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Drugs and Health Products

BEXSERO

Contact: Office of Regulatory Affairs, Biologics and Genetic Therapies Directorate

Summary Basis of Decision (SBD)

Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Bexsero is located below.

Recent Activity for Bexsero

SBDs written for eligible drugs approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decision was negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.

Post-Authorization Activity Table (PAAT) for Bexsero

Updated: 2016/03/09

The following table describes post-authorization activity for Bexsero, a product which contains the medicinal ingredient Recombinant Neisseria meningitidis serogroup B Neisseria Heparin Binding Antigen (NHBA) fusion protein, Recombinant Neisseria meningitidis serogroup B Neisserial Adhesin A fusion protein (NadA), Recombinant Neisseria meningitidis serogroup B factor H binding protein (fHBP) fusion protein, and Recombinant Neisseria meningitidis serogroup B Outer Membrane Vesicles. For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II.

For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.

Drug Identification Number (DIN):

  • DIN 02417030
  • Recombinant Neisseria meningitidis serogroup B Neisseria Heparin Binding Antigen (NHBA) fusion protein, 50 g/0.5 mL;
  • Recombinant Neisseria meningitidis serogroup B Neisserial Adhesin A fusion protein (NadA), 50 g/0.5 mL;
  • Recombinant Neisseria meningitidis serogroup B factor H binding protein (fHBP) fusion protein, 50 g/0.5 mL;
  • Recombinant Neisseria meningitidis serogroup B Outer Membrane Vesicles, 25 g/0.5 mL.
  • Suspension, intramuscular injection.
Post-Authorization Activity Table (PAAT)
Activity/Submission Type, Control Number Date Submitted Decision and Date Summary of Activities
(the most recent activities are listed first)
NC #187695 2015/09/14 Issued No Objection Letter 2015/12/23 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to update an in-process control used in the manufacturing process. The submission was reviewed and considered acceptable, and a No Objection Letter was issued.
NDS #188754 2015/10/21 Issued NOC 2015/12/11 Submission filed to transfer ownership of the product [that is (i.e.) drug sponsor name)] from Novartis Vaccines and Diagnostics, Inc. to GlaxoSmithKline Inc. Notice of Compliance issued.
New safety review started by Health Canada Not applicable Started between 2015/07/01 and 2015/09/30 Health Canada started a safety review for Bexsero between 2015/07/01 and 2015/09/30.
SNDS # 176603 2014/08/01 Issued NOC 2015/03/16 Submission filed as Level I – Supplement to make updates to the manufacturing process of the 961c vaccine antigen drug substance. The information was reviewed and considered acceptable. An NOC was issued.
NC # 179792 2014/11/14 Issued No Objection Letter 2015/01/15 Submission filed as a Level II (90 day) Notifiable Change (Safety Change) to update the Warnings and Precautions and Adverse Reactions sections of the Product Monograph, as well as Part III: Consumer Information. The submission was reviewed and considered to be acceptable, and a No Objection Letter was issued.
NC # 177503 2014/08/26 Issued No Objection Letter 2014/10/10 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to propose an additional aseptic filling line used in the manufacture of Bexsero drug product. The submission was reviewed and a No Objection Letter was issued.
NC # 175336 2014/06/13 Issued No Objection Letter 2014/09/23 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to qualify a new lot of reference standard against the approved reference standard, for the immunogenicity test of the Bexsero vaccine product. The submission was reviewed and a No Objection Letter was issued.
NC # 176029 2014/06/30 Issued No Objection Letter 2014/08/12 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to update three process parameters in the purification phase during manufacture of the drug substance. The submission was reviewed and a No Objection Letter was issued.
Drug product (DIN 02417030) market notification Not applicable Date of first sale: 2014/02/26 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Next link will take you to another Web site Food and Drug Regulations.
NDS # 147275 2011/05/26 Issued NOC 2013/12/06 Notice of Compliance issued for New Drug Submission.

Summary Basis of Decision (SBD) for Bexsero

Date SBD Issued: 2014/01/23

The following information relates to the original authorization of the new drug submission for Bexsero.

  • Recombinant Neisseria meningitidis serogroup B Neisseria Heparin Binding Antigen fusion protein, 50 g /0.5 mL;
  • Recombinant Neisseria meningitidis serogroup B Neisserial Adhesin A protein, 50 g/0.5 mL;
  • Recombinant Neisseria meningitidis serogroup B factor H binding protein fusion protein, 50 g/0.5 mL;
  • Neisseria meningitidis serogroup B Outer Membrane Vesicles, 25 g/0.5 mL, suspension, intramuscular injection.
  • Drug Identification Number (DIN): 02417030
  • Novartis Vaccines and Diagnostics, Inc.
  • New Drug Submission Control Number: 147275

On December 6, 2013, Health Canada issued a Notice of Compliance to Novartis Vaccines and Diagnostics, Inc. for the vaccine, Bexsero.

The market authorization was based on quality (chemistry and manufacturing), non-clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada's review, the benefit/risk profile of Bexsero is favourable for active immunization of individuals from 2 months through 17 years old against invasive disease caused by Neisseria meningitidis serogroup B strains.

  1. What was approved?
  2. Why was Bexsero approved?
  3. What steps led to the approval of Bexsero?
  4. What follow-up measures will the company take?
  5. What post-authorization activity has taken place for Bexsero?
  6. What other information is available about drugs?
  7. What was the scientific rationale for Health Canada's decision?

1. What was approved?

Bexsero, an active immunizing agent, was authorized for active immunization of individuals from 2 months through 17 years old against invasive disease caused by Neisseria meningitidis serogroup B strains.

As the expression of antigens included in the vaccine is epidemiologically variable in circulating group B strains, meningococci that express them at sufficient levels are predicted to be susceptible to killing by vaccine-elicited antibodies.

Bexsero is a multicomponent Meningococcal B vaccine that contains three purified recombinant Neisseria meningitidis serogroup B protein antigens: NadA (Neisserial adhesin A) as a single protein, NHBA (Neisseria Heparin Binding Antigen) as a fusion protein, fHbp (factor H binding protein) as a fusion protein; and PorA P1.4 as the main antigen of Outer Membrane Vesicles (OMV) derived from Neisseria meningitidis serogroup B, strain NZ 98/254.

Bexsero is contraindicated for individuals who are hypersensitive to this vaccine or to any ingredient in the formulation or components of the container closure. Bexsero was approved for use under the conditions stated in the Bexsero Product Monograph taking into consideration the potential risks associated with the administration of this vaccine.

Bexsero is presented as a suspension for injection. In addition to the active ingredients mentioned above, the vaccine contains aluminium hydroxide, sodium chloride, histidine, sucrose, and water for injection.

For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

Additional information may be found in the Bexsero Product Monograph, approved by Health Canada and available through the Drug Product Database.

2. Why was Bexsero approved?

Health Canada considers that the benefit/risk profile of Bexsero is favourable for active immunization of individuals from 2 months through 17 years old against invasive disease caused by Neisseria meningitidis serogroup B strains.

Invasive meningococcal disease (IMD) is a serious disease. IMD caused by Neisseria meningitidis serogroup B (MenB) is increasing in distribution and incidence among all Neisseria meningitidis serogroups. MenB is also a significant cause of endemic and epidemic outbreaks of IMD in countries worldwide. Currently, there are no serogroup B meningococcal vaccines available in Canada. Vaccines based on protein antigens, such as outer membrane vesicles (OMV) vaccines, have been effective in controlling MenB outbreaks in other countries, providing evidence that bactericidal antibodies against protein antigens of MenB can confer protection. As compared to OMV vaccines, Bexsero is a more complex formulation containing OMV and additional antigens that are conserved across different serotypes. These additional antigens include NadA (Neisserial adhesin A), NHBA (Neisseria Heparin Binding Antigen) and fHbp (factor H binding protein). The inclusion of multiple antigens in Bexsero can potentially improve coverage for MenB strains.

Protection by the vaccine was inferred from immune responses against the four antigens of the vaccine. The primary immunogenicity measure was the proportion of subjects with a serum bactericidal assay using human complement (hSBA) response equal to or above the threshold of 1:5 (or 1:4 in a few studies) against each of the meningococcal serogroup B reference strains. Robust immune responses were shown in infants, young children and adolescents against fHbp, NadA, and OMV (PorA P1.4) antigens. The immune response to the NHBA antigen was also demonstrated in infants and young children in some studies. A booster dose after the priming series was shown to restore the antibodies to protective levels in infants and toddlers. There were insufficient data to support the indication in adults.

The safety profile of Bexsero was based on data from 15 clinical studies. A total of 5,853 infants and toddlers, 298 children, 1,963 adolescents and 81 adults were included in the safety analysis. Bexsero was generally well-tolerated. Most local adverse reactions (tenderness/pain, erythema, swelling and induration) and most systemic adverse reactions (change in eating habits, sleepiness, irritability, unusual crying, vomiting, diarrhea, rash, fever ≥38C in infants and children <2 years of age; as well as myalgia, arthralgia, nausea, malaise, headache and fever in adolescents and adults) were of a mild to moderate nature and resolved within 48 hours after vaccination with Bexsero.

A Risk Management Plan (RMP) for Bexsero was submitted by Novartis Vaccines and Diagnostics, Inc. to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product.

Based on the Health Canada review of data on quality, safety and efficacy, Health Canada considers that the benefit/risk profile of Bexsero is favourable for individuals from 2 months through 17 years old for the prevention of the invasive disease caused by Neisseria meningitidis serogroup B strains. Bexsero may not provide protection against all circulating meningococcal serogroup B strains because only meningococci that express antigens included in the vaccine at sufficient levels are predicted to be killed. The vaccine antigens present in Bexsero are also expressed by meningococci belonging to serogroups other than serogroup B; however, protection against IMD caused by other serogroups has not been studied. Protection against IMD caused by other serogroups should not be assumed.

Overall, Bexsero has an acceptable safety profile based on the non-clinical data and clinical studies. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Bexsero Product Monograph to address the identified safety concerns.

This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Next link will take you to another Web site Food and Drug Regulations. For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

3. What steps led to the approval of Bexsero?

The sponsor filed a request for Priority Review Status under the Priority Review Policy for the review of the new drug submission (NDS) for Bexsero. Priority Review status was granted, as invasive meningococcal disease (IMD) is a serious and life-threating disease and no vaccine is presently marketed for IMD in Canada. However, upon review, deficiencies (quality issues and clinical concerns) were reported and a Notice of Deficiency (NOD) was issued. In the response to the NOD, additional information and data were provided. Most of the issues outlined in the NOD were satisfactorily addressed, resulting in the issuance of a Notice of Compliance.

Submission Milestones: Bexsero
Submission Milestone Date
Pre-submission meeting: 2010/08/04
2010/09/07
Request for priority status
Filed: 2011/04/04
Approval issued by Director: 2011/04/29
Submission filed: 2011/05/26
Screening 1
Screening Deficiency Notice issued: 2011/06/24
Response filed: 2011/08/19
Screening Acceptance Letter issued: 2011/09/13
Review 1
On-Site Evaluation: 2011/11/07 to 2011/11/12
2011/11/14 to 2011/11/18
Quality Evaluation complete: 2012/03/06
Clinical Evaluation complete: 2012/03/06
Notice of Deficiency (NOD) issued by Director General (safety, efficacy, and quality issues): 2012/03/06
Response filed: 2012/12/20
Screening 2
Screening Acceptance Letter issued: 2013/02/15
Review 2
Quality Evaluation complete: 2013/11/25
Clinical Evaluation complete: 2013/12/03
Labelling Review complete: 2013/12/04
Notice of Compliance (NOC) issued by Director General: 2013/12/06

The Canadian regulatory decision on the quality, non-clinical and clinical review of Bexsero was based on a critical assessment of the Canadian data package. Health Canada used the European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) Day 120, 150 and 180 List of Questions as an added reference.

For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.

4. What follow-up measures will the company take?

As part of the marketing authorization for Bexsero, Health Canada requested and the sponsor agreed to several commitments to be addressed post-market. In addition to requirements outlined in the Next link will take you to another Web site Food and Drugs Act and Next link will take you to another Web site Regulations, the sponsor agreed to provide the following information as soon as it is available:

  • The persistence data of bactericidal antibodies after the administration of two catch-up doses of Bexsero in children 2 to 10 years of age.
  • The data from ongoing study V72_28 and its extension study V72_28E1 in infants 6-12 months of age.
  • The persistence data of bactericidal antibodies, including antibodies against Neisseria Heparin Binding Antigen in Canadian adolescents.
  • Explore possibilities for conducting observational post-market safety and effectiveness studies, and generate a bi-annual Periodic Benefit Risk Evaluation Report.

5. What post-authorization activity has taken place for Bexsero?

Summary Basis of Decision documents (SBDs) for eligible drugs authorized after September 1, 2012 will include post-authorization information in a table format. The Post-Authorization Activity Table (PAAT) will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decision was negative or positive. The PAAT will continue to be updated during the product's lifecycle.

The PAAT for Bexsero is found above.

For the latest advisories, warnings and recalls for marketed products, see MedEffect Canada.

6. What other information is available about drugs?

Up to date information on drug products can be found at the following links:

7. What was the scientific rationale for Health Canada's decision?

Clinical Basis for Decision

Clinical Pharmacology

Bexsero is a vaccine containing both purified, recombinant protein antigens and outer membrane vesicles (OMV) derived from Neisseria meningitidis. Protection against invasive meningococcal disease (IMD) is mediated mainly by bactericidal antibodies against these antigens that are components of the bacterium. Immunization with Bexsero is intended to raise the titre of bactericidal antibodies that specifically bind the antigens NadA (Neisserial adhesin A), NHBA (Neisseria Heparin Binding Antigen), fHbp (factor H binding protein) and PorA P1.4 (the immunodominant antigen present in the OMV component). Meningococci that express either the PorA P1.4 antigen or sufficient levels of any of the other antigens (NadA, fHbp, NHBA), defined as the positive bactericidal threshold, are predicted to be susceptible to killing by vaccine-elicited immune serum.

The pharmacodynamics of Bexsero were assessed through the analysis of immunogenicity described in the Clinical Efficacy section.

Vaccines do not require an evaluation of pharmacokinetic properties; therefore, no pharmacokinetic studies were conducted with Bexsero.

For epidemiology data, please refer to the Bexsero Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

No efficacy studies were performed during the clinical development of Bexsero because of a low incidence of IMD. Protection by the vaccine was inferred from immune responses against four antigenic components of the vaccine. In all studies, the sera from vaccinees were tested by a serum bactericidal assay using human complement (hSBA) using strains H44/76, 5/99, and NZ98/254 for antigens fHbp, NadA and OMV, respectively. Strain M10713 was also used in hSBA for antigen NHBA in a few studies and the rest of the studies provided Enzyme-Linked Immunosorbent Assay (ELISA) data.

After review of the information in the original submission, a Notice of Deficiency (NOD) was issued. The major clinical issues identified in the NOD were related to the estimation of vaccine coverage; the choice of reference strains for hSBA; the limited or lack of data to support the indication for infants 6-12 months of age, children 2-10 years of age, and adults; and lack of information regarding antibody persistence and booster dose. The sponsor submitted a response to the NOD and additional data. Most of the issues outlined in the NOD were sufficiently addressed by the sponsor to Health Canada's satisfaction.

The original submission contained five studies (V72P13, V72P13E1, V72P12, V72P9, and V72P6) in infants and children (<10 years of age), one study (V72P10) in adolescents (11 to 17 years of age), and two studies (V72P4 and V72P5) in adults (18 to 50 years of age) using the final formulation of Bexsero. In the response to the NOD, further data were made available from studies V72P6E1, V72P9E1, V72P10, V72P10E1, V72P12E1, V72P13E2, V72P16, and V72_41.

Overall, robust immune responses to the vaccine, as measured by hSBA with the reference strains, were shown in infants (at 2 months of age), children (<10 years of age) and adolescents (11-17 years of age). A booster dose after the priming series can restore the antibodies to protective levels in infants and toddlers (<2 years of age). The study designs and serum bactericidal antibody responses to the antigenic components of the vaccine are included in the Bexsero Product Monograph, approved by Health Canada, and available through the Drug Product Database. Further discussions regarding the clinical data are included below.

Estimation of strain coverage of Bexsero

The strain coverage by Bexsero was estimated using a Meningococcal Antigen Typing System (MATS). The MATS was developed to relate antigen profiles of different strains of meningococcal group B bacteria to killing of the strains in hSBA. Using the bactericidal thresholds that were derived using serum pools from infants (post-immunization of Bexsero at 2, 4, 6 and 12 months of age), a survey of approximately 157 invasive serogroup B isolates collected during 2006-2009 by the IMPACT (Immunization Monitoring Program ACTive) surveillance network revealed that 66% of isolates were predicted to have an appropriate type and sufficient antigen content and to be covered by Bexsero, with empirical variability in coverage ranging from 43% to 78%. However, this prediction is subject to some limitations and its accuracy may only be verified during post-market use. This limitation is reflected in the Bexsero Product Monograph.

Reference strains in hSBA

Four virulent strains of serogroup B meningococci that were isolated from cases of IMD were selected as reference strains in hSBA, including strains H44/76, 5/99, NZ98/254 and M10713. Based on the whole body of data on selection of reference strains in the original submission and the response to the NOD, these reference strains are considered to be acceptable for use in hSBA for clinical studies.

Studied populations

The clinical studies included infants from 2 months, children 6-8 months of age for catch-up vaccination, children 12-15 months of age for primary vaccination, adolescents 11-17 years of age, and to some extent adults 18-50 years of age. In the response to the NOD, additional data were provided for children aged 24-62 months from studies V72P6E1, V72P9E1, V72P12E1 and V72P13E2 and for adolescents aged 11-17 years from study V72_41.

Dose-finding

In study V72P16, the full dose (150 ug) of rMenB (three recombinant protein antigens without OMV) induced higher hSBA geometric mean titres (GMTs) for strains H44/76 and 5/99 after the priming series and booster as compared to 1/2 dose (75 ug) of rMenB. The dose-dependent immune response of OMV has been demonstrated by using the full, and doses of OMV.

Primary-dose schedules

For primary-dose schedules in infants, two dosing schedules were assessed, including a 2, 3 and 4 month schedule in studies V72P12 and V72P16 and a 2, 4, 6 month schedule in studies V72P6, V72P12, and V72P13. In those two schedules, immune response to the vaccine was considered sufficient for all 3 reference strains H44/76, NZ98/254 and 5/99. However, the 2, 4, 6 month schedule induced a higher immune response to NHBA (seropositive rate and GMT) as compared to the 2, 3 and 4 month schedule.

The dose schedule in infants 6-8 months of age was studied in V72P9 as two doses given 2 months apart, with a third dose at approximately 12 months of age. There are limited data to support the two-dose priming schedule in infants of 6-11 months of age. However, the available information in the age groups <6 months and >12 months indirectly support the use of the vaccine in the 6-11 months group. Additional data in this age group from ongoing study V72_28 and its extension V72_28E1 are required to be submitted, when available.

Dose schedules in infants aged 12-15 of months were studied by two doses at 12 and 14 or 13 and 15 months of age in studies V72P13E1 and V72P12E1. The data are considered to support the primary-dose schedule in this age group.

A two-dose series in children aged 2 to 10 years of age was assessed in studies V72P12E1 (24-26 months of age), V72P13E2 (24-26 months of age), V72P6E1 (40-44 months of age), and V72P9E1 (40-44 and 60-62 months of age). The data demonstrated that a two-dose series elicited a robust bactericidal antibody response.

For adolescents (11-17 years), a study in Chilean adolescents supports at least a two-dose priming in this age group. However, most of the subjects live in an MenB endemic region and might be exposed to the MenB strains that cross-react to the reference strains. Health Canada requested data from Canadian adolescents and these were provided in the response to the NOD. The results confirmed the difference of pre-immune status between the two regions. Following immunization, the GMTs against all three tested antigens (fHbp, NadA and PorA) and the seropositive rate of PorA were lower in Canadian adolescents than in Chilean adolescents. However, the study supports the two-dose schedule in Canadian adolescents.

The dosing schedule in adults 18-50 years of age was studied in two studies (Phase I and Phase II) with a limited number of subjects. The immunogenicity objectives were exploratory and there was no statistical null hypothesis associated with these objectives. No hSBA data for NHBA were available in the adults. There were insufficient data to support the proposed indication in adults.

Antibody persistence

The response to the NOD includes additional new data of the antibody persistence in infants, children and adolescents against three of four antigens (e.g, fHbp, NadA and PorA). Currently, data on bactericidal antibody persistence are available for 18-20 months in infants after a three-dose primary series (2, 4, 6 or 2, 3, 4-month series) from study V72P12E1, 28-32 months in infants after three doses (6, 8 and 12 months of age) from study V72P9E1 and after four doses (2, 4, 6 and 12 months of age) from study V72P6E1, 12 months after a two-dose toddler series (12 and 14 or 13 and 15 months of age) from study V72P13E2, and 22-23 months after a two-dose series in adolescents (0, 1 or 0, 2 month schedule) from study V72P10E1. The provided data showed that the antibodies against PorA rapidly declined in infants and children over 6 months but not in adolescents. The antibodies against fHbp also declined over 12 months in infants from study V72P12E1. There are no data available for more than 6 months following the second vaccination for fHbp in young children (2-10 years of age). Antibodies against the three antigens in the Chilean adolescents were maintained at a high level (% seropositive rate) 18 to 23 months after two doses.

Booster vaccinations

A booster dose was studied at 12 months of age, 6 months after three priming vaccinations in studies V72P6 and V72P13E1 and at 12 months of age after two primary vaccinations at 6 and 8 months in study V72P9. A booster dose given at 12 months of age after these priming series was shown to restore the antibodies to protective levels in infants and toddlers (<2 years of age). A booster dose at 12 months after a two-dose series in toddlers also restored hSBA ≥1:5 to 99%-100% of subjects for all four strains in a study.

It remains to be determined whether a booster dose is required in Canadian adolescents after a primary vaccination course with two doses of Bexsero.

The need for and timing of a further booster dose remain to be determined for toddlers who received two primary vaccinations at 6 and 8 months. Also, the need for and timing of a booster dose remain to be determined for individuals who received a primary series at 12 months of age and older.

Concomitant use of vaccines

Bexsero can be given concomitantly with any of the following vaccine antigens, either as monovalent or as combination vaccines: diphtheria, tetanus, acellular pertussis, Haemophilus influenzae type b, inactivated poliomyelitis, hepatitis B, heptavalent pneumococcal conjugate,measles, mumps, rubella and varicella.

Concomitant use of Bexsero with routine infant vaccines [that is (i.e.) Infanrix-hexa, Prevenar] was studied in studies V72P12 and V72P13. The immune response in both studies met the sufficient immune response criterion that the lower limit of the two-sided 95% Confidence Interval (CI) for the percentage of subjects with hSBA ≥1:5 at 1 month following the third vaccination was ≥70% for all three reference strains H44/76, NZ98/254 and 5/99. However, in one study (V72P12), the percentage of subjects with hSBA ≥1:5 for strain NZ98/254 was lower in the concomitant use group (79%, 95% CI 75-82) than in the intercalated group (87%, 95% CI 84-89) at 1 month after the third vaccination [the lower 95% confidence limit (95% LCL) was -12%]. When administered alone, Bexsero also elicited higher hSBA GMTs for all strains as compared to the concomitant use group. The clinical implication of these differences remains unknown.

Non-inferiority of responses to concomitantly administered routine infant vaccines was demonstrated for most antigens in studies V72P12 and V72P13. However, inconsistent results were seen across the studies for responses to inactivated poliovirus type 2 and pneumococcal conjugate serotype 6B; lower antibody titres to the pertussis pertactin antigen were also noted. These data do not suggest clinically significant interference.

For concomitant use of Bexsero and MMRV (measles, mumps, rubella and varicella vaccine) in study V72P13E1, the non-inferiority was achieved for the vaccine antigens Measles, Mumps and Rubella. For Varicella, the non-inferiority was demonstrated for seroconversion [≥1.25 Glycoprotein Enzyme-Linked Immunosorbent Assay (gpELISA) units/mL] but could not be demonstrated for seroprotection (≥5 gpELISA units/mL) at the first dose. The clinical significance of the results remains unknown.

Information regarding concomitant use of Bexsero with these vaccines is included in the Bexsero Product Monograph.

Prophylactic use of paracetamol for vaccination

In a clinical study, prophylactic use of paracetamol (or acetaminophen) had no impact on the immune responses of Bexsero and most antigens of routine vaccines.

Lot to lot consistency

Three consecutively manufactured Bexsero vaccine lots demonstrated the consistency of immunogenicity in infants and adolescents.

Conclusion

The efficacy of Bexsero has been inferred by measuring bactericidal antibody responses to each of the vaccine antigens fHbp, NadA, NHBA and PorA P1.4, using a set of four meningococcal serogroup B reference strains (H44/76, 5/99, M10713 and NZ98/254, respectively).

In the studies submitted, robust hSBA responses against three selected reference strains (H44/76 and 5/99 and NZ98/254) were demonstrated in infants (at 2 months of age), children (<10 years of age) and adolescents (11-17 years of age). In addition, hSBA response against strain M10173 for NHBA was also demonstrated in some studies. There were insufficient data to support the indication in adults.

A booster dose given in the second year of life after the priming series was shown to restore the antibodies to protective levels in infants and toddlers (<2 years of age).

Bexsero can be given concomitantly with any of the following vaccine antigens, either as monovalent or as combination vaccines: diphtheria, tetanus, acellular pertussis, Haemophilus influenzae type b, inactivated poliomyelitis, hepatitis B, heptavalent pneumococcal conjugate,measles, mumps, rubella and varicella.

For more information, refer to the Bexsero Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

In the original drug submission, a total of 6,427 subjects were exposed to at least one dose of Bexsero from eight studies, and 1,630 infants received a booster dose in the second year of life. Additional data were provided in response to the NOD, increasing the safety analysis to include a total of 5,853 infants and toddlers, 298 children, 1,963 adolescents and 81 adults.

When Bexsero was administered to infants 2 months of age with or without routine childhood vaccines (Infanrix Hexa and Prevenar), local reactions associated with Bexsero were common. Tenderness followed by erythema and induration were the most commonly reported local reactions after concomitant administration of Bexsero with routine vaccines (i.e., Bexsero + Routine group). Most of the reactions were transient and resolved by 7 days after vaccination. The majority of reactions were mild or moderate in nature. Subjects receiving Bexsero co-administered with routine vaccines also reported higher rates of systemic reactions compared to those receiving MenC conjugate with routine vaccines or the routine vaccines alone. The most commonly reported systemic reactions after the concomitant use were fever (i.e., body temperature ≥38.0C), irritability, sleepiness, change in eating habits and unusual crying. Most of the systemic reactions occurred within the first several days of vaccination and resolved by Day 7. The fever associated with Bexsero vaccination was highest at the 6 hour time-point after vaccination and decreased on the following day.

When Bexsero was given concomitantly with the MMRV vaccine, the fever was mostly reported during the 1-4 days after vaccination with Bexsero alone and during the 5-28 days after the MMRV vaccination alone.

The most commonly reported local and systemic reactions after vaccination with the fourth (booster) dose of Bexsero were tenderness followed by erythema, induration and irritability.

In children 2 to 10 years of age, the most commonly reported solicited local reaction across studies were pain/tenderness, followed by erythema; the most commonly reported solicited systemic reactions were irritability followed by sleepiness and change in eating habits following vaccination with Bexsero. Most of the solicited reactions were mild or moderate in severity and transient.

In adolescents, the incidence rates of local reactions were higher in the Bexsero group than in the placebo group. The most commonly reported local reaction after any Bexsero dose was pain, followed by erythema. The incidence rate of the individual systemic reactions was slightly higher in the Bexsero group than in the placebo group. The most commonly reported systemic reactions after any Bexsero dose were malaise, myalgia and headache. A higher percentage of subjects stayed home after each dose compared with the placebo group. Limited safety data were available in individuals from 18 to 50 years of age.

A total of 10 febrile seizures and 15 non-febrile seizures were reported in the first year of life in studies V72P12 and V72P13. Of these, only 2 febrile seizures in Bexsero subjects were reported within 2 days of vaccination. In the second year of life, among the 4 febrile seizures which were observed within two weeks of vaccination, all occurred at least one week after vaccination with Bexsero (3 cases) or routine vaccines alone (1 case).

There were 7 cases of suspected Kawasaki Disease (KD) reported, 6 cases with Bexsero subjects and 1 in subjects that were administered MenC conjugate. These few KD cases do not allow a definitive assessment of the causal relationship between Bexsero vaccination and the disease.

Two cases of arthritis were observed in adolescents and considered possibly related to the vaccine. Two other cases were found in infants and one case was possibly related to the vaccine. In addition, two hypotonic-hyporesponsive episode (HHE) cases were observed, one within 1 day of vaccination with Bexsero co-administered with routine vaccines and the other on the same day of vaccination with the routine vaccines.

Overall, Bexsero was generally well-tolerated. Appropriate warnings and precautions are in place in the approved Bexsero Product Monograph to address the identified safety concerns. For more information, refer to the Bexsero Product Monograph, approved by Health Canada and available through the Drug Product Database.

Non-Clinical Basis for Decision

The single and repeat-dose toxicity studies indicated that meningococcal B (Men B) vaccine was generally well-tolerated in male and female rabbits when administered intramuscularly once or five times during eight weeks. The Men B vaccine formulations were also immunogenic in tested animals and with two immunizations were able to induce high immunoglobulin G antibody titres and bactericidal activity.

Three reproductive and developmental toxicity studies were carried out with Bexsero, given intramuscularly at 1 or 2 times the human dose in female rabbits. There were no significant treatment-related effects observed on female fertility, major fetal malformations, and post-natal neurobehavioral and developmental effects. The vaccine formulated with or without the OMV component was not teratogenic at the dose levels tested. Bexsero elicited an antibody response in treated does, and antibodies were passed to fetuses and persisted in pups through Day 29 of lactation.

In addition, in vitro studies were performed using human cell models to explore any potential safety issues associated with the three recombinant meningococcal B (rMenB) protein antigens or OMV that might be related to the pathogenesis of disease caused by serogroup B strains of Neisseria meningitidis. Binding of the rMenB and OMV antigens to endothelial cells was observed, but was not associated with cytotoxicity.

In conclusion, the non-clinical studies did not show significant safety concerns for Bexsero. There are no pharmacological/toxicological issues within this submission which preclude authorization of the product.

For more information, refer to the Bexsero Product Monograph, approved by Health Canada and available through the Drug Product Database.

Quality Basis for Decision

Bexsero is a multicomponent meningococcal B vaccine, and contains four Neisseria meningitidis serogroup B antigens: Neisserial Adhesin A (NadA) as a single protein, Neisseria Heparin Binding Antigen (NHBA) and factor H binding protein (fHBP) as fusion proteins, as well as PorA P1.4 as the main antigen of Outer Membrane Vesicles (OMV).

Characterization of the Drug Substance

Detailed characterization studies were performed to provide assurance that all four medicinal ingredients consistently exhibit the desired characteristic structure and biological activity.

Results from process validation studies indicate the methods used during processing are sufficient to control the levels of product- and process-related impurities. The impurities that were reported and characterized were found to be within established limits.

The drug substance manufacturing process has been optimized. The process changes introduced at each generation of the process development were adequately described. The results of in-process and release testing, the stability data, and characterization data have also been provided and support the comparability assessment.

Manufacturing Process and Process Controls of the Drug Substance and Final Product

Bexsero is composed of four Neisseria meningitidis serogroup B antigens: Neisserial Adhesin A (NadA) as a single protein, Neisseria Heparin Binding Antigen (NHBA) and factor H binding protein (fHBP) as fusion proteins, as well as PorA P1.4 as the main antigen of Outer Membrane Vesicles (OMV). The antigens are adsorbed on aluminium hydroxide. The sequences of the recombinant protein antigens are derived from the following Neisseria meningitidis serogroup B strains: NHBA is derived from strain NZ 98/254 and is fused with accessory protein 953 derived from strain 2996; NadA is derived from strain 2996 and fHbp is derived from strain MC58 and is fused with accessory protein 936, derived from strain 2996. The OMV antigen is a suspension that consists of small, membranous spherical vesicles, or fragments of vesicles, in which the native complex antigen composition of the subcapsular cell surface of Neisseria meningitidis serogroup B, strain NZ98/254 (B:4:P1.7-2,4) is highly conserved and contains outer membrane protein PorA P1.4 as the main antigen. The recombinant proteins are prepared by recombinant deoxyribonucleic acid (DNA) technology using extrachromosomal expression plasmid vectors in Escherichia coli cells. The OMV antigen is produced by fermentation of Neisseria meningitidis strain NZ98/254, followed by inactivation of the bacteria with deoxycholate, which also mediates vesicle formation.

The manufacturing process for each of the four drug substances has been evaluated. The materials used in the manufacturing of the drug substances are considered suitable for their intended use. The manufacturing processes are also considered to be adequately validated.

All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Next link will take you to another Web site Food and Drug Regulations. The compatibility of the active ingredients with the excipients is supported by the stability data provided.

Control of the Drug Substance and Final Product

Validation reports are considered satisfactory for all analytical procedures used for in-process, release, and stability testing of the drug substances. The specifications provided for each of the drug substances are considered acceptable. Data from the batch analyses of each of the drug substances were reviewed and are within the proposed acceptance criteria.

The drug substance packaging is also considered acceptable.

Issues concerning the release testing of the drug product were identified, and led to the issuance of a Notice of Deficiency (NOD) on March 6, 2012. The sponsor responded to the NOD on December 20, 2012 and addressed all noted deficiencies accordingly. The response to NOD was accepted and as a result, the test specifications and analytical methods used are considered acceptable for all procedures used for in-process, release, and stability testing for the drug product. The specifications proposed were in line with the characteristics of the vaccine lots tested in clinical studies. Data from the batch analyses of each of the drug product components were reviewed and were within the proposed acceptance criteria.

Stability of the Drug Substance and Final Product

Based on the stability data submitted, the proposed shelf-life and storage conditions for the drug substance and drug product were adequately supported and are considered to be satisfactory. The proposed 24-month shelf-life at 2 to 8C for Bexsero is considered acceptable.

The compatibility of the drug product with the container closure system was demonstrated through compendial testing and stability studies. The container closure system met all validation test acceptance criteria.

The proposed packaging and components are considered acceptable.

Facilities and Equipment

The design, operations, and controls of the facilities and equipment that are involved in the production are considered suitable for the activities and products manufactured.

An On-Site Evaluation (OSE) was conducted on November 7 to 18, 2011 at both drug substance and drug product facilities to evaluate the production of the Bexsero vaccine. Overall, the operations and facilities were found to be satisfactory.

Adventitious Agents Safety Evaluation

Raw materials of animal origin used in the manufacturing process pose no transmissible spongiform encephalopathy risk. Adequate tests are performed on all raw materials to ensure freedom from adventitious agents. The excipients used in the drug product formulation are not from animal or human origin.