The legally binding text is the original French version TRANSPARENCY COMMITTEE OPINION. 18 July 2012

Transcription

1 The legally binding text is the original French version TRANSPARENCY COMMITTEE OPINION 18 July 2012 FLUENZ, nasal spray suspension Influenza vaccine (live attenuated, nasal) B/10 nasal applicators, 0.2 ml each (CIP code: ) Applicant: ASTRAZENECA Reassortant influenza virus, live attenuated ATC code (2012): J07BB03 (influenza vaccines, influenza live attenuated) List I Medicinal product subject to medical prescription Date of MA (centralised procedure): 27 January 2011 Reason for request: Following the request from the Directorate-General for Health received on 26 June 2012, the Committee is examining FLUENZ with a view to including it on the list of medicines approved for hospital use. Medical, Economic and Public Health Assessment Division 1/25

2 1. CHARACTERISTICS OF THE MEDICINAL PRODUCT 1.1. Active ingredient Reassortant live attenuated, trivalent influenza virus*, each dose of 0.2 ml containing ±0.5 viral particles of the strains** A/H1N1, A/ H3N2 and B. Each of the strains of a vaccine is obtained from a reassortment of the wild and an attenuated strain (donor virus). * propagated in fertilised hen s eggs from healthy chicken flocks. ** produced in Vero cells by reverse genetic technology. This product contains genetically modified organisms (GMOs) Background FLUENZ is the first nasally administered influenza vaccine Indication Prophylaxis of influenza in individuals 24 months to less than 18 years of age. The use of FLUENZ should be based on official recommendations Dosage "Children and adolescents from 24 months: 0.2 ml (administered as 0.1 ml per nostril). For children who have not previously been vaccinated against seasonal influenza, a second dose should be given after an interval of at least 4 weeks. FLUENZ should not be used in infants and toddlers below 24 months of age because of safety concerns. Method of administration: Immunisation must be carried out by nasal administration. DO NOT INJECT FLUENZ." 1.5. Contraindications "Hypersensitivity to the active substances, to any of the excipients (e.g. gelatin), to gentamicin (a possible trace residue), to eggs or to egg proteins (e.g. ovalbumin). Children and adolescents who are clinically immunodeficient due to conditions or immunosuppressive therapy such as: acute and chronic leukaemias; lymphoma; symptomatic HIV infection; cellular immune deficiencies; and high dose corticosteroids. FLUENZ is not contraindicated for use in individuals with asymptomatic HIV infection; or individuals who are receiving topical/inhaled corticosteroids or low-dose systemic corticosteroids or those receiving corticosteroids as replacement therapy, e.g. for adrenal insufficiency. 2/25

3 Children and adolescents younger than 18 years of age receiving salicylate therapy because of the association of Reye's syndrome with salicylates and wild-type influenza virus infection." 1.6. Special warnings and precautions for use "As with most vaccines, appropriate medical treatment and supervision should always be readily available in case of an anaphylactic event following the administration of FLUENZ. FLUENZ should not be administered to children and adolescents with severe asthma or active wheezing because these individuals have not been adequately studied in clinical studies. Do not administer FLUENZ to infants and toddlers younger than 12 months. In a clinical study, an increase in hospitalisations was observed in infants and toddlers younger than 12 months after vaccination. It is not recommended to administer FLUENZ to infants and toddlers months of age. In a clinical study, an increased rate of wheezing was observed in infants and toddlers months of age after vaccination. Vaccine recipients should be informed that FLUENZ is an attenuated live virus vaccine and has the potential for transmission to immunocompromised contacts. Vaccine recipients should attempt to avoid, whenever possible, close association with severely immunocompromised individuals (e.g. bone marrow transplant recipients requiring isolation) for 1-2 weeks following vaccination. Peak incidence of vaccine virus recovery occurred 2-3 days post-vaccination in clinical studies. In circumstances where contact with severely immunocompromised individuals is unavoidable, the potential risk of transmission of the influenza vaccine virus should be weighed against the risk of acquiring and transmitting wild-type influenza virus. FLUENZ should under no circumstances be injected. No data exist regarding the safety of intranasal administration of FLUENZ in children with unrepaired craniofacial malformations." 3/25

4 2. SIMILAR MEDICINAL PRODUCTS 2.1. ATC classification (2012) J : General anti-infectives for systemic use J07 : Vaccines J07B : Viral vaccines J07BB : Influenza vaccines J07BB03 : Influenza, live attenuated None Medicines in the same therapeutic category Strictly comparator medicinal products Non-strictly comparator medicinal products These are the other trivalent, influenza vaccines which can be administered to patients from 24 months old to under 18 years old: AGRIPPAL, suspension for injection in prefilled syringe FLUARIX, suspension for injection in prefilled syringe IMMUGRIP, suspension for injection in prefilled syringe INFLUVAC, suspension for injection in prefilled syringe VAXIGRIP, suspension for injection in prefilled syringe FLUVIRINE, suspension for injection in prefilled syringe (no longer marketed) MUTAGRIP, suspension for injection in prefilled syringe (no longer marketed) PREVIGRIP, suspension for injection in prefilled syringe (no longer marketed) Unlike FLUENZ, these vaccines: - are administered by injection. - contain inactivated viruses - are indicated for use in a wider population (particularly adults) Data from other countries MA obtained in other countries - United States: MA granted on 17 June 2003 for the indication "Prevention of influenza in people from 2 to 49 years old". Marketed in box of 10 nasal applicators. - Canada: MA granted on 22 June 2010 for the indication "Prevention of influenza in people from 2 to 59 years old". Marketed in box of 10 nasal applicators Reimbursement in the European Union - Germany: primary care and hospital reimbursement. - United Kingdom: primary care and hospital reimbursement for children from 5 to 12 years old (from 2014). - Finland, Denmark and Sweden: no reimbursed. 4/25

5 FLUENZ should be marketed in these countries for the 2012/2013 season in boxes of 10 nasal applicators. 3. ANALYSIS OF AVAILABLE DATA In support of its application the company submitted nine clinical studies conducted between 1995 and 2005 which evaluated the efficacy and safety of FLUENZ (live attenuated influenza vaccine, nasal) in a paediatric population: - five placebo-controlled studies, - three studies against an injectable inactivated trivalent vaccine (ITV), - one dose-ranging study (D153-P513 1 ) which will not be described in this opinion. The company also presented the results of several meta-analysis intended to evaluate FLUENZ in paediatric populations Protective efficacy All of the clinical studies presented had in common: - the primary efficacy endpoint: influenza confirmed by positive viral culture caused by strains which were antigenically related to the vaccine strains. - a secondary endpoint: influenza confirmed by a positive viral culture regardless of strain, whether or not antigenically related to the vaccine strain. In the data description, the "efficacy of FLUENZ was defined as the percentage reduction in the incidence of the endpoint compared to the comparator group (placebo or comparator vaccine). "Relative" efficacy described the comparisons between FLUENZ and the comparator vaccine and "absolute" efficacy described the comparisons with the placebo Placebo-controlled studies Only results for the primary and secondary endpoints described above will be shown in the description of these studies Study D153-P501 2 Objectives: the primary objective was to assess the efficacy of the FLUENZ vaccine on the incidence of influenza due to strains which were antigenically related to the vaccine strains during an influenza season in children from 12 months old to under 36 months old. In particular, the secondary objective of this study was to evaluate the efficacy of a booster vaccination of FLUENZ in the influenza season following the first vaccination. Methodology: double-blind, randomised placebo-controlled study. The inclusion criteria included: children from 12 months to under 36 months old, in good health based on their medical history, a physical examination and clinical opinion. The non-inclusion criteria included: chronic disease (signs of heart or renal failure or severe malnutrition, progressive neurological disease, etc.), Down's syndrome or cytogenetic abnormality, immune system disease or immunosuppressant therapy, previous influenza 1 Forrest BD, Pride MW, Dunning AJ, et al. Correlation of cellular immune responses with protection against culture-confirmed influenza virus in young children. Clin. Vaccine Imm. 2008; 15: Tam JS, Capeding MRZ, Lum LCS, et al. Efficacy and safety of a live attenuated, cold-adapted influenza vaccine, trivalent against culture-confirmed influenza in young children in Asia. Pediatr. Infect. Dis. J. 2007; 26: /25

6 vaccination, any previous vaccination with a live vaccine, respiratory disease within two weeks before the start of the study, intake of aspirin or treatment for influenza within two weeks before inclusion. Treatments: A total of 3174 children were included in the first year of the study and randomised (3:2) to the following two treatment groups: - FLUENZ, two doses, 1 month apart, n= Placebo, two doses, 1 month apart, n=1274. At the beginning of the second season (second year), 2947 children from the first series were randomised again (1:1), irrespective of their treatment allocation in the first year, into the following two treatment groups: - FLUENZ one dose, n=1477. Of these patients, 881 had already received FLUENZ in the first year and 596 had received the placebo. - placebo, one dose, n=1470. Of these patients, 876 had received FLUENZ in the first year and 594 had already received the placebo. Results: In the first influenza season the incidence of influenza due to strains of virus related to the vaccine strains was 3.4% in the FLUENZ group compared to 12.5% in the placebo group, i.e. the absolute efficacy of FLUENZ was 72.9% compared to the placebo. The results at the end of the first year are shown in Table 1 below. Table 1. Study D153-P501: Efficacy of FLUENZ against influenza confirmed by viral culture during the first influenza season. Treatment group Absolute efficacy, % Strains of influenza FLUENZ Placebo [95% CI ] N* n** (%) N* n** (%) Influenza strains antigenically related to the vaccine strains (primary endpoint) PP population All vaccine strains (3.4) (12.5) 72.9 ( ) A/H1N (1.4) (7.3) 80.9 ( ) A/H3N (0.2) (2.4) 90.0 ( ) B (1.8) (3.2) 44.3 ( ) ITT population All vaccine strains (3.7) (12.3) 70.1 ( ) All strains regardless of antigenic correspondence (secondary endpoint) PP population, all vaccine strains (4.9) (16.4) 70.1 ( ) ITT population, all vaccine strains (5.2) (16.0) 67.8 ( ) * Number of children in the analysis ** Number of children with a positive viral culture. Results from the second year vaccination are shown in Table 2 below. During the second year, the absolute efficacy of FLUENZ in children who had been given two doses in the first year and a booster dose in the second year was 84.3% against strains of viruses related to those included in the vaccine (1.6% incidence in the FLUENZ/FLUENZ group compared to 9.9% in the placebo/placebo group). If vaccination was not given again in the second year, the efficacy of FLUENZ was 56.2% (4.3% incidence in the FLUENZ /placebo group compared to 9.9% in the placebo/placebo group). These findings suggest that FLUENZ maintains protection in the influenza season following the vaccination season, together with the benefit of a booster vaccination (Cf. FLUENZ/FLUENZ versus FLUENZ/placebo comparison). 6/25

7 Table 2. Study D153-P501: Absolute efficacy of FLUENZ against influenza confirmed by viral culture during the second year. Strains antigenically related to the All strains vaccine strains (antigenically related or not) Cases of Treatments compared Cases of influenza/ Absolute Absolute influenza/ (Treatment Year 1/ Comparison efficacy, % efficacy, % Comparison Treatment Year 2) populations [95% CI] [95% CI] populations FLUENZ/FLUENZ versus. 12/771 versus. 33/771 versus [ ] 64.2 [ ] placebo/placebo 49/494 59/494 FLUENZ/placebo versus. 33/759 versus. 70/759 versus [ ] 44.8 [ ] placebo/placebo 49/494 59/494 FLUENZ/FLUENZ versus. 12/771 versus. 33/771 versus [ ] 35.0 [ ] FLUENZ/placebo 33/759 50/759 FLUENZ/FLUENZ versus. 12/771 versus. 33/771 versus [ ] 17.2 [ ] placebo/fluenz 20/503 26/503 placebo/fluenz placebo/placebo versus. 20/503 versus. 49/ [ ] 26/503 versus. 59/ [ ] Study D153-P502 3 Objectives: the primary objective was to evaluate the efficacy of the FLUENZ vaccine on the incidence of influenza due to strains which were antigenically related to the vaccine strains in an influenza season in children from 6 months to under 36 months old. One particular secondary objective of the study was to evaluate the efficacy of booster vaccination with FLUENZ in the influenza season following the first vaccination. Methodology: double-blind, randomised, placebo-controlled phase III study. The inclusion criteria included: children from 6 months to under 36 months old, in good health based on their medical history, a physical examination and clinical opinion. Non-inclusion criteria: identical to those in study D above. Treatments: A total of 1784 children were included in the first year of the study and randomised (3:2) into the two following treatment groups: - FLUENZ, two doses 35±7 days apart, n= placebo, two doses 35±7 days apart, n=725. During the second season (second year), children were given a dose of the same vaccine (FLUENZ, n=658 or placebo, n=461) as the one given in the first year. Results: In the first influenza season the incidence of influenza due to strains of virus related to the vaccine strains was 1.6% in the FLUENZ group compared to 10.8% in the placebo group, i.e. the absolute efficacy of FLUENZ was 85.4% compared to the placebo. Efficacy could not be evaluated for the A/H3N2 subtype as there were too few cases. FLUENZ was found to be similarly effective (85.9%) regardless of the genetic correspondence of the strains (related or otherwise). The results from the first year are shown in Table 3 below. 3 Vesikari T, Fleming DM, Aristegui JF, et al. Safety, efficacy, and effectiveness of cold-adapted influenza vaccine trivalent against community-acquired, culture-confirmed influenza in young children attending day care. Paediatrics. 2006; 118: /25

8 Table 3. Study D153-P502: Absolute efficacy of FLUENZ against influenza confirmed by viral culture during the first influenza season. Treatment Strains of influenza FLUENZ Placebo Absolute efficacy, % [95% CI] N* n** (%) N* n** (%) Strains antigenically related to the vaccine strains (primary endpoint) PP population All strains (1.6) (10.8) 85.4 [ ] A/H1N (0.6) (7.7) 91.8 [ ] A/H3N (0.0) (0.2) Not established B (0.9) (3.5) 72.6 [ ] ITT population All strains All strains, regardless of their antigenic correspondence (secondary endpoint) (1.8) (10.9) 83.5 [ ] PP population, all vaccine strains (1.9) (13.4) 85.9 [ ] ITT population, all vaccine strains (2.2) (13.4) 83.8 [ ] * Number of children in the analysis ** Number of children with a positive culture During the second influenza season the overall efficacy of the vaccine on strains related to the vaccine strains was 88.7%, 95% CI [ ] i.e. a 3.3% incidence in the FLUENZ group compared to 29.1% in the placebo group. The absolute efficacy of FLUENZ was 85.8%, 95% CI [ ] in the second year for all strains, whether or not antigenically related Study D153-P504 4 Objectives: the primary objective was to independently evaluate one and two doses of FLUENZ on the incidence of influenza due to strains which were antigenically related to the vaccine strains, during an influenza season in children aged 6 to 36 months old. A particular secondary objective of the study was to evaluate a booster FLUENZ vaccination in the influenza season following the first vaccination. Methodology: double-blind, randomised, placebo-controlled, phase III study. The inclusion criteria included: children from 6 to under 36 months old, in good health based on their medical history, a physical examination and clinical opinion. The non-inclusion criteria included: these were identical to those in the previous studies. Treatments: A total of 3200 children were included in the first year of the study and randomised into one of the four following treatment groups (2:2:1:1): - FLUENZ, two doses 35±7 days apart, n= FLUENZ, one dose, n= placebo (saline solution) 5, two doses 35±7 days apart, n= placebo (excipient), two doses, 35±7 days apart, n= Bracco HN, Farhat CK, Tregnashi MW, et al. Efficacy and safety of one and two doses of live attenuated influenza vaccine in vaccine-naive children. Pediatr. Infect. Dis. J. 2009; 28: Children in the placebo group were given a saline solution or placebo excipient consisting of the vaccine excipient alone (i.e. pig gelatine treated by acid hydrolysis). The difference between the two placebos was only taken into account for the safety study. 8/25

9 In the second season, a total of 2202 patients were included: - children who had received at least one or two doses of FLUENZ in the first year were again given a further dose of FLUENZ (n=1467); - patients who were given a placebo vaccine in the first year were all given a dose of placebo saline solution (n=735). PP population results 6 : In the first year, administration of one dose of FLUENZ had an absolute efficacy of 57.7%, 95% CI [44.7; 67.9] against strains which were antigenically related to the vaccine strains and administration of two doses had an efficacy of 73.5%, 95% CI [63.6; 81.0]. The relative efficacy of two doses of FLUENZ compared to strains antigenically related to the vaccine strains was 37.3%, 95% CI [9.5; 56.9]. In the first influenza season most of the cases of influenza were due to strains which were antigenically related to the vaccine strains. The absolute efficacy of a dose of FLUENZ administered in the second influenza season against strains which were antigenically related to the vaccine strains was: %, 95% CI [31.2; 82.8] for patients who had been given one dose of FLUENZ during the first influenza season, %, 95% CI [33.3; 91.2] for patients who had been given two doses of FLUENZ during the first influenza season, %, 95% CI [10.9; 83.8] for patients who had been given two doses of placebo during the first influenza season Study AV006 7 This study involved two phases, an initial phase covering the first influenza season and a second covering the subsequent influenza season. Objectives: The primary objective of the first year was to demonstrate the efficacy of one or two doses of FLUENZ on the incidence of influenza confirmed by positive viral culture and caused by strains which were antigenically related to the vaccine strains, in children from 15 to 71 months old. The primary objective of the second phase was to demonstrate the efficacy of a further vaccination of one dose of FLUENZ in patients vaccinated with FLUENZ in the previous influenza season using the same endpoint. Methodology: double-blind, randomised, placebo-controlled study. The inclusion criteria included: children from 15 to under 71 months old, in good health based on their medical history, a physical examination and clinical opinion. The children had not to have received any previous influenza vaccination. Vaccine regimen: During the first year of the study, 1602 children were included and randomised into one of the following two treatment groups (2:1): - FLUENZ, n= Placebo, n=532 Patients were given one dose (n=288) or two doses (n=1314) of vaccine. Allocation of the number of doses administered was not randomised. 6 The incidence of influenza in each group is not available in the file submitted by the company. 7 Belshe RB, Mendelman PM, Treanor J. et al. The efficacy of live attenuated, cold-adapted, trivalent, intranasal influenza virus vaccine in children. N. Engl. J. Med. 1998; 338: /25

10 In the second influenza season, 1358 children of those who completed the first part of the study were given a further dose of the vaccine given the year previously: - FLUENZ (n=917) - Placebo (n=441) Results 8 : The efficacy results for FLUENZ during the first year are shown in Table 4 below. Table 4. Study AV006 Year 1: absolute efficacy of FLUENZ in preventing cases of influenza confirmed by viral culture and due to antigenically related strains (primary endpoint). Treatment received Strain Absolute efficacy of FLUENZ [95% CI] All strains 93.4% [ ] Two doses of FLUENZ One dose of FLUENZ All subjects randomised H3N2 96.0% [ ] B 90.5% [ ] All strains 88.8% [ ] H3N2 86.9% [ ] B 91.3% [ ] All strains 92.6% [ ] H3N2 94.5% [ ] B 90.6% [ ] During the first year, the absolute vaccination efficacy of two doses of FLUENZ was 93.4%, 95% CI [87.5; 96.5] on the incidence of influenza confirmed by positive viral culture and caused by strains which were antigenically related to the vaccine strains. Efficacy was 88.8% in the group of patients who were only given a single dose, regardless of whether or not the strains were related to the vaccine strains. After a further FLUENZ vaccination in the second influenza season, the absolute efficacy of FLUENZ was 100%; 95% CI [63.1; 100] against antigenically related strains and 87.1%; 95% CI [77.7; 92.6] against all strains, whether or not related Comparative studies against injectable trivalent vaccine Study M1-CP111 9 Primary endpoint: to evaluate the relative efficacy and safety of the Fluenz vaccine versus the inactivated trivalent vaccine (ITV) over an influenza season 10, in patients from 6 to 59 months old. Methodology: double-blind, double-placebo, randomised phase III study against ITV Vaccination regimen: A total of 8475 children were included and randomised (1:1) into one of the following two treatment groups: - FLUENZ, n= Intramuscular ITV, n=4232 Children who had already been vaccinated against influenza were given one dose of vaccine whereas those who were being vaccinated for the first time were given two doses, 28 to 42 days apart. 8 The incidence of influenza in each group is not available in the file submitted by the company. 9 Belshe RB, Edwards KM, Vesikari T, et al. Live attenuated compared to inactivated influenza vaccine in infants and young children. N. Engl. J. Med. 2007; 356: VAXIGRIP in Europe, containing 15 µg of each subtype. 10/25

11 In the ITV group, the dose of vaccine depended on age (0.25 ml in children from 6 to 35 months old and 0.5 ml in children over 35 months old). Randomisation was stratified by age, country, past history of influenza vaccination and past history of wheezing. The inclusion criteria included: age from 6 to 59 months old and parents available to monitor the children and attend the necessary medical visits. The non-inclusion criteria included: immunodeficiency, including HIV or concomitant receipt of immunosuppressant therapy, past history of wheezing diagnosed or treated within the 42 days before inclusion, past history of severe asthma, receipt of aspirin within the month before inclusion. Primary efficacy endpoint: relative efficacy of FLUENZ compared to ITV in preventing culture-confirmed influenza caused by strains related to the vaccine strains. Non-inferiority of FLUENZ was established if the lower limit of the 95% CI for efficacy was > -30 and superiority if the lower limit of the 95% CI was > 0 (limits defined prospectively). The secondary endpoints included: - relative efficacy of FLUENZ compared to ITV in preventing culture confirmed influenza caused by strains unrelated to the vaccine strains and by any strain of virus. - incidence of acute otitis media (AOM) and respiratory tract infections. Patient characteristics (ITT population): 47.5% of the patients included were between 6 to 23 months old (off-label population), 32.9% were from 24 to 35 months old and 19.6% were from 36 to 59 months old. These proportions were similar in both treatment groups. Almost 9% of patients were suffering from an underlying disease, mostly (76%) chronic lung disease. Approximately 21% of the patients included had a past history of wheezing, 6% had a past history of recurrent wheezing and 4% had asthma (benign or moderate form). Results: The relative efficacy results for FLUENZ compared to ITV are shown in Table 5 below. FLUENZ was superior to the injectable vaccine in terms of reducing the incidence of viral culture-confirmed influenza caused by strains which were antigenically related to the vaccine strains with a relative efficacy of 44.5% (95% CI limit > 0) with an incidence of influenza of 1.4% (53/3893) in the FLUENZ group compared to 2.4% (93/3943) in the ITV group. FLUENZ is particularly effective against the A/H1N1 subtype but was not shown to be superior against the B subtype. 11/25

12 Table 5. Study MI-CP111: Results for the primary endpoint (cases of viral culture-confirmed influenza due to strains antigenically related to the vaccine). Number of cases of influenza n FLUENZ N=3893 Attack rate n/n Number of cases of influenza n ITV N=3943 Attack rate n/n Relative efficacy 95% CI All strains % % 44.5% [22.4; 60.6] A/H1N % % 89.2% [67.7; 97.4] A/H3N % 0 0.0% B % % 27.3% [-4.8; 49.9] Results according to stratification factors Previous influenza vaccination Age Yes % % 39.3% [-9.2; 66.9] No % % 46.9% [20.0; 65.2] 6 to 23 months % % 29.1% [-21.2; 59.1] 24 to 35 months % % 32.6% [-25.8; 82.4] 36 to 59 months % % 65.6% [36.3; 82.4] The relative efficacy of FLUENZ compared to ITV in reducing the incidence of viral cultureconfirmed influenza due to strains which were antigenically not related to the vaccine strains was 58.2%, 95% CI [47.4; 67.0], with a 2.6% incidence of influenza in the FLUENZ group compared to 6.2%. The overall efficacy of FLUENZ was 54.9%, 95% CI [45.4; 62.9], whether or not the strains were related to the vaccine strains. The incidence of acute otitis media and lower respiratory tract infections associated with a positive culture for the influenza virus, regardless of antigenic correspondence, was lower in the FLUENZ group than in the ITV group, with a relative efficacy of 50.6%, 95% CI [21.5; 69.5] and 45.9%, 95% CI [4.4; 70.2] respectively. The incidence of influenza-related AOM was 5.0% in the FLUENZ group and 10% in the ITV group Study D153-P Primary objective: to demonstrate that the efficacy of the FLUENZ vaccine was not inferior to that of an injectable inactivated trivalent vaccine (ITV) in preventing cases of influenza confirmed by viral culture over an influenza season in patients from 6 to 71 months old with a past history of recurrent respiratory tract infections. Methodology: open, randomised, comparative phase III study against ITV. Vaccination regimen: A total of 2187 children were included and randomised (1:1) into one of the following two treatment groups: - FLUENZ, two doses, n= Intramuscular ITV 12, two doses, n=1086 In the ITV group the dose of vaccine depended on age (0.25 ml in children from 6 to 35 months old and 0.5 ml in children over 35 months old). 11 Ashkenazi S, Vertruyen A, Aristegul J, et al. Superior relative efficacy of live attenuated influenza vaccine compared with inactivated influenza vaccine in young children with recurrent respiratory tract infections. Pediatr. Infect. Dis J. 2006; 25: Vaccine containing 15 µg of each of the three sub-types. 12/25

13 The inclusion criteria included: - age from 6 months to under 72 months old at inclusion - past history of recurrent respiratory infections defined as: two or more visits to a doctor for a respiratory infection in the previous 12 months (or since birth). The respiratory infections included particularly colds, acute otitis media and lower respiratory tract infections (bronchiolitis, bronchitis and pneumonia). The non-inclusion criteria included: previous influenza vaccination, any experimental vaccination in the month before inclusion, serious chronic disease (including progressive neurological disease), Down's syndrome or other cytogenetic abnormality, known/suspected immune system disease or immunosuppressant therapy (including systemic corticosteroids), past history of severe asthma, receipt of aspirin within the 2 weeks before inclusion. Primary efficacy endpoint: relative efficacy of FLUENZ compared to ITV in preventing culture-confirmed influenza caused by strains related to the vaccine strains. Non-inferiority of FLUENZ compared to ITV was established if the lower limit of the 90% CI for relative efficacy was > -0.5 and superiority was established if the lower limit of the 95% CI was > 0. The secondary endpoints included: - relative efficacy of FLUENZ compared to ITV in preventing culture-confirmed influenza, regardless of strain of virus, - relative efficacy of FLUENZ compared to ITV on the: incidence of acute otitis media, the incidence of hospital admission, unplanned medical visits, use of antibiotics or other medicinal products to treat respiratory tract infections, episodes of wheezing associated with a flu-like illness and days of absence from school or childcare facility. Patient characteristics at inclusion: The patients included in the two treatment groups were similar in terms of age, sex, ethnic origin and medical history. Almost 45% of the patients in each group had a past history of wheezing and approximately 23% were asthmatic. Results The relative efficacy results for FLUENZ compared to ITV are shown in Table 6 below. The incidence of influenza confirmed by viral culture and caused by strains which were antigenically related to the vaccine strains was 2.3% (24/1050) in the FLUENZ group compared to 4.8% (50/1035) in the ITV group. The superiority of FLUENZ was demonstrated against ITV with a relative efficacy of 52.7% (lower 95% CI limit > 0). FLUENZ was not shown to be superior for the A/H3 subtype from the strain subtype analyses. 13/25

14 Table 6. Study D153-P514: Results for the primary endpoint (influenza confirmed by viral culture and due to strains which were antigenically related to the vaccine strains). FLUENZ N=1050 ITV N=1035 Number of cases of influenza n* Attack rate n/n Number of cases of influenza n* Attack rate n/n Relative efficacy % 95% CI Per protocol population All strains of the vaccine % % 52.7 [21.6; 72.2] A/H % 8 0.8% 100 [42.3; 100.0] A/H % 6 0.6% [-540.2; 31.5] B % % 68.0 [37.3; 84.8] * n= number of children suffering from influenza confirmed by a positive viral culture. The relative efficacy of FLUENZ compared to ITV regardless of antigenic correspondence of the strains was 52.4%; 95% CI [24.6; 70.5]. No statistically significant difference was found in the incidence of AOM associated with a positive viral culture for an influenza virus which was antigenically related to the vaccine strains between the two vaccines. There were two cases in the FLUENZ group and 6 in the ITV group. No difference in efficacy was found between FLUENZ and ITV on the incidence of hospital admissions, use of antibiotics or other medicinal products to treat respiratory tract infections or in episodes of wheezing associated with a flu-like illness. Statistically fewer unplanned visits to a health care professional were found in the FLUENZ group compared to the ITV group (relative efficacy: 8.9%; 90% CI [1.5; 15.8], absolute difference between the groups of 0.1 visits) statistically fewer days of absence from school/childcare facility were also found in the FLUENZ group (relative efficacy 16.2%; 90% CI [10.4; 21.6], absolute difference between the groups 0.4 days) Study D153-P Primary objective: to demonstrate that the efficacy of the FLUENZ vaccine is not inferior to that of the injectable inactivated trivalent vaccine (ITV) in terms of preventing cases of influenza confirmed by viral culture over an influenza season in asthmatic children and adolescents from 6 months to under 18 years old. Methodology: open, randomised, comparative phase III study against ITV. Vaccine regimen: A total of 2229 children were included and randomised (1:1) into one of the following two treatment groups: - FLUENZ, one dose, n= Intramuscular ITV, 14 one dose, n= Fleming D, Crovari P, Wahn U, et al. Comparison of the efficacy and safety of live attenuated cold-adapted influenza vaccine, trivalent, with trivalent inactivated influenza virus vaccine in children and adolescents with asthma. Pediatr. Infect. Dis. J. 2006; 25: Vaccine containing 15 µg of each of the three sub-types. 14/25

15 The inclusion criteria included: - age from 6 to 17 years old at inclusion - patients with stable, medically treated asthma (clinical diagnosis based on the ICD9 classification 15 and patients who needed to receive at least one medicinal product to treat asthma in the previous 12 months), The non-inclusion criteria included: previous influenza vaccination, any experimental vaccination within the month before inclusion, serious chronic disease (including progressive neurological disease), Down's syndrome or other cytogenetic abnormality, known/suspected immune system disease or immunosuppressant therapy (including high dose 16 systemic corticosteroids), past history of severe asthma, receipt of aspirin within 2 weeks prior to inclusion. Primary efficacy endpoint: relative efficacy of FLUENZ compared to ITV in preventing culture-confirmed influenza caused by strains related to the vaccine strains. FLUENZ was established to be non-inferior to ITV if the lower limit of the 90% CI for relative efficacy was > -0.5 and superiority if the lower limit of the 95% CI was > 0. The secondary endpoints included: - relative efficacy of FLUENZ compared to ITV in preventing culture-confirmed influenza, regardless of the strain of virus. - relative efficacy of FLUENZ compared to ITV on the incidence of exacerbations of asthma, hospitalisations, unplanned medical visits, use of antibiotics or other medicinal products to treat respiratory tract infections and days of absence from school or childcare facility due to influenza. Patient characteristics at inclusion: The patients included in two treatment groups were similar in terms of age, sex, ethnic origin and history of asthma (age at diagnosis, number of hospital admissions, previous and current treatments). Approximately 69% (1539/2229) of patients in each group were taking an inhaled corticosteroid treatment. Results The relative efficacy results of FLUENZ compared to ITV are shown in Table 7 below. The incidence of influenza confirmed by viral culture and caused by strains which were antigenically related to those in the vaccine was 4.1% (46/1109) in the FLUENZ group and 6.4% (70/1102) in the ITV group. FLUENZ was therefore shown to offer greater efficacy than ITV with a relative efficacy of 34.7% (lower limit of the 95% CI > 0). FLUENZ was not established to be non-inferior for the A/H3 subtype from the results by strain subtype. 15 ICD9: International Classification of Diseases, Ninth revision. 16 A "high dose" was defined as a dose 2 mg/kg/d (children under 10 kg) or 20 mg/d of prednisolone or its equivalent. In order to be included patients who had already received high dose corticosteroids had to have stopped their treatment for at least 1 month before inclusion. 15/25

16 Table 7. Study D153-P515: Results for the primary endpoint (influenza confirmed by viral culture and due to strains which were antigenically related to the vaccine strains). Per protocol population FLUENZ ITV Efficacy Cases of influenza* n (%) Cases of influenza* n (%) Relative efficacy % 90% CI 95% CI All strains of the vaccine 46 (4.1) 70 (6.4) 34.7 (9.4; 53.2) (3.9; 56.0) A/H1 0 (0.0) 5 (0.5) (18.5; 100.0) (-8.4; 100.0) A/H3 12 (1.1) 12 (1.1) 0.6 (-111.7; 53.4) (-141.8; 59.2) B 34 (3.1) 53 (4.8) 36.3 (6.6; 56.8) (0.1; 59.8) ITT population All strains of the vaccine 46 (4.1) 70 (6.3) 34.2 (8.7; 52.9) (3.2; 55.7) * n=number of children suffering from influenza confirmed by positive viral culture The relative efficacy of FLUENZ compared to ITV, regardless of the antigenic correspondence of the strains, was 31.9%; 95% CI [1.1; 53.5], with a 4.5% incidence of influenza in the FLUENZ group compared to 6.6% in the ITV group. No significant difference was seen in the incidence of exacerbations of asthma, hospital admissions, unplanned medical visits, use of antibiotics or other medicinal products to treat respiratory tract infections and absence from school or childcare facility between the two groups Meta-analysis data The following will not be described in the opinion: - the Belshe 2008 meta-analysis 17 as this is based on three studies included in the Rhorer 2009 meta-analysis. - the Osterholm 2011 meta-analysis 18 as no randomised studies evaluating ITV in patients from 2 to 17 years old (MA population) were included Rhorer, 2009 meta-analysis 19 The purpose of the Rohrer meta-analysis was to evaluate the protective efficacy of the FLUENZ live attenuated vaccine compared to placebo and to an injectable inactivated trivalent vaccine (ITV). This meta-analysis included nine randomised paediatric clinical studies, eight of which have been described previously in this opinion and which consisted of six placebo-controlled studies (AV006, D153-P501, D153-P502, D153-P504, D153-P513, D153-P522) and three studies versus ITV (D153-P514, D153-P515, M1-CP111). These included almost 25,000 children from 6 to 71 months old and 2000 children from 6 to 17 years old. Depending on the study, the children were given one or two doses of vaccine during the first influenza season and could be given one dose in the following influenza season. The endpoint was the efficacy of the FLUENZ vaccine in terms of reducing the number of cases of influenza confirmed by a positive viral culture, against the comparator group. 17 Belshe RB, Ambrose CS, Tingting Y. Safety and efficacy of live attenuated influenza vaccine in children 2 7 years of age. Vaccine 26S. 2008; D10 D16 18 Osterholm MT, Kelley NS, Sommer A, Belongia EA. Efficacy and effectiveness of influenza vaccines: a systematic review and meta-analysis Lancet Infect Dis 2012; 12: Rhorer J, Ambrose CS, Dickinson S, Hamilton H, Oleka N, Malinoski F, Wittes J. Efficacy of live attenuated influenza vaccine in children: A meta-analysis of nine randomized clinical trials. Vaccine ; /25

17 Results Efficacy of two doses of FLUENZ in children who had previously not been vaccinated against influenza. The overall efficacy of FLUENZ in children under 3 years old was 77% (95% CI [72%, 80%], p< 0.001) compared to the placebo for strains which were antigenically related to the vaccine strains and 72% for unrelated strains. By viral strain subtype, the efficacy of FLUENZ was 85% against the A/H1N1 subtype, 76% for the A/H3N2 subtype and 73% for the B subtype (antigenically related strains). Efficacy of one dose of FLUENZ in children who had not previously been vaccinated against influenza Compared to the placebo, the efficacy of FLUENZ after administration of one dose was 60% (p<0.001) for antigenically related strains with a 6% incidence of influenza confirmed by viral culture in the FLUENZ group and 15% in the placebo group. Efficacy of one dose of FLUENZ in children vaccinated with FLUENZ the year previously Compared to the placebo, the efficacy of re-vaccination with a dose of FLUENZ in children who had been given two doses of FLUENZ in the previous season was 87% for antigenically related strains. The incidence of influenza confirmed by viral culture was 2% in children given FLUENZ and 13% in children given the placebo. Efficacy of FLUENZ compared to ITV The comparative data are based on the combined results of three studies which included approximately 13,000 children from 6 months to 17 years old. The relative efficacy of FLUENZ in the studies which compared two doses of FLUENZ to two doses of ITV in vaccination-naïve children under 6 years old was 46% for antigenically related strains. In studies which included older children (from 6 to 17 years old) who had previously been vaccinated, the children who were given a dose of FLUENZ had 35% fewer cases of influenza than those who were given a dose of ITV. The authors concluded in particular that: - FLUENZ was demonstrated to be effective compared to placebo, although no difference was found according to patient age or viral subtype. - The efficacy of FLUENZ was always greater than that of ITV in the studies conducted against ITV. It should be noted that some authors declared that they were paid as consultants by MedImmune, a subsidiary of AstraZeneca and licence holder of the intranasal live attenuated vaccine particularly in the United States Belshe 2010 meta-analysis 20 The aim of this meta-analysis was to establish whether the efficacy of the FLUENZ vaccine varied according to age of the children vaccinated. Four randomised paediatric clinical studies were included in this meta-analysis: 1 placebocontrolled study (AV00: children from 15 to 83 months old) and 3 studies against ITV (M1- CP111, D153-P514, D153-P515: children from 6 months to 17 years old). The authors concluded in particular from the results of this meta-analysis that the protective efficacy of FLUENZ did not vary with age: - in children from 15 to 84 months old, compared to the placebo, - in children from 6 months to 17 years old compared to ITV. 20 Belshe RB, Toback SL, Tingting Y, Ambrose CS. Efficacy of live attenuated influenza vaccine in children 6 months to 17 years of age. Influenza and Other Respiratory Viruses. 2010; 4(3), /25

18 It should be noted that on the date of publication of this meta-analysis, three of the authors were employed by MedImmune, a subsidiary of AstraZeneca and the licence holder for the live attenuated intra-nasal vaccine, particularly in the United States Block, The aim of this pooled analysis was to evaluate the efficacy of FLUENZ on the incidence of acute otitis media (AOM) compared to placebo and to an injectable inactivated trivalent vaccine (ITV), as the influenza virus can be associated with AOM in children. This analysis included eight randomised, paediatric studies, six of which were placebocontrolled (studies AV006, D153-P501, D153-P502, D153-P504 and D153-P513) and two were against ITV (D153-P514, M1-CP111). Of the 24,046 children from 6 to 83 months old who were included, 47% were under 24 months old, 84% were in good health and 11% had a past history of wheezing. One of the secondary endpoints of these studies was the efficacy of FLUENZ against acute otitis media. Results: In the pooled analysis of the two studies versus ITV, the incidence of influenza-associated AOM, confirmed by viral culture, regardless of antigenic correspondence of the strain, was 0.6% (28/4966) in children vaccinated with FLUENZ and 1.2% (61/4971) in children who were given ITV. The relative efficacy of FLUENZ in preventing influenza-associated AOM was 54.0% (95% CI [27.0%; 71.7%]) compared to ITV. In the placebo-controlled studies, the absolute efficacy of FLUENZ was 85.0% (95% CI [78.3%; 89.8%]). The incidence of AOM in children who developed influenza despite being vaccinated was similar in the FLUENZ and ITV groups (15.38% compared to 15.33%). It should be noted that writing of this article was funded by MedImmune Adverse effects Safety data from the SPC The safety data on FLUENZ were obtained from more than 28,500 children and adolescents from 2 to 17 years old from clinical studies and from more than 52,500 children and adolescents from post-authorisation safety studies. Additional safety data were obtained during the use of the vaccine after it was marketed. The most commonly reported adverse effects in clinical studies in children were nasal congestion/rhinorrhoea. The most commonly reported adverse effects were as follows: - very common ( 1/10): nasal congestion/rhinorrhoea, reduced appetite, headaches, malaise. - common ( 1/100, < 1/10): myalgia, headaches. 21 Block SL, Heikkinen T, Toback SL, Zheng W, Ambrose CS. The efficacy of live attenuated influenza vaccine against influenza-associated acute otitis media in children. The paediatric infectious disease journal. March Volume 30, number 3. 18/25

19 An increased number of hospital admissions (all causes combined) was found in the 180 days after administration of the last dose of the vaccine in infants and children from 6 to 11 months old in the MI-CP111 clinical study (FLUENZ versus injectable inactivated trivalent vaccine), (6.1% with FLUENZ compared with 2.6% with the injectable influenza vaccine). The hospital admission rate was not increased in one-year-old and older patients who were given FLUENZ. An increased incidence of episodes of wheezing was reported in this study over 42 days in infants and children from 6 to 23 months old (5.9% with FLUENZ compared to 3.8% with the injectable influenza vaccine). The incidence of episodes of wheezing did not increase in one-year-old and older patients who were given FLUENZ. FLUENZ is not indicated for use in infants and children under 24 months old. Very rare cases of Guillain-Barré syndrome and exacerbation of Leigh's syndrome (mitochondrial encephalomyopathy) have also been reported since FLUENZ was first marketed Other safety data The majority of expected adverse effects reported in the clinical trials were mild to moderate in severity and short-lasting. They were generally less common following the second dose than the first dose in first vaccination or annual vaccination. The most commonly reported adverse effects with a significantly higher incidence in the FLUENZ group than in the comparator groups (placebo and injectable inactivated vaccine) were nasal rhinorrhoea/congestion, headaches and myalgia. Pharmacovigilance data collected since FLUENZ was first marketed (in other countries) have not revealed any particular or new signal. The safety profile of FLUENZ in children from 2 to 17 years old is consistent with what is described in the SPC. During the period from 17 June 2011 until 16 December 2011 (the period covering the last PSUR), 11.5 million patients were exposed to the FLUENZ vaccine, all ages combined. Total exposure since the first MA (2003) is more than 52 million people. 22 Examination of clinical trial data and data from its use since it was first marketed show that FLUENZ has a similar safety profile to that of the injectable inactivated vaccines Conclusion Data on the protective efficacy of FLUENZ in children and adolescents aged from 24 months to under 18 years old are based principally on the results of five randomised placebo-controlled studies and three controlled studies versus an injectable inactivated trivalent vaccine (ITV). The aim of all of these studies was to evaluate the efficacy of FLUENZ defined as the percentage reduction in the incidence of influenza in the FLUENZ group, compared either to the placebo or to an injectable inactivated, trivalent vaccine. In the three controlled studies versus ITV, FLUENZ was demonstrated to be superior in reducing the number of cases of influenza caused by strains related to the vaccine strains. The absolute reduction in the incidence of influenza compared to ITV was between 1.2 and 2.5%, i.e. a relative efficacy of between 35% and 53% depending on the study. The incidence in the M1-CP111 study in children from 6 to 59 months old was 1.4% in the FLUENZ group compared with 2.4% n the ITV group. The incidence of influenza in the D153-P514 study in children from 6 to 71 months old with a past history of recurrent lower 22 During the first 4 years when it was marketed, FLUENZ was approved for vaccination in subjects from 5 to 49 years old. The indication for FLUENZ vaccination has been extended to children from 24 to 59 months old since /25

20 respiratory tract infections was 2.3% in the FLUENZ group compared with 4.8%. The incidence of influenza in study D153-P515 in children from 6 to under 18 years old suffering from non-severe asthma was 4.1% in the FLUENZ group compared to 6.4% in the ITV group. No difference was demonstrated between FLUENZ and ITV in the incidence of hospital admissions or use of antibiotics associated with influenza in patients from 2 to 18 years old. The absolute efficacy of FLUENZ in terms of the incidence of influenza caused by antigenically-related strains in the placebo-controlled studies in children from 6 to 71 months old who were in good health, ranged from 62.2% to 93.4% depending on the study. In terms of safety, the FLUENZ safety data have been obtained from more than 28,500 children and adolescents from 2 to 17 years old in clinical studies and from more than 52,500 children and adolescents in post-authorisation safety studies. The most commonly adverse effects (AE) reported in the clinical studies in patients given FLUENZ were nasal congestion/rhinorrhoea, headaches and myalgia. These AE were reported more commonly for FLUENZ than for the placebo or ITV. Post-marketing pharmacovigilance data on FLUENZ in other countries have not shown any particular signal. FLUENZ has a similar safety profile to that of the injectable inactivated vaccines. 20/25