TRANSPARENCY COMMITTEE OPINION. 4 March 2009

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1 The legally binding text is the original French version TRANSPARENCY COMMITTEE OPINION 4 March 2009 MENCEVAX powder and solvent for solution for injection Meningococcal polysaccharide vaccine for serogroups A, C, Y, W 135 Powder and solvent in prefilled syringe with needles B/1 (CIP: ) Powder and solvent in vials B/1 (CIP: ) Powder and solvent in 10-dose vials B/50 (CIP: ) Applicant: GLAXOSMITHKLINE Serogroup A Neisseria meningitidis Serogroup C Neisseria meningitidis Serogroup Y Neisseria meningitidis Serogroup W 135 Neisseria meningitidis List I ATC Classification: J07AH04 Date of Marketing Authorisation (MA): 19 May 2008 Procedure: Mutual Recognition Reason for request: Inclusion on the list of medicines approved for use by hospitals. Medical, Economic and Public Health Assessment Division 1

2 Active ingredient Serogroup A Neisseria meningitidis Serogroup C Neisseria meningitidis Serogroup Y Neisseria meningitidis Serogroup W 135 Neisseria meningitidis CHARACTERISTICS OF THE MEDICINAL PRODUCT Indication Active immunisation of adults, adolescents and children over 2 years of age against invasive meningococcal disease caused by serogroup A, C, W 135 and Y meningococci. MENCEVAX must be used in accordance with the official recommendations. Dosage One 0.5 ml dose. Patients who remain exposed to an increased risk of invasive meningococcal disease may be revaccinated. The revaccination intervals should be in accordance with the official recommendations. SIMILAR MEDICINAL PRODUCTS ATC Classification (2009) J: Antiinfectives for systemic use J07: Vaccines J07A: Bacterial vaccines J07AH: Meningococcal vaccines J07AH04: Meningococcus, tetravalent purified polysaccharides antigen Medicines in the same therapeutic category Comparator medicines There is no comparable vaccine that covers the four serogroups (A, C, W 135, Y). Medicines with a similar therapeutic aim - Meningococcal polysaccharide vaccine for serogroups A + C (PASTEUR VACCINS) - Indicated from the age of 18 months (not reimbursed, approved for hospital use) - Meningococcal protein conjugate vaccines for serogroup C, indicated from the age of 2 months: MENINGITEC MENINVACT MENJUGATE - NEISVAC (not reimbursed, approved for hospital use). 2

3 ANALYSIS OF AVAILABLE DATA Reminder: MENCEVAX obtained its first national Marketing Authorisation in Belgium in Following the development of a new manufacturing process, a new MA was granted in Belgium on 5 March 2007 on the basis of a non-inferiority study versus the previous MENCEVAX formulation (not marketed in France). Within the scope of the Mutual Recognition Procedure, the AFSSAPS (the French Health Products Safety Agency) granted the Marketing Authorisation in France on 19 May 2008 for the current MENCEVAX formulation. In particular, the clinical dossier contains the following documentation about: - the current MENCEVAX formulation: Immunogenicity and tolerance: The study (MenACWY-004) evaluating the non-inferiority (in terms of immunogenicity and tolerance) of the current formulation compared with the previous formulation of MENCEVAX in subjects 2 to 30 years of age (N=161). - the previous MENCEVAX formulation (not marketed in France): Immunogenicity and tolerance: - Four studies: MenACWY-001, MenACWY-TT-003, MenACWY-TT-004, MenACWY-004 evaluating the immunogenicity and tolerance of the previous formulation of MENCEVAX (N = 341) - Immunogenicity and tolerance data in subjects with terminal complement component deficiency. Persistence of immunogenicity: - The extension of the MenACWY-TT-003 study (MenACWY-TT-006, MenACWY-TT-007) evaluating the persistence of the immune response in subjects 18 to 25 years of age (N = 50) - A study conducted in Ghana with the WHO in subjects 15 to 34 years of age assessing the persistence of the immune response induced by the previous formulation of the MENCEVAX vaccine (N = 177) compared with the trivalent vaccine (A, C, W 135 ) not marketed in France. Efficacy data: The efficacy of the vaccine was evaluated with the trivalent vaccine for serogroups A, C, and W 135 during the Burkina Faso mass vaccination campaign conducted in response to an epidemic of meningococcal disease, in which the W 135 serogroup was the predominant strain Immunogenicity: Study (MenACWY-004 Lebanon, 2005): comparing the new formulation with the previous formulation 3

4 Main objective: to demonstrate the immunogenicity non-inferiority of three batches manufactured in accordance with the current MENCEVAX formulation compared with the immunogenicity of the previous formulation of the vaccine. Methodology: Open-label phase IV study comparing the immunogenicity of three batches of the new MENCEVAX formulation (N= 161) with that of the previous formulation (N=161) in subjects 2 to 30 years of age stratified into four age groups: 2-5 years, 6-12 years, years, years. Primary endpoint: Geometric Mean Titres (GMT) of Serum Bactericidal Antibodies (SBA) for the four serogroups (A, C, W 135, Y) one month after vaccination. Non-inferiority was achieved if the upper limit of the 95% confidence interval for the ratio between the GMTs obtained for the batch of previous formulation and the pooled results from the three batches of the current formulation was less than 2. Results: Geometric Mean Titres (GMT) of Serum Bactericidal Antibodies (SBA) for the four serogroups one month after vaccination with the previous formulation or the current formulation (three pooled batches) of MENCEVAX (Per Protocol Population): MENCEVAX GMT Previous Previous formulation / Antibodies Current formulation formulation current formulation N GMT N GMT % 95% CI SBA-Men A 126 9, , [ ] SBA-Men C 137 1, , [ ] SBA-Men W 139 1, , [ ] SBA -Men Y 139 2, , [ ] N: Number of subjects for whom the results were available before and after vaccination This study demonstrated the immunological non-inferiority of the current MENCEVAX formulation compared with the previous formulation of the vaccine for the four serogroups (A, C, W 135 and Y). In addition, the percentage of subjects with a Serum Bactericidal Antibody response to serogroup A was higher in the current formulation group than in the previous formulation group (0.82%, CI 95% : ) MenACWY-001, MenACWY-TT-003, MenACWY-TT-004, MenACWY-004 studies evaluating the immunogenicity of the previous formulation of MENCEVAX ACW 135 Y in subjects 2 to 30 years of age: 341 out of 879 vaccinated subjects received the previous MENCEVAX formulation 4

5 . MenACWY-001 study (Taiwan-2003): Open-label Phase III study in subjects 2 to 30 years of age stratified into three age groups (N=105): 2-5 years, 6-15 years, years. MenACWY-TT-003 study (Belgium-2003): Open-label Phase II study in subjects 18 to 25 years of age who received a dose of MENCEVAX AC W 135 Y (N=25) compared with the tetravalent conjugate vaccine MenACWY-TT (not marketed in France). MenACWY-TT-004 study (Poland-2004): Open-label Phase II study conducted in children 3 to 5 years of age who received a dose of MENCEVAX ACW 135 Y (N=50) compared with various formulations of the tetravalent conjugate vaccine MenACW 135 Y-TT. MenACWY-004 study (Lebanon) This open-label Phase IV study compared the immunogenicity of three batches of the new MENCEVAX ACW 135 Y vaccine formulation (N= 161) versus the previous formulation (N=161) in subjects 2 to 30 years of age (study mentioned in section ). Endpoints: Two endpoints were measured before vaccination and one month after vaccination in these four studies: - the Serum Bactericidal Antibody (SBA) titre - the Anti-Polysaccharide Antibody (anti-ps) titre. These endpoints were measured for each of the four serogroups (A, C, W 135 and Y) before vaccination and one month after vaccination. Results: The results in terms of immunogenicity one month after vaccination were expressed for each of the four serogroups (A, C, W 135, Y) for two age groups (2-5 and 6-30 years of age), notably as a function of: - the seroprotection rate: percentage of vaccinated subjects with a Serum Bactericidal Antibody (SBA) titre of 1:8 or higher - the response to vaccination: percentage of initially seronegative subjects who become seropositive with a Serum Bactericidal Antibody titre of 1:8 or higher and initially seropositive subjects with a Serum Bactericidal Antibody titre four times higher after vaccination than before vaccination - the seroconversion rate: percentage of vaccinated subjects with an anti-polysaccharide antibody (anti-ps) titre 0.30 µg/ml. Results in terms of immunogenicity in the clinical studies in 341 subjects who received the previous MENCEVAX formulation, by age range (N = 336 in per protocol population): children 2 to 5 years of age (three studies) subjects 6 to 30 years of age (three studies). A C W Y Age range Clinical studies Endpoints 2-5 years MenACWY-004 Pre-vaccination SBA % - 100% 15.2% % 16.1% % % 5

6 90.3% 90.9% 100% 100% MenACWY-TT Response to % % 90.3% % 87.1% % 61.5% % vaccination 6-30 years [N = 215] MenACWY-004 MenACWY-001 MenACWY-TT-003 MenACWY- Post- Pre-vaccination anti % % 2.1% - 6.3% 0.0% - 4.3% 2.0% - 6.3% PS Post-vaccination anti- 3 31% - 49% 97.0% - 100% 96.9% - 100% 97.0% - 100% PS Pre-vaccination SBA % - 100% 30% - 80% 22.6% % 73.5% % Post-vaccination SBA 1 100% 97.9% - 100% 97.1% - 100% 100% Response to 2 50% - 85% 84% - 100% 76% - 100% 65.2% % vaccination Pre-vaccination anti % % 0.0% % 5.7% - 48% 8.8% - 40% PS Post-vaccination anti- 3 PS 96% - 100% 100% 96.0% - 100% 96.0% - 100% 1 Percentage (minimum to maximum values) of subjects with a Serum Bactericidal Antibody (SBA) titre of 1:8 or higher before and after vaccination 2 Percentage (minimum to maximum values) of subjects with a response to vaccination 3 Percentage (minimum to maximum values) of subjects with an anti-polysaccharide antibody (anti-ps) titre 0.30 µg/ml before and after vaccination. Seroprotection rate (percentage of vaccinated subjects with a Serum Bactericidal Antibody (SBA) titre of 1:8 or above): The percentages of initially seronegative subjects who became seropositive one month after vaccination were 100% for the A and Y serogroups and at least 92.9% for the C and W 135 serogroups. Response to vaccination (percentage of initially seronegative subjects who became seropositive with a Serum Bactericidal Antibody titre of 1:8 or above and percentages of initially seropositive subjects with a Serum Bactericidal Antibody titre four times higher after vaccination than before vaccination): Overall, based on the individual data from the subjects observed in the studies conducted with the previous formulation of MENCEVAX, the percentages of patients with a response to vaccination one month after vaccination were as follows: - In vaccinated children 2 to 5 years of age: Serogroup A 69.1%, Serogroup C 93.1%, Serogroup W %, Serogroup Y 79.2% - In vaccinated subjects 6 to 30 years of age: Serogroup A 72.2%, Serogroup C 95.4%, serogroup W %, Serogroup Y 81.2% Seroconversion rate (percentage of vaccinated subjects with an anti-polysaccharide antibody [anti-ps] titre 0.30 µg/ml): 6

7 The percentages of vaccinated subjects with an anti-polysaccharide antibody (anti-ps) titre 0.30 µg/ml vary from 31% in children 2 to 5 years of age (Serogroup A) to 96%-100% in children and adults (Serogroups C, W 135, Y ) Persistence of the immune response A study was conducted in Ghana in subjects 15 to 34 years of age who were assigned to two groups: 183 subjects received the trivalent MENCEVAX ACW 135 vaccine (not marketed in France) and 177 subjects received the tetravalent MENCEVAX ACW 135 Y vaccine (previous formulation). The percentages of subjects with a Serum Bactericidal Antibody titre of 1:8 or higher were: 100% for serogroup A, 88.4% for serogroup C and 93.5% for serogroup W I35, approximately one year after vaccination with MENCEVAX A C W135 Y. A Phase II study (N=25) (MenACWY-TT-007 study, an extension of MenACWY-TT-003) demonstrated, two years after vaccination, that 100% of subjects 18 to 25 years of age had a Serum Bactericidal Antibody titre of 1:8 or higher for serogroup A, W 135 and Y meningococci and 96% for serogroup C. According to the data from the literature, the Serum Bactericidal Antibody response induced by the vaccine persists for at least three years. In subjects with a complement deficiency (carriers of a terminal complement component deficiency, properdin deficiency or anatomical or functional asplenia), the antibodies persisted for three years after vaccination with MENCEVAX ACW 135 Y, and revaccination restored the antibody concentrations in the studies conducted Efficacy data 1 In response to an epidemic of meningococcal disease in Burkina Faso, a mass vaccination campaign with the trivalent MENCEVAX A, C, W 135 vaccine (not marketed in France) was conducted in this country among more than 1.68 million children and adults 2 to 29 years of age. The efficacy of the vaccine was evaluated in subjects 2 to 29 years of age in six Burkina Faso regions during this campaign, which took place from 3 March 2003 to 31 May In these regions, the W 135 serogroup was the predominant strain, and the A and C subgroups were also identified. Index cases and controls were recruited in order to evaluate the efficacy of the vaccine for serogroups A and W 135. A total of 35 index cases (serogroup A or W 135 meningitis diagnosed at least 10 days after vaccination) and 103 controls (without diagnosed meningitis) were recruited. The efficacy (reduction in the relative risk of meningitis occurrence) versus serogroup A and W 135 disease was 95.8% (95% CI: 81.8% %) in subjects for whom vaccination was reported. 1 Soriano-Gabarro M, Toe L, Tiendrebeogo S et al. Effectiveness of a trivalent serogroup A/C/W135 meningococcal polysaccharide vaccine. 2003; Burkina Faso. Vaccine 2007; 25S: A92-A96 7

8 3.4. Adverse effects (from the SPC) In clinical studies (MenACWY-004, MenACWY-001, MenACWY-TT-003, MenACWY-TT- 004), MENCEVAX A, C, W 135, Y (previous and current formulations) was administered to 502 subjects. The most frequently reported adverse effects were pain and redness at the injection site. Most of the adverse effects, which occurred during these trials, were reported within 48 hours of the vaccination. The adverse effects considered to be at least possibly related to the vaccination were as follows: - Very common ( 1/10): headaches, pain and redness at the injection site, fatigue - Common ( 1/100, < 1/10): somnolence, gastrointestinal symptoms (such as nausea, vomiting and diarrhoea), loss of appetite, fever, swelling at the injection site, irritability In a study conducted by the WHO in Ghana, the following adverse effects were observed for MENCEVAX ACW 135 Y (previous formulation): - Very common ( 1/10): sensitivity at the injection site - Common ( 1/100, < 1/10): induration at the injection site. Furthermore, other adverse effects were also reported up until May 2006 in the course of the post-marketing surveillance for the MENCEVAX A, MENCEVAX A C and MENCEVAX A C W 135 Y vaccines (not marketed in France): They were as follows: - Angioneurotic oedema - Arthralgia, musculoskeletal stiffness - Flu-like symptoms, chills - Allergic reactions, including anaphylactic and anaphylactoid reactions Conclusion The non-inferiority in terms of immunogenicity of the current MENCEVAX formulation compared with the previous formulation of the vaccine (not marketed in France) was demonstrated in a study conducted in Lebanon in 161 subjects 2 to 30 years of age. The immunogenicity of the previous MENCEVAX A, C, W 135, Y formulation was evaluated in four clinical studies conducted in Belgium, Lebanon, Poland and Taiwan (N=341) in subjects 2 to 30 years of age. Overall, based on the individual data documented in the studies conducted with the previous MENCEVAX formulation, the percentages of patients with a response to vaccination 2 one month after vaccination were as follows: - In vaccinated children 2 to 5 years of age: Serogroup A 69.1%, Serogroup C 93.1%, Serogroup W %, Serogroup Y 79.2% - In vaccinated subjects 6 to 30 years of age: Serogroup A 72.2%, Serogroup C 95.4%, Serogroup W %, Serogroup Y 81.2%. According to the data from the literature, the Serum Bactericidal Antibody response induced by the vaccine persisted for at least three years. 2 percentage of initially seronegative subjects with a Serum Bactericidal Antibody titre of 1:8 or above and initially seropositive subjects with a bactericidal serum antibody titre four times higher after vaccination than before vaccination 8

9 In response to an epidemic of meningococcal disease in Burkina Faso, a mass vaccination campaign was conducted with the trivalent MENCEVAX A, C, W 135 vaccine (not marketed in France) among more than 1.68 million children and adults aged 2 to 29 years of age. The efficacy of the vaccine in terms of protection against serogroup A and W 135 diseases was 95.8% (95% CI: 81.8% %) in subjects in whom vaccination was reported. The most frequently reported adverse effects were pain and redness at the injection site. Most were reported within 48 hours of the vaccination. TRANSPARENCY COMMITTEE CONCLUSIONS Actual benefit This vaccine prevents serious, potentially life-threatening infections. These proprietary medicinal products are used as preventive treatment. The efficacy (immunogenicity)/adverse effects ratio for these medicinal products is high. There is no alternative vaccine that includes serogroups Y and W 135. Public health benefit: In France, the burden of Invasive Meningococcal Disease (IMD) caused by the W 135 and Y serogroups - the two serogroups for which no vaccines exist other than MENCEVAX - can be considered to be limited. A need exists for vaccination against meningococcal infections caused by serogroups A, C, W 135 and Y (recommendations of the Haut conseil de la santé publique [French High Council for Public Health], requirements by the Saudi authorities for pilgrims visiting Mecca). 9

10 The efficacy data for MENCEVAX are based mainly on the immune response. The quality of the evidence is acceptable. The transferability of the trial data to clinical practice is considered to be acceptable. The type of impact expected is both direct (prevention of IMD in vaccinated individuals) and indirect (prevention of epidemics). The expected impact on the health of the population is fairly small owing to the relatively low incidence of IMD caused by serogroups W 135 and Y, despite the epidemic potential of this disease. In this sense, MENCEVAX meets the identified need. There is a potential beneficial impact of MENCEVAX on the health system organisation owing to epidemic prevention. MENCEVAX presents a public health benefit. This benefit may be considered small at the present time. It could increase, however, if changes were to occur in the epidemiology of invasive meningococcal infections. The actual benefit of this vaccine is substantial in the populations targeted by the Haut Conseil de la Santé Publique recommendations. Improvement in actual benefit (IAB) As with the MENOMUNE vaccine, whose Marketing Authorisation was revoked on 6 April 2008, the Committee considers MENCEVAX to represent a major improvement in actual benefit (IAB I) in the prevention of invasive meningococcal infections caused by serogroups Y and W 135 in children over 2 years of age, adolescents and adults in the populations recommended by the Haut Conseil de la Santé Publique Therapeutic use OPINION of the Haut Conseil de la Santé Publique dated 5 September 2008 relating to the use of the MENCEVAX vaccine (for the opinion in its entirety, see the appendix). The Haut Conseil de la Santé Publique recommends considering the MENOMUNE and MENCEVAX v accines as equivalents and applying the previous recommendations for the MENOMUNE vaccine to MENCEVAX in: Adults, adolescents and children over 2 years of age: - with terminal complement component deficiency, properdin deficiency or anatomical or functional asplenia - travelling to an area with a confirmed risk of W 135 meningococcal infection - for post-exposure prophylaxis (see Circular no.dgs/5c/2006/458 dated 23 October 2006) Target population The MENCEVAX target population includes the following subgroups: - Children over two years of age suffering from terminal complement component deficiency, properdin deficiency or anatomical or functional asplenia. These immune deficiencies are very rare conditions for which no estimates are available. The number of people affected is marginal compared with the other subgroups. 10

11 - Exposed travellers visiting an area with a confirmed risk of meningitis caused by W 135 meningococci. No data are available. - People going on pilgrimages to Mecca (Hajj or Umrah). i This subgroup may be included in the preceding subgroup. In 2007, there were 30,120 pilgrims who travelled from France to Mecca ii - Subjects who come into contact with cases of invasive meningococcal disease (IMD) caused by serogroups W 135 and Y. In view of the fact that about 40 cases of IMD caused by serogroups W 135 and Y were reported in 2006 and that, for the vaccination group cases, the average number of vaccinated people within the network of contacts was 8.3 iii this target sub-population is estimated to be approximately 350 people The estimated target population for this vaccine is therefore at least 35,000 people. Transparency Committee recommendations The Transparency Committee recommends inclusion on the list of medicines approved for use by hospitals and various public services in the indications and at the dosages in the MA for the populations targeted by the Haut Conseil de la Santé Publique recommendations. 11

12 Appendices: - Opinion of the Haut Conseil de la Santé Publique (High Council for Public Health) relating to the use of the MENCEVAX vaccine (5 September 2008) health recommendations for travellers OPINION relating to use of the MENCEVAX vaccine Haut Conseil de la Santé Publique 5 September 2008 The Haut Conseil de la Santé Publique: takes note of the withdrawal of the serogroup A, C, Y, W 135 MENOMUNE meningococcal vaccine, whose Marketing Authorisation was revoked on 6 April 2008 takes note of the fact that a Marketing Authorisation was granted on 19 May 2008 (via a Mutual Recognition Procedure with Belgium as the reference state) for the serogroup A, C, Y, W 135 meningococcal vaccine MENCEVAX. This vaccine, registered in Belgium in 1982 and then in 50 other countries, had its manufacturing process changed, prompting the issuing of a new MA in Belgium on 5 March The MENOMUNE and MENCEVAX vaccines have a very similar composition and, in particular, contain the same concentration of serogroup A, C, W 135 and Y Neisseria meningitidis antigens (50 µg/0.5 ml each). They differ only in terms of their excipient composition (replacement of lactose with sucrose and presence of trometamol as a stabilising agent). Likewise, the wording of the indications for the two vaccines is almost identical: Active immunisation of adults, adolescents and children over 2 years of age against invasive meningococcal disease caused by serogroup A, C, W 135 and Y meningococci. MENCEVAX must be used in accordance with the official recommendations. has taken note of the report generated by the AFSSAPS (the French Health Products Safety Agency) concerning the MENCEVAX vaccine during the Mutual Recognition Procedure. The studies compared the immunogenicity and safety of the current vaccine formulation (four groups of 54 subjects for the 2-5, 6-12, and age groups) with the old formulation (162 subjects). These studies demonstrated the noninferiority of the current vaccine compared with the old formulation. The percentage of subjects with an antibody response to serogroup A was significantly higher in the new production group than in the old production group. In addition, the drug safety data for the old formulation of the vaccine give no cause for concern. The adverse effects observed most frequently in the studies with the current formulation are local reactions, usually of moderate intensity. Severe systemic reactions are infrequent. Consequently, the Haut Conseil de la Santé Publique recommends considering the MENOMUNE and MENCEVAX vaccines as equivalents and applying the previous recommendations for the MENOMUNE 1 vaccine to MENCEVAX. 1 Adults, adolescents and children over 2 years of age: - with terminal complement component deficiency, properdin deficiency or anatomical or functional asplenia - travelling to an area with a confirmed risk of W 135 meningococcal infection - for post-exposure prophylaxis. 12

13 2008 Health Recommendations for travellers Haut Conseil de la Santé Publique (High Council for Public Health) Invasive meningococcal infections Three meningococcal vaccines are currently available in France: - The conjugate vaccine against serogroup C meningococci - The vaccine against serogroup A and C meningococci - The tetravalent vaccine against serogroup A, C, Y, W 135 meningococci currently restricted to vaccination centres authorised to administer yellow fever vaccinations owing to limited availability. The current status of invasive meningococcal infection epidemics can be viewed on the WHO website at the following address: Vaccination against invasive meningococcal infections is recommended (see CSHP [High Council for Public Health] opinion below): - for children over 2 years of age and young adults (under 30 years of age) visiting an area where there is an epidemic - for people visiting this area in order to work in the health care sector or with refugees - for people visiting an endemic area (African meningitis belt) during meningitis season under conditions of close and prolonged contact with the local population. Vaccination is not recommended for other travellers, including those who, although staying briefly in an area experiencing an epidemic, will have little contact with the local population. The tetravalent vaccine must be reserved for exposed travellers visiting areas where the risk of W 135 meningococcal meningitis is confirmed. The Saudi authorities require vaccination with the tetravalent vaccine for people going on pilgrimages to Mecca and Medina (Hajj or Umrah). The vaccine must be given at least 10 days and at most three years prior to the pilgrimage. i World Health Organisation. International travel and health Geneva: WHO Available at: (consulted on 12/02/2009) ii French Ministry of Foreign Affairs. Press briefing by the spokesperson on Pilgrimage to Mecca. Available at: (consulted on 12/02/2009) iii Parent du Châtelet I, Taha MK, Lepoutre A, Lévy-Bruhl D. Les infections invasives à méningocoque en France en 2006 (Invasive Meningococcal Infections in France in 2006). BEH 2007;51-52: