The legally binding text is the original French version

TRANSPARENCY COMMITTEE Opinion 26 June 2013 INFANRIX HEXA, powder and suspension for suspension for injection in a pre-filled syringe. Diphtheria (D), tetanus (T), pertussis (acellular, multicomponent) (aP), hepatitis B (rDNA) (HBV), poliomyelitis (inactivated) (IPV) and Haemophilus influenzae type b (Hib) conjugate vaccine (adsorbed) 1 glass vial – 1 pre-filled 0.5 ml glass syringe + 2 needles (CIP: 34009 354 958 3 9) 10 glass vials – 10 pre-filled 0.5 ml glass syringes + 20 needles (CIP: 34009 562 112 6 5)

Applicant: GLAXOSMITHKLINE

INN

Haemophilus influenzae type b polysaccharide Bordetella pertussis antigen: toxoid Bordetella pertussis antigen: filamentous haemagglutinin Bordetella pertussis antigen: pertactin Diphtheria toxoid Tetanus toxoid Recombinant hepatitis B surface antigen Inactivated poliovirus type 1 (Mahoney strain) Inactivated poliovirus type 2 (MEF-1 strain) Inactivated poliovirus type 3 (Saukett strain)

ATC code (2012)

J07CA09 (Bacterial and viral vaccines, combined)

Reason for the review

Renewal of inclusion Re-assessment of the Improvement in Actual Benefit at the company’s request, in accordance with article R.163-12 of the French Social Security Code

Lists concerned

National Health Insurance (French Social Security Code L.162-17) Hospital use (French Public Health Code L.5123-2)

Indication concerned

“INFANRIX HEXA is indicated for primary and booster vaccination of infants against diphtheria, tetanus, pertussis, hepatitis B, poliomyelitis and infections caused by Haemophilus influenzae type b.”

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Actual Benefit

Improvement Actual Benefit Public Benefit

Substantial in the populations recommended.

in

Health

In view of the data submitted to the Committee, INFANRIX HEXA continues to provide a minor (level IV) improvement in actual benefit in comparison with a pentavalent vaccine with an acellular pertussis component (INFANRIX QUINTA – PENTAVAC) combined with a Hepatitis B vaccine (HB-VAX-PRO 5 or ENGERIX B10 or GENHEVACB). The public health benefit provided by the proprietary medicinal product INFANRIX HEXA is moderate.

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01

Administrative and regulatory information

Marketing Authorisation (procedure) Prescribing and dispensing conditions / special status

ATC Classification

02

Initial Marketing Authorisation: 23 October 2000 (centralised procedure)

List I

2012 J J07 J07C J07CA J07CA09

General anti-infectives for systemic use Vaccines Bacterial and viral vaccines, combined Bacterial and viral vaccines, combined Diphtheria – Haemophilus influenzae b – Pertussis – Poliomyelitis – Tetanus – Hepatitis B

Background

Review of a proprietary medicinal product included on the list of medicines refundable by National Health Insurance for a duration of 5 years from 26 March 2008 (Official Gazette of 26 March 2008) and re-assessment of IAB and public health benefit at the company’s request. INFANRIX HEXA is the only hexavalent vaccine refunded in France (since March 2008) for the primary and booster vaccination of infants against diphtheria, tetanus, pertussis, hepatitis B, poliomyelitis and infections caused by Haemophilus influenzae type b. The company has submitted an application for renewal of registration, requesting that its substantial actual benefit be maintained and claiming a level III improvement in actual benefit and a substantial public health benefit in view of new data available. When INFANRIX HEXA was first included (opinion of 10 July 2002), the Transparency Committee had awarded it a minor (level IV) IAB because of its convenience of use in comparison with a pentavalent vaccine with an acellular pertussis component combined with a hepatitis B vaccine. In its agreement with the Economic Committee for Health Products (CEPS), the company had undertaken to provide a set of studies allowing the public health benefit of vaccination with INFANRIX HEXA in France to be measured. To meet this requirement, two studies were conducted: the PopCorn study and the PRALINE study. This assessment of the company’s application is based primarily on these two studies as well as on three Vaccinoscopie investigations, on data published by the French Institute for Public Health Surveillance (InVS) and on efficacy and safety data from the literature.

03

Therapeutic indications

“INFANRIX HEXA is indicated for primary and booster vaccination of infants against diphtheria, tetanus, pertussis, hepatitis B, poliomyelitis and infections caused by Haemophilus influenzae type b.” HAS - Medical, Economic and Public Health Assessment Division

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04

Dosage

See SPC.

05

Therapeutic need

In view of the company’s claims, the therapeutic need discussed relates only to hepatitis B. Infection with the hepatitis B virus (HBV) can be transmitted sexually, through blood, from mother to child at birth, and through family contact. The mode of HBV transmission remains unknown in almost 30% of cases. It is most often asymptomatic and can progress into severe forms: cirrhosis and hepatocellular carcinoma (chronic form).1 The acute or so-called fulminant form may be fatal without a liver transplant. Increasing vaccination coverage is a target that must be met to reduce the incidence of hepatitis B. The French public health plan has set this target as 80% hepatitis B vaccination coverage (complete course) at the age of 24 months by 2015.2,3 Vaccination is, in fact, the most effective preventative measure against infection with the hepatitis B virus.4 The High Council for Public Health recommends that hepatitis B vaccination should continue to be offered as a priority to all infants. It also recommends that catch-up hepatitis B vaccination should be continued in children and adolescents up to and including the age of 15 years.5 INFANRIX HEXA is indicated for primary and booster vaccination of infants against diphtheria, tetanus, pertussis, hepatitis B, poliomyelitis and infections caused by Haemophilus influenzae type b. The alternatives to this vaccine that can be used for the primary and booster vaccination of infants are described in the following section. INFANRIX HEXA differs from other vaccines in that it is the only hexavalent vaccine providing protection against diphtheria, tetanus, pertussis, hepatitis B, poliomyelitis and infections with Haemophilus influenzae type b. The schedule of administration for INFANRIX HEXA requires only three injections, which are timed as follows: - Primary vaccination: two injections of INFANRIX HEXA at the age of 2 and 4 months - Booster vaccination: one dose of INFANRIX HEXA at the age of 11 months In comparison, separate administration of a pentavalent vaccine (DTaP/IPV/Hib) and a monovalent hepatitis B vaccine requires six injections: three injections of pentavalent vaccine and three injections of monovalent hepatitis B vaccine at the age of 2, 4 and 11 months.

1

BEH of 10 July 2012 – No. 29-30 HCSP. Objectifs de santé publique : Evaluation des objectifs de la loi du 9 août 2004 et propositions. April 2010 3 HCSP. Rapport du Haut Conseil de la Santé Publique. Principales recommandations et propositions en vue de la prochaine loi pour une politique de santé publique. December 2009 4 DGS-R12/12 January 2009. Plan National de Lutte contre les Hépatites B et C : 2009-2012 5 BEH of 19 April 2013 – No.14-15 2

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06

Clinically relevant comparators

06.1

Medicinal products

The relevant comparators are the pentavalent vaccines (diphtheria, pertussis, tetanus, poliomyelitis and Haemophilus influenzae type b) containing an acellular pertussis component and the monovalent hepatitis B vaccines used in paediatrics: Name Company INFANRIX QUINTA GSK

PENTAVAC

ENGERIX B10

GenHevac B PASTEUR vaccine

HBVAXPRO 5 µg

Indication This vaccine is indicated in the combined prevention of invasive infections caused by Haemophilus influenzae type b (meningitis, septicaemia, cellulitis, arthritis, epiglottitis, etc.), diphtheria, tetanus, pertussis and poliomyelitis, for primary vaccination and for booster at the age of 16 to 18 months one year after primary vaccination. This vaccine does not protect against infectious diseases caused by other types of Haemophilus influenzae or against meningitis of other origins. This vaccine has only been studied in children aged under 36 months.

This vaccine is indicated in the combined prevention of diphtheria, tetanus, pertussis, poliomyelitis and invasive infections caused by Haemophilus influenzae type b (meningitis, septicaemia, cellulitis, arthritis, epiglottitis, etc.): • For primary vaccination of infants from the age of 2 months • For booster one year after primary vaccination within the second year of life This vaccine does not protect against infectious diseases caused by other types of Haemophilus influenzae or against meningitis of other origins. ENGERIX B is indicated for active immunisation against hepatitis B virus infection (HBV) caused by all known subtypes in nonimmunized subjects of any age. The population categories to be immunised are determined on the basis of official recommendations. It can be expected that hepatitis D will also be prevented by immunisation with ENGERIX B as hepatitis D (caused by the delta agent) does not occur in the absence of hepatitis B infection. This vaccine is indicated for active immunisation against hepatitis B virus infection caused by all known subtypes in subjects of any age considered to be at risk of exposure to the virus. The risk groups to be vaccinated are determined on the basis of official recommendations. Hepatitis D, caused by the delta agent, does not occur in the absence of hepatitis B infection. Therefore, immunisation with this vaccine provides indirect protection against infection with the delta agent. HBVAXPRO is indicated for active immunisation against hepatitis B virus infection caused by all known subtypes in subjects from birth to the age of 15 years considered to be at risk of exposure to the hepatitis B virus.

Date of opinion 07/09/2011

Substantial

04/01/2012

Substantial

05/10/2011

Substantial

21/01/2009

Substantial

29/03/2006

Substantial

AB

*pharmacotherapeutic group

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06.2

Other health technologies

Not applicable. Conclusion INFANRIX HEXA is the only hexavalent combination vaccine marketed in France. The comparators listed are all clinically relevant as long as a pentavalent vaccine is combined with a monovalent vaccine.

07

Summary of previous assessments

Date of opinion (reason for request) Indication

AB (wording) IAB (wording)

Studies requested

10 July 2002 (inclusion on the list of medicines refundable by National Health Insurance and on the list of medicines approved for hospital use) INFANRIX HEXA is indicated for primary and booster vaccination of infants against diphtheria, tetanus, pertussis, hepatitis B, poliomyelitis and infections caused by Haemophilus influenzae type b. “The actual benefit of this proprietary medicinal product is substantial.” “The administration of six vaccine components in a single injection will facilitate vaccination. INFANRIX HEXA provides a minor (level IV) improvement in actual benefit because of its convenience of use in comparison with a pentavalent vaccine with an acellular pertussis component (INFANRIX QUINTA – PENTAVAC) combined with a Hepatitis B vaccine (HB-VAXPRO 5 or ENGERIX B10 or GenHevacB). This convenience of use (one injection rather than two) could help to facilitate the acceptance of hepatitis B vaccination by parents, which remains a significant public health problem.” Not applicable.

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08 08.1

Analysis of available data Efficacy

8.1.1 Data from the literature 8.1.2 Vaccination with INFANRIX HEXA The company has provided the published data summarised in the table below as well as one study6 comparing administration of INFANRIX HEXA to a whole-cell pertussis vaccine. Since whole-cell pertussis vaccines are no longer available in France, the results of that study are not presented in this document.

6

Guiso N, Njamkepo E, Vié le Sage F et al. Long-term humoral and cell-mediated immunity after acellular pertussis vaccination compares favourably with whole-cell vaccines 6 years after booster vaccination in the second year of life. Vaccine 2007; 25: 1390-1397

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Study Zepp, 7

2004

Type of study and objective Two open-label randomised controlled trials conducted in Germany with similar experimental designs were pooled* to evaluate the safety** (primary objective) and reactogenicity** of INFANRIX HEXA versus coadministration of a pentavalent (DTaP/IPV/Hib) vaccine and a monovalent (HBV) vaccine.

Numbers A total of 2883 patients were included across the two studies. Immunogenicity was evaluated in 474 patients.

Immunogenicity was evaluated in one of the two studies in patients who had all received the hexavalent vaccine, but there was no comparison with a control group.

Heininger, 8

2007

Open-label study conducted in Germany with the aim of evaluating the immunogenicity (and reactogenicity**) of one booster dose of INFANRIX HEXA administered to children aged 12 to 18 months who had received a complete primary vaccination course with INFANRIX HEXA or with 2 pentavalent (DTaP/IPV/Hib) and monovalent (HBV) vaccines. The aim was also to analyse the long-term persistence of the immune (antibody) response in patients aged 4 to 6 years (included in this study and in another study conducted in Germany).

443 children were included (341 in the hexavalent vaccine group and 102 in the pentavalent (DTaP/IPV/Hib) and monovalent (HBV) vaccines group.

Vaccination schedule INFANRIX HEXA was administered at the age of 3, 4 and 5 months and the pentavalent and monovalent vaccines were coadministered at the age of 3 and 5 months. Immunogenicity was evaluated in patients who had all received the hexavalent vaccine at the age of 3, 4 and 5 months. - Primary vaccination at the age of 3, 4 and 5 months - One booster dose at the age of 16-18 months

Endpoints

Results

Evaluation of immunogenicity 1 month rd after the 3 dose of hexavalent vaccine.

The protection rates obtained were greater than 95% for each of the 6 components of the vaccine.

Evaluation of immunogenicity: the primary endpoint was the percentage of patients with anti-PrP antibody levels ≥ 1 µg/ml (corresponding to the Hib component) one month after the booster dose. (The secondary endpoints concerned response rates and antibody levels for all vaccine components.)

Primary endpoint: the % of patients with anti-PrP antibody levels ≥ 1 µg/ml one month after the booster dose was 99% in the hexavalent vaccine group and 100% in the control group. The antibody response persisted (3.5 to 4 years after the complete course of vaccination) in more than 90% of patients in both groups for diphtheria, hepatitis B, Hib and poliomyelitis, and in 76.4% of patients in the hexavalent vaccine group and 80.6% of patients in the control group for tetanus. For pertussis, ≥ 98% of patients had anti-filamentous haemagglutinin antibodies and ≥ 87% had anti-pertactin antibodies. 34.5% of patients in the hexavalent vaccine group and 22.2% of patients in the control group had detectable anti-pertussis toxin

Evaluation of the longterm persistence of efficacy in 89 patients (3.5 to 4 years after the complete vaccination 7

Zepp F, Knuf M, Heininger U et al. Safety, reactogenicity and immunogenicity of a combined hexavalent tetanus, diphtheria, acellular pertussis, hepatitis B, inactivated poliovirus vaccine and Haemophilus influenzae type b conjugate vaccine, for primary immunization of infants. Vaccine 2004; 22: 2226-2233 8 Heininger U, Sänger R, Jacquet JM et al. Booster immunization with a hexavalent diphtheria, tetanus, acellular pertussis, hepatitis B, inactivated poliovirus vaccine and Haemophilus influenzae type b conjugate combination vaccine in the second year of life: safety, immunogenicity and persistence of antibody responses. Vaccine 2007; 25: 1055-1063

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course). Study Zinke, 9

2010

Type of study and objective

Numbers

Evaluation based on data from 2 open-label studies conducted in Germany examining the immunological persistence of the different components of the INFANRIX HEXA vaccine in children aged 4 to 6 years (study A) and 7 to 9 years (study B).

392 children were included (199 from study A and 193 from study B).

This study was funded by GSK.

Vaccination schedule The children had received primary vaccination with 3 doses of hexavalent vaccine and had received one booster dose during the second year of life.

Endpoints Antibody titre for each vaccine component.

antibodies. Results The average time from the fourth dose of vaccine to serological follow-up ranged from 3.6 to 6.4 years. th After the 4 dose of vaccine, antibody levels persisted up to the age of 9 years in: - ≥ 90% of children for poliomyelitis and Hib - 86.3% of children for diphtheria - 77.2% of patients for hepatitis B - 64.7% of patients for tetanus. For pertussis, 98.1% of patients had antifilamentous haemagglutinin antibodies and 87% had anti-pertactin antibodies. Only 32.2% of patients had detectable antipertussis toxin antibodies.

* The protocols of both studies provided for the pooling of data. ** Safety and reactogenicity are discussed in section 08.2.

9

Zinke M, Disselhoff J, the DTPa-HBV-IPV-110 and -111 study groups et al. Immunological persistence in 4-6 and 7-9 year olds previously vaccinated in infancy with hexavalent DTPa-HBV-IPV/Hib. Human vaccines 2010; 6:2: 189-193

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8.1.3 Vaccination with INFANRIX HEXA co-administered with other vaccines The company submitted a study published in 2006.10,11 This was an open-label randomised controlled trial evaluating immunogenicity and reactogenicity from two vaccination schedules. A total of 350 patients received: - either INFANRIX HEXA at 2, 4 and 6 months (n = 115); - or ENGERIX B (HBV) at birth, INFANRIX HEXA at 2 and 6 months and INFANRIX QUINTA at 4 months (n = 115). In both groups, patients also received two doses of MenC-TT conjugate vaccine (NEISVAC*) at 2 and 4 months. The control group received three doses of conjugate MenC-CRM197 vaccine (MENINGITEC*) and of INFANRIX HEXA at 2, 4 and 6 months (n = 120). Immunogenicity was evaluated by measuring antibody concentrations for the different vaccine components at 2, 6 and 7 months. The protection rates obtained after vaccination (after the second or third dose depending on the component) ranged from 90% to 100% in each group. The concomitant administration of the INFANRIX HEXA or INFANRIX QUINTA vaccines with two doses of NEISVAC did result in immunogenicity. * NEISVAC and MENINGITEC are indicated in the active immunisation of children from 2 months of age, adolescents and adults for the prevention of invasive disease caused by Neisseria meningitidis serogroup C.

The company submitted four other studies: - Two studies12,13 evaluating co-administration of INFANRIX HEXA with heptavalent pneumococcal conjugate vaccine. - One study14 evaluating the immunogenicity and safety of 13-valent pneumococcal conjugate vaccine versus heptavalent pneumococcal vaccine co-administered with INFANRIX HEXA. - One study15 pooling the results of two studies that had evaluated the immunogenicity of INFANRIX HEXA co-administered with 13-valent pneumococcal conjugate vaccine or with heptavalent pneumococcal vaccine. As heptavalent pneumococcal vaccine is no longer recommended in France,16 the results of these studies will not be presented in this document. According to the recommendations of the 2013 vaccination schedule, INFANRIX HEXA may be co-administered with a 13-valent pneumococcal conjugate vaccine (PREVENAR 13).

10

Tejedor JC, Moro M, Ruiz-Contreras J et al. Immunogenicity and Reactogenicity of Primary Immunization with a Hexavalent Diphtheria-Tetanus-Acellular Pertussis-Hepatitis B-Inactivated Polio-Haemophilus Influenzae Type B Vaccine Coadministered With Two Doses of a Meningococcal C-Tetanus Toxoid Conjugate Vaccine. Pediatr Infect Dis J 2006; 25: 713-20 11 This study was funded by GSK. 12 Knuf M, Habermehl P, Cimino C et al. Immunogenicity, reactogenicity and safety of a 7-valent pneumococcal conjugate vaccine (PCV7) concurrently administered with a DTPa-HBV-IPV/Hib combination vaccine in healthy infants. Vaccine 2006; 24: 4727-4736 13 Reinert P, Dejos V, Clyti N et al. Immunogénicité et réactogénicité des vaccins DTCa-P-HepB/Hib et DTCa-P/Hib coadministrés avec le vaccin pneumococcique osidique conjugué, adsorbé, chez les nourrissons en primovaccination et en rappel selon le calendrier vaccinal Français. Arch Pediatr 2008; 15: 263-70 14 Esposito S, Tansey S, Thompson A et al. Safety and immunogenicity of a 13-valent pneumococcal conjugate vaccine compared to those of a 7-valent pneumococcal conjugate vaccine given as a three-dose series with routine vaccines in healthy infants and toddlers. Clinical and vaccine immunology 2010; 17: 1017-1026 15 Gimenez-Sanchez F, Kieninger DM, Kueper K et al. Immunogenicity of a combination vaccine containing diphtheria toxoid, tetanus toxoid, three-component acellular pertussis, hepatitis B, inactivated polio virus, and Haemophilus influenzae type b when given concomitantly with 13-valent pneumococcal conjugate vaccine. Vaccine 2011; 29: 60426048 16 HCSP. Avis relatif à la vaccination par le vaccin pneumococcique conjugué 13-valent. 11 December 2009

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08.2

Safety/Adverse effects

The company has submitted the following data from the literature: - The 2004 study by Zepp et al. (described in section 8.1.1), which had the primary objective of demonstrating the non-inferiority of the hexavalent vaccine to co-administered pentavalent (DTaP/IPV/Hib) and monovalent (HBV) vaccines in terms of the percentage of patients reporting at least one grade 3 adverse effect (adverse effect requiring medical intervention and affecting daily activity). Non-inferiority was confirmed if the upper limit of the 90% confidence interval for the difference in number of grade 3 adverse effects was no greater than 5%. The safety analysis examined 2829 patients. The difference observed between the group that had received the hexavalent vaccine and the control group was -1.97 (90% CI: -3.89 to -0.52). Non-inferiority was therefore demonstrated. In addition, an evaluation of reactogenicity undertaken in one of the two studies demonstrated a similar incidence of solicited adverse events between the groups. - The 2007 study by Heininger et al. (described in section 8.1.1) evaluated safety and reactogenicity by calculating the percentage of vaccinated individuals who had a solicited adverse event within four days of the booster dose in the second year of life. On the whole, the results obtained for the hexavalent vaccine were similar to those for the co-administered pentavalent (DTaP/IPV/Hib) and monovalent (HBV) vaccines. - The 2006 study by Tejedor et al. (described on page 10) evaluated the safety and reactogenicity of different vaccination schedules. No difference in reactogenicity was observed between the groups. The concomitant administration of the INFANRIX HEXA or INFANRIX QUINTA vaccine with two doses of NEISVAC was well tolerated. The company submitted new safety data (PSUR covering the period from 23 October 2010 to 22 October 2011). This did not point to any new adverse effects. Since its inclusion (see TC opinion of 10 July 2002), changes have been made to the SPC for INFANRIX HEXA. These were reported in the most recent Committee opinion dated 18 March 2009. The known safety profile of this proprietary medicinal product has not changed.

08.3

Usage/prescription data

8.3.1 Prescription data According to IMS data (moving annual total winter 2012), 1,892,201 prescriptions were issued for this proprietary medicinal product. 44% of prescriptions for INFANRIX HEXA were issued by generalist physicians and 56% by paediatricians. In 95% of cases, the prescriptions were for patients aged under 24 months.

8.3.2 PopCorn and PRALINE studies In the agreement signed between the company GSK and CEPS on 22/02/2008, GSK undertook to “provide a set of studies allowing the public health impact of vaccination with INFANRIX HEXA to be measured in France.” To meet this requirement, the company concurrently initiated two prospective, national, repeated cross-sectional studies: the PopCorn study conducted in the general population from a representative sample of households with infants aged 27 months or under selected by quota sampling, and the PRALINE study conducted in a representative sample of private generalist physicians and private or mixed-practice paediatricians selected randomly from the Cegedim survey database. The primary objective of the PopCorn study was to evaluate changes in hepatitis B vaccination coverage in children aged 12-15 months and 24-27 months between one period before HAS - Medical, Economic and Public Health Assessment Division

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reimbursement of the hexavalent vaccine and three successive post-reimbursement periods at intervals of one year. The secondary objectives were to evaluate the acceptability to parents of hepatitis B vaccination and how this changed over time, and to evaluate changes in vaccination coverage for other recommended and non-recommended vaccines in these age groups. Data were collected through face-to-face interviews with parents and from Child Health Record booklets in periods T117 from May to July 2009, T218 from May to July 2010, T319 from May to July 2011, and T420 from May to July 2012. The PRALINE study aimed to evaluate changes in the acceptability of hepatitis B vaccination to doctors themselves, from the vaccination status of children aged 12 to 15 months and 24 to 27 months who had attended for vaccination with the participating doctor from birth (or who were under their care in the first 6 months of life) and who were seen in consultation during two inclusion periods, T1 from November 2009 to June 2010 and T2 from November 2011 to February 2012. The secondary objectives were to describe the vaccination practices of generalist physicians and paediatricians and to record children’s ages upon administration of the first dose of the vaccine. The data were collected by telephone interviews with the doctors and from Child Health Records. A quantitative indicator of acceptability was calculated as the proportion of children who had had at least one dose of hepatitis B vaccine before the age of 6 months, among all children who had attended for vaccination with the participating doctors. This proportion was calculated only for doctors with a minimum threshold of 7 children attending for vaccination. From this indicator of acceptability, doctors were considered to be “practising hepatitis B vaccination” if more than half of the children included in the study had received one dose of hepatitis B primary vaccination before the age of 6 months. In the two studies, acceptability to parents and doctors in the different evaluation periods was evaluated from: - a semi-qualitative questionnaire consisting of 32 questions on vaccination, with nine questions on the acceptability of hepatitis B vaccination, in the PopCorn study (general population), and - a specific vaccine practice questionnaire consisting of 25 questions, with 16 questions on the acceptability of hepatitis B vaccination, in the PRALINE study (generalist physicians and paediatricians). The acceptability analysis was performed after a multiple correspondence analysis and using a mixed classification (k-means and hierarchical ascendant classification) that allowed three parent response profiles (“favourable,” “moderately favourable” and “unfavourable”) and two doctor response profiles (“favourable” and “unfavourable”) to be formed in T1, then classified in terms of acceptability in the other evaluation periods (T2, T3 and T4 in the PopCorn study and T2 in the PRALINE study).

8.3.3 Main results of the PopCorn study (general population) Almost 1,200 children were included in each period of the study. Child Health Records were available for almost 96% of children included in each period analysed.

17

First evaluation period studying children born in 2007 aged between 24 and 27 months in T1 (mid-2009) and children born in 2008 aged between 12 and 15 months in T1 (mid-2009) 18 Second evaluation period studying children born in 2008 aged between 24 and 27 months in T2 (mid-2010) and children born in 2009 aged between 12 and 15 months in T2 (mid-2010) 19 Third evaluation period studying children born in 2009 aged between 24 and 27 months in T3 (mid-2011) and children born in 2010 aged between 12 and 15 months in T3 (mid-2011) 20 Fourth evaluation period studying children born in 2010 aged between 24 and 27 months in T4 (mid-2012) and children born in 2011 aged between 12 and 15 months in T4 (mid-2012)

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The hepatitis B vaccination coverage in children aged 24 to 27 months was 33.0% in T1 (pre-reimbursement period) and 60.7% in T4 (three years into reimbursement) for a complete course of vaccine consisting of two doses plus one booster dose. The coverage in children aged 12 to 15 months who had received at least 2 doses of hexavalent vaccine before the age of 6 months was 36.6% in T1 (peri-reimbursement period) and 64.5% in T4 (four years into reimbursement). The increase in vaccination coverage occurred from T2 in both age groups studied and it continued to increase in the next two periods (Table 1). Table 1: Estimated hepatitis B vaccination coverage (adjusted population*) Adjusted population* in T1 (N=1,133) At least one dose of Children 24-27 hepatitis B vaccine aged 20.72 before the age of 6 months months Children aged 12-15 47.04 months At least two doses of Children 24-27 hepatitis B vaccine aged 7.21 before the age of 6 months months Children aged 12-15 36.58 months Complete vaccination Children aged 24-27 course** 32.95 months

(%) in the four data collection periods Adjusted population* in T2 (N=1,190)

Adjusted population* in T3 (N=1,195)

Adjusted population* in T4 (N=1,201)

49.88

71.87

72.77

70.67

73.86

72.77

39.61

61.79

59.04

57.99

60.53

64.53

42.51

58.52

60.73

* Adjusted for region and size of town of the 1,379,988 households with at least one child (or grandchild) aged under 3 years (INSEE 1999) ** At least two doses plus one booster dose 5 months later

In parallel with this, a significant increase in the use of INFANRIX HEXA for hepatitis B primary vaccination in both age groups was observed. Its use in children aged 24-27 months was 17% in T1 and had risen to over 90% four years later. This change was accompanied by a significant reduction in the median age of administration of the first dose. In children aged 24-27 months, the median age was estimated as 6.3 months in T1 versus 2.2 months three years later. There was no change in vaccination coverage for other recommended or non-recommended paediatric vaccines. Across the four periods, acceptability to parents was evaluated in a total of 4,360 households that agreed to complete the questionnaire, out of 4,773 households contacted (i.e. 91.3% of the initial sample). The proportion of parents described as “favourable to HBV vaccination” remained stable across the four evaluation periods (between 17% and 22%, p=0.09, χ² test). Almost 70% of parents were defined as “favourable” or “moderately favourable” to hepatitis B vaccination. However, fears about this vaccination are still present, since half of all parents interviewed in any evaluation period were “a little” or “extremely” worried about the vaccination. It should be noted that almost 20% of parents stated that their child had not been vaccinated against hepatitis B while the Child Health Record confirmed that hepatitis B vaccination had occurred.

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8.3.4 Main results of the PRALINE study (generalist physicians and paediatricians) A total of 325 generalist physicians and 448 paediatricians actively participated in the study. One hundred and fifty-four (154) generalist physicians actively participated in the first evaluation period, T121 (66% of the sample of doctors who agreed to take part) and 171 in the second evaluation period, T222 (70%). Their mean age was 50 years; one-third were women, and almost all were in private practice. Two hundred and twenty-three (223) paediatricians participated actively in T1 (93% of the sample questioned) and 225 in T2 (94%). Their mean age was 55-56 years; women were in the majority, and almost all were in private practice. In the first evaluation period (T1), of the 10,395 children included, 9,652 (92.9%) were analysed comprising 4,889 aged 12-15 months and 4,763 aged 24-27 months. In the second evaluation period (T2), of the 10,404 children included, 9,904 (95.2%) were analysed comprising 5,086 aged 12-15 months and 4,818 aged 24-27 months. About 66% were under the care of a paediatrician in each evaluation period and in both age groups. However, as the analysis was restricted to doctors with a minimum threshold of seven children attending for vaccination, only the practices of 90 out of 154 generalist physicians active in T1 (58.4%) and 100 / 171 active in T2 (58.5%) could be included in the analysis of the acceptability indicator. Among the paediatricians, the practices of 221 out of 223 paediatricians active in T1 (99.1%) and 207 out of 225 active in T2 (97.3%) could be analysed. The analysis thus covered 5,959 children in T1 (61.7% of the sample) comprising 3,184 aged 12-15 months and 2,775 aged 24-27 months, and 5,999 children in T2 (60.6% of the sample) comprising 3,218 aged 12-15 months and 2,751 aged 24-27 months. The proportion of generalist physicians described as “practising hepatitis B vaccination” (at least 50% of children under their care had received one dose of vaccine before the age of 6 months) in children aged 24 to 27 months was 47% in T1 (peri-reimbursement period) and 79% in T2 (two years into reimbursement) for the same age group. The proportion of paediatricians described as “practising hepatitis B vaccination” (at least 50% of children under their care had received one dose of vaccine before the age of 6 months) in children aged 24 to 27 months was 51% in T1 (peri-reimbursement period) and 94% in T2 (two years into reimbursement) for the same age group. The proportion of doctors described as “favourable to HBV vaccination” remained stable between the two evaluation periods (between 95% and 97%, p=0.12, χ² test). There was a statistically significant change in acceptability of hepatitis B vaccination in the 418 generalist physicians (90% in T1 versus 95% in T2, p=0.03). More than 98% of the 463 paediatricians were defined as “favourable” to hepatitis B vaccination in T1 and T2. Hepatitis B vaccination coverage (with the complete vaccination course) in children aged 24 to 27 months was 38% in T1 (pre-reimbursement period) in general practice and 58% in paediatrics. In T2 (two years into reimbursement), the proportion of children who had had a complete course of vaccine had reached 60% for generalist physicians and 78% for paediatricians (Tables 2 and 3).

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T1 from 27/10/2009 to 30/06/2010: first evaluation period studying children born in 2007 aged between 24 and 27 months in T1 and children born in 2008 aged between 12 and 15 months in T1 22 T2 from 08/09/2011 to 25/02/2012: second evaluation period studying children born in 2007 aged between 24 and 27 months in T1 and children born in 2008 aged between 12 and 15 months in T1

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Table 2: Change in hepatitis B vaccination coverage (%) in general practice (N=6,610) In T1 In T1 In T2 In T2 Children Children Children Children aged 24-27 aged 12-15 aged 24-27 aged 12-15 months months months months N=1,634 N=1,634 N=1,584 N=1,758 At least one dose of hepatitis B vaccine before 40.7 60.6 70.7 76.9 the age of 6 months At least two doses of hepatitis B vaccine before 31.2 54.2 61.2 68.9 the age of 6 months Complete vaccination 38.0 59.8 course**

p*1 p*2