group of 147 children aged 3 months to < 9 years (Group B) were enrolled in the study. All 298 participants received dose 1 of vaccine (Group A 0.25 ml; Group B 0.5 ml) and 287 (96.3%) of these provided a post dose serum sample for analysis. The second dose was administered to 293 participants (98.3%) and 271 of these (90.9%) provided a serum sample for analysis. Five participants were withdrawn prior to completing the study. The primary phase immunogenicity data for the two age groups, Groups A and B are presented in Tables 1 and 2. Conclusions of the Study The vaccine met the CHMP criteria for all three strains in both age groups following dose 2. The post-dose 2 responses were consistently higher for each of the strains, such that all three assessment criteria were met for each of the three strains. The results are consistent with the dosage recommendation for previously unvaccinated children, where two doses of vaccine given approximately 4 weeks apart are recommended for induction of an adequate immune response. Page 8 (17)

9 Booster Dose (Day ): This stage of the trial has not yet been reviewed. Page 9 (17)

10 Table 1: Study CSLCT-FLU Summary of Serological Immunogenicity Results for Group A Antigen Criterion CHMP Requirements Dose 2 (n=139) H 1 N 1: A/New Caledonia/20/99(IVR-116)(A/New Caledonia/20/99 (H 1 N 1 )like) Seroconversion or insignificant increase Fold increase in mean GMT % with HI titre 40 Overall (Pass/Fail) >40% >2.5 >70% 95.0% % Pass H 3 N 2: A/Wellington /1/2004(IVR-139)(A/Wellington /1/2004 (H 3 N 2 )like) Seroconversion or insignificant increase Fold increase in mean GMT % with HI titre 40 Overall (Pass/Fail) >40% >2.5 >70% 90.6% % Pass B Strain: B/Jiangtsu/10/2003(B/Shanghai/361/2002-like) Seroconversion or insignificant increase Fold increase in mean GMT % with HI titre 40 Overall (Pass/Fail) >40% >2.5 >70% 94.2% % Pass Table 2: Study CSLCT-FLU Summary of Serological Immunogenicity Results for Group B Antigen Criterion CHMP Requirements Dose 2 (n=132) H 1 N 1 A/New Caledonia/20/99(IVR-116)(A/New Caledonia/20/99(H 1 N 1 )-like) Seroconversion or insignificant increase Fold increase in mean GMT % with HI titre 40 Overall (Pass/Fail) >40% >2.5 >70% 93.9% % Pass H 3 N 2: A/Wellington /1/2004(IVR-139)(A/Wellington /1/2004 (H 3 N 2 )like) Seroconversion or insignificant increase Fold increase in mean GMT % with HI titre 40 Overall (Pass/Fail) >40% >2.5 >70% 70.5% % Pass B Strain: B/Jiangtsu/10/2003(B/Shanghai/361/2002-like) Seroconversion or insignificant increase Fold increase in mean GMT % with HI titre 40 Overall (Pass/Fail) >40% >2.5 >70% 93.2% % Pass Page 10 (17)

11 Study CSLCT-NHF-05-11: This study was a phase IV, randomised, observer-blind study where the immunogenicity and tolerability of the CSL vaccine (Enzira /Afluria ) was evaluated and compared to an EU-licensed influenza vaccine. The study was conducted in the UK in healthy adults (aged 18 and <60 years) and older adults ( 60 years) during October and November The influenza strain composition of the vaccine was consistent with the recommendations of the CHMP BWP Ad hoc Influenza Working Group for the 2005/2006 Northern Hemisphere season: Influenza A/H1N1 (A/New Caledonia/20/99), Influenza A/H3N2 (A/New York/55/2004) and Influenza B (B/Jiangtsu/10/2003). One hundred and two healthy adults and 104 healthy older adults participated in this study and received a single dose of Enzira / Afluria vaccine. One hundred and two healthy adults and 98 older healthy adults received a single dose of the comparator vaccine (EU-licensed influenza vaccine). Serum antibody titres to HA were measured immediately prior to vaccination and 3 weeks post vaccination. All subjects enrolled were included in the evaluable population for safety and in the analysis for primary efficacy/immunogenicity. The demographic profile of the Enzira /Afluria recipients showed an age range of 18 to 59 years with a mean age of 42 years for the adult population and an age range of 60 to 83 years with a mean age of 67 years for the older adults. In the older adults population, 58% of the vaccine recipients were aged 65 years. The demographic profile of the recipients of the comparator vaccine (EU-licensed influenza vaccine) revealed an age range of 19 to 59 years, with a mean age of 43 years for the adult population and age range of 60 to 92 years with a mean age of 68 years for the older adults. In the Older Adults population, 61% of the EU-licensed influenza vaccine recipients were aged 65 years. The immunogenicity results are presented in Tables 3 and 4 and show that the CHMP criteria were met for both the adult and the older adults. Enzira /Afluria vaccine satisfied all three assessment criteria for each of the three strains in both the adult and older adult populations including for the H1N1 strain. The EU-licensed comparator vaccine met all three criteria for each of the strains tested in the adult population but did not meet the requirement that > 60% of the older adult participants should have a post vaccination HI titre of 40 for either the H1N1 (58%) or B (57%) strains. Furthermore, the immunogenicity of Enzira /Afluria vaccine was noninferior for all three strains in both populations when compared to EU-licensed vaccine. Conclusions of the Study Both Enzira /Afluria and EU-licensed influenza vaccine met the immunogenicity criteria specified in the CPMP/BWP/214/96 NfG in both the adult (<60 years) and older adult ( 60 years) group, The immunogenicity of Enzira /Afluria was non-inferior to that of EU-licensed influenza vaccine for any of the three strains in both the adult (<60 years) and older adult ( 60 years) group. Page 11 (17)

12 Table 3: CSLCT-NHF Summary of Serological Immunogenicity Results for the Adult Population (aged >18 and <60 years), Comparison of Results for CSL s Enzira vaccine and an EU-Registered Comparator Vaccine strain Assessment criteria Pass Criteria Enzira H3N2 Overall outcome H1N1 Overall outcome B Overall outcome Number of seroconversions or significant increase in antihaemagglutinin antibody titre Mean geometric fold increase The proportion of subjects achieving an HI titre 40 Immunogenicity Assessment H3N2 Number of seroconversions or significant increase in antihaemagglutinin antibody titre Mean geometric fold increase The proportion of subjects achieving an HI titre 40 Immunogenicity Assessment H1N1 Number of seroconversions or significant increase in antihaemagglutinin antibody titre Mean geometric fold increase The proportion of subjects achieving an HI titre 40 Immunogenicity Assessment H1N1 > 40% > 2.5 > 70% > 40% > 2.5 > 70% > 40% > 2.5 > 70% 93% % 65% % 63% % EU-licensed Influenza Vaccine 90% % 71% % 64% % Page 12 (17)

13 Table 4: CSLCT-NHF Summary of Serological Immunogenicity Results for the Older Adult Population (aged 60 years), Comparison of Results for CSL s Enzira vaccine and an EU-Registered Comparator Vaccine strain Assessment criteria Pass Criteria Enzira H3N2 Overall outcome H1N1 Overall outcome B Overall outcome Number of seroconversions or significant increase in antihaemagglutinin antibody titre Mean geometric fold increase The proportion of subjects achieving an HI titre 40 Immunogenicity Assessment H3N2 Number of seroconversions or significant increase in antihaemagglutinin antibody titre Mean geometric fold increase The proportion of subjects achieving an HI titre 40 Immunogenicity Assessment H1N1 Number of seroconversions or significant increase in antihaemagglutinin antibody titre Mean geometric fold increase The proportion of subjects achieving an HI titre 40 Immunogenicity Assessment H1N1 > 30% > 2.0 > 60% > 30% > 2.0 > 60% > 30% > 2.0 > 60% 84 % % 49% % 48% % EU-licensed Competitor Vaccine 76% % 41% % Pass (2/3) 45% % Pass (2/3) Page 13 (17)

14 IV.5 Clinical Safety Summary of Clinical Safety Data from First Round MRP A consolidated review of the clinical and post marketing experience for the period 1997 through 2002 with the thiomersal containing Fluvax was undertaken when an application for renewal was submitted to the MPA. The available safety data for the thiomersal-free vaccine formulation is derived from Post Marketing surveillance reports and the results of clinical study conducted in accordance with the CPMP NfG (CPMP/BWP/214/96). In the period from l9 June to 5 July 2002 about 15 million doses of Fluvax (0.01% thiomersal) were sold with the majority of doses being supplied to the Australian market. At the time of submission of the first round MRP dossier, data were available for 6.3 million doses of thiomersal-free vaccine and approximately 24 million doses of thiomersal-containing vaccine. No new AE by body system or unexpected adverse events have been reported that are not already known for the 0.01%w/v Fluvax or other inactivated influenza virus vaccines. The current experience with the vaccine is small in terms of the total exposure database for the thiomersal free formulation alone and only gross changes would be detected. The profile of local and general reactions was unremarkable and consistent with the reactions described previously in the Fluvax SmPC (0.01% w/v thiomersal) and the Company Core Data Sheet. Postvaccination reactions were transient and self-limiting and peaked within the first 24 to 48 hours following vaccination, leading to resolution of symptoms within a 5-day period. The available clinical data demonstrates that the thiomersal free vaccine satisfies the CPMP criteria for influenza virus vaccines (CPMP/BWP/214/96) in healthy adults and healthy elderly populations. The available post marketing surveillance data demonstrates that the safety profile of the vaccine is consistent with that of the 0.01% w/v thiomersal containing vaccine Fluvax which has been manufactured by CSL in Australia for more than 15 years. The extent of use of the vaccine in the paediatric population in Australia is not well understood and the available post marketing surveillance data has few reports of adverse events in children. This issue was raised in the assessment of the documentation submitted for the national approval in Sweden. Therefore, to improve the information available to support the paediatric indication for the vaccine, the Company had committed to conduct a clinical study, planned to commence in Australia prior to the Southern Hemisphere Influenza Season in Update of Clinical Safety Documentation for Repeat-Use MRP Subsequent to the first MRP round for registration of the thiomersal-free vaccine formulation in Europe, two studies have been conducted to meet registration requirements. A paediatric study was conducted as a post-licensure commitment to the Swedish MPA. Also, a comparator study against an EU-licensed influenza vaccine was conducted as a registration study for Afluria /Enzira vaccine: CSLCT-FLU-04-05: an open-label, multi-centre, phase III study to evaluate the safety, tolerability and immunogenicity of CSL s influenza vaccine in a paediatric population ( 6 months to < 9 years of age). CSLCT-NHF-05-11: a phase IV, randomised, observer-blind study to evaluate immunogenicity and tolerability of CSL s Enzira vaccine against an EU-licensed comparator vaccine. A summary of the clinical safety data from these studies is presented. Page 14 (17)

15 Study CSLCT-FLU Safety Evaluation All participants who received at least one dose of Study Vaccine were included in the Safety Population. All participants (298) enrolled in the study received Dose 1 and 293 received Dose 2. The primary objective of the study was to determine the safety of CSL s inactivated influenza vaccine in a paediatric population ( 6 months to <3 years and 3 years to < 9 years) through the assessment of: Local and systemic solicited AEs for 7 days post vaccination Unsolicited AEs for 30 days post each vaccination Serious adverse events (SAE) for 6 months after the last primary vaccination. Solicited Local Adverse Events and Solicited Systemic Adverse Events Overall, CSL s Inactivated Influenza Vaccine was safe and well tolerated in a paediatric population ( 6 months to <9 years of age). The first occurrence of all solicited local AEs were considered related to the Study Vaccine, and all subsequent occurrences were to be assessed by the PI/delegate with respect to causality. Overall, all solicited local AE were related to the study vaccine. In Group A ( 6 months to <3 years of age) and Group B ( 3 years to <9 years of age) following Dose 1 and 2, Pain and Redness were the most commonly reported solicited local AEs, whereas Rhinitis and Irritability were the most frequently reported solicited systemic AEs. The majority of systemic AEs were considered possibly, probably or definitely related to the Study Vaccine. Unsolicited Adverse Events A total of 658 unsolicited AEs were reported in the Safety population (n=298); 388 in Group A and 270 in Group B. Seventy-six events (11.6%) were assessed by the PI/delegate as possibly, probably or definitely related to the Study Vaccine. Of the total number of unsolicited AEs reported 309 (47%) were assessed as mild, 273 (41.5%) as moderate and 76 (11.6%) as severe. No participants withdrew as a result of an adverse event. Three SAEs occurred within the 30 day post-vaccination period post-dose 1 or post-dose 2. All SAEs were assessed by the PI/delegate as not related to the Study Vaccine. Conclusions of the Study The majority of the vaccine-related adverse events were of a mild severity. The PI/Delegate assessed the SAEs reported as not related to the Study Vaccine. No deaths occurred during the study. CSL s Inactivated Influenza Vaccine is generally safe, well tolerated and immunogenic in children aged 6 months to < 9 years. Study CSLCT-NHF-05-11: Safety Evaluation Safety was also evaluated in this study. Participants were issued with a 4-day Solicited and Unsolicited Adverse Events Diary Card. Subjects were requested to contact the Principle Investigator/Delegate in the event of flu-like symptoms being experienced to enable clinical confirmation. At day , an Exit Evaluation was conducted to elicit if any SAEs had occurred since Day 1. A brief medical examination and if clinically indicated, a physical examination were also performed prior to study exit. The type, frequency and intensity of solicited symptoms and the frequency of unsolicited symptoms following vaccination with Enzira /Afluria and with an EU-licensed influenza vaccine were compared. Page 15 (17)

16 Solicited Local Adverse Events and Solicited Systemic Adverse Events Systemic symptoms: The majority of participants, 90.3% in the Enzira /Afluria group and 89.0% in the EU-licensed comparator vaccine group did not experience any general symptoms during Day 0 to day 3. No events in either group were considered serious. Of the solicited symptoms the most common event was malaise, which occurred in 7.4% and 8.5% of the Enzira /Afluria and EU-licensed comparator groups respectively. The majority of malaise was considered to be probably or possibly related to the Study Vaccine in both groups. Malaise was significantly higher in Adults compared to Older Adults. Only a small number of participants, 1.5% in the Enzira /Afluria group and 1% in the EU-licensed comparator group experienced a temperature above 38.0 C for 24 hours or longer. Chills occurred in 0.5% participants receiving Enzira /Afluria and in 2.5% in the EU-licensed comparator group all of which were considered possibly or probably related to the study vaccine. There was no difference in the overall percentage of participants experiencing general symptoms in either age group. Local symptoms: A moderate number of 27.2% participants receiving Enzira /Afluria and 33% participants receiving the EU-licensed comparator reported local symptoms during the period Day 1 to 3. The most common local symptoms in both groups were pain and erythema. Overall 18% of participants in the Enzira /Afluria group and 16% in the EU-licensed comparator group experienced pain. Overall, erythema occurred in 11.2% receiving Enzira /Afluria and in 17.5% in the EU-licensed comparator group. Induration > 50 mm occurred in 0.5% in the Enzira /Afluria group and in 2.0% in the EUlicensed comparator group. Reactogenicity Comparison Between Study Vaccines The objective of this study with respect to safety was to demonstrate that Enzira /Afluria is no more reactogenic in healthy adults and older adults than an EU-licensed comparator vaccine according to the CHMP criteria. For both Adults and Older Adults the upper CI did not exceed 15% for the difference between Enzira /Afluria and EU-licensed comparator. Thus Enzira /Afluria vaccine was shown to be noninferior to the EU-licensed comparator vaccine in terms of reactogenicity. Unsolicited Adverse Events All AEs in both Adult and Older Adult groups in both study groups were TEAEs. The overall incidence of AEs was small with both Study Vaccines, 1.9% in the Enzira /Afluria group and 4.5% in the EU-licensed comparator group; 1% and 2% of the AEs in each group respectively were considered to be related to the Study vaccine. A total of 2 participants receiving Enzira /Afluria experienced related AEs (all considered moderate in severity): One Adult participant experienced myalgia and one Older Adult experienced headache. A total of 4 participants (2 Adults and 2 Older Adults) receiving EU-licensed comparator experienced a related AE each (all considered mild in severity). The 2 AEs in the Adult group was an injection site reaction and sneezing and the 2 AEs in the Older Adult group were injection site pain and joint stiffness. Conclusions of the Study No AEs were severe and there were no discontinuations due to AEs. There were no SAEs or deaths in this study. The Enzira /Afluria vaccine was no more reactogenic than EU-licensed influenza vaccine in either age group, thus satisfying the objective that Enzira /Afluria is no more reactogenic in healthy adults and older adults than the EU-licensed influenza vaccine. Page 16 (17)

17 Both Study Vaccines were safe and well tolerated. V. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION Overall, the preservative and thiomersal free inactivated influenza vaccine satisfied the CHMP criteria for immunogenicity for influenza vaccine irrespective of the formulation tested. Moreover, the reduction and removal of thiomersal in the manufacturing process and the introduction of the sterile filtration step did not prevent acceptable immunogenicity of the vaccine as tested in elderly subjects. The profile of local and general reactions was consistent with the reactions described previously in the Fluvax SmPC (0.01% w/v thiomersal) and the Company Core Data Sheet. Post-vaccination reactions were transient and self-limiting and peaked within the first 24 to 48 hours following vaccination, leading to resolution of symptoms within a 5-day period. The available clinical data demonstrated that the thiomersal free vaccine satisfies the CHMP criteria for influenza virus vaccines (CPMP/BWP/214/96) in healthy adults and healthy elderly populations. The study of immunogenicity and safety in a paediatric population according to the commitment made to the RMS has been satisfactorily conducted. The study results indicated that the immunogenicity evaluation of the CSL s Inactivated Influenza Vaccine Afluria meets with the CHMP requirements. The safety profile is favourable and no SAEs generating any new safety signals have been identified. No reports on vaccine failure were presented although any such adverse reactions have to be closely monitored. However, the results from the administration of a booster dose in this study population will subsequently confirm the protective effect of the vaccination in a paediatric population. The final study results from the booster vaccination have not yet been reviewed. User testing of the package leaflet has been performed. The risk/benefit evaluation is considered positive. Page 17 (17)