Summary Basis of Decision for Vaxneuvance

Review decision

The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.


Product type:

Drug

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

Recent Activity for Vaxneuvance

The SBDs written for eligible drugs (as outlined in Frequently Asked Questions: Summary Basis of Decision [SBD] Project: Phase II) 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 decisions were negative or positive. The PAATs will be updated regularly with post-authorization activity throughout the product life cycle.

 

The following table describes post-authorization activity for Vaxneuvance, a product which contains the medicinal ingredient pneumococcal 15-valent Conjugate Vaccine (CRM197 Protein), adsorbed. 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 and to the List of abbreviations found in Post-Authorization Activity Tables (PAATs).

 

For additional information about the drug submission process, refer to the Guidance Document: The Management of Drug Submissions and Applications.

 

Updated: 2024-08-15

 

Drug Identification Number (DIN):

DIN 02522403 – Each 0.5 mL dose contains: 2.0 mcg each of polysaccharide serotypes 1, 3, 4, 5, 6A, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F, and 33F, and 4.0 mcg of polysaccharide serotype 6B, conjugated to 30 mcg of CRM197 carrier protein, suspension, intramuscular injection

 

Post-Authorization Activity Table (PAAT)

 

Activity/Submission Type, Control Number

Date Submitted

Decision and Date

Summary of Activities

SNDS # 283525

2024-02-06

Issued NOC 2024-06-26

Submission filed as a Level I – Supplement to update the PM to meet Health Canada’s labelling requirements for all pneumococcal vaccines. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions and Clinical Pharmacology sections of the PM, and corresponding changes were made to Part III: Patient Medication Information and to the package insert. An NOC was issued.

NC # 277037

2023-07-05

Issued NOL 2023-09-21

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the supplier for a primary container closure component. The submission was reviewed and considered acceptable, and an NOL was issued.

SNDS # 267092

2022-08-17

Issued NOC 2023-07-07

Submission filed as a Level I – Supplement to update the PM with new clinical data from Study 022 and Study 026. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Indications; Adverse Reactions; Dosage and Administration; and Clinical Trials sections of the PM, and corresponding changes were made to Part III: Patient Medication Information and to the package insert. An NOC was issued.

SNDS # 264965

2022-06-07

Issued NOC 2023-01-04

Submission filed as a Level I – Supplement to add a new drug product manufacturing facility. The submission was reviewed and considered acceptable, and an NOC was issued.

NC # 267885

2022-09-14

Issued NOL 2022-12-14

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the shelf‐life for the drug product. The submission was reviewed and considered acceptable, and an NOL was issued.

Drug product (DIN 02522403) market notification

Not applicable

Date of first sale: 2022-09-02

The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.

NC # 263931

2022-05-03

Issued NOL 2022-07-19

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the shelf‐life for the drug substance or for a stored intermediate of the drug substance. The submission was reviewed and considered acceptable, and an NOL was issued.

SNDS # 259725

2021-12-20

Issued NOC 2022-07-08

Submission filed as a Level I – Supplement to expand the indication. The submission was reviewed under the Priority Review of Drug Submissions Policy. The indication authorized was: Active immunization of infants, children and adolescents from 6 weeks through 17 years of age (prior to the 18th birthday) for the prevention of invasive disease (including sepsis, meningitis, bacteremic pneumonia, pleural empyema and bacteremia) caused by Streptococcus pneumoniae serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F and 33F). The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published.

NDS # 247042

2020-12-04

Issued NOC 2021-11-16

NOC issued for New Drug Submission.
Summary Basis of Decision (SBD) for Vaxneuvance

Date SBD issued: 2022-02-25

The following information relates to the New Drug Submission for Vaxneuvance.

Pneumococcal 15-valent Conjugate Vaccine (CRM197 Protein), adsorbed

Drug Identification Number (DIN):

  • DIN 02522403 - Each 0.5 mL dose contains: 2.0 mcg each of polysaccharide serotypes 1, 3, 4, 5, 6A, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F, and 33F, and 4.0 mcg of polysaccharide serotype 6B, conjugated to 30 mcg of CRM197 carrier protein, suspension, intramuscular injection

Merck Canada Inc.

New Drug Submission Control Number: 247042

 

On November 16, 2021, Health Canada issued a Notice of Compliance to Merck Canada Inc. for the vaccine Vaxneuvance.

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 Vaxneuvance is favourable for the active immunization of adults 18 years of age and older for the prevention of invasive disease (including sepsis, meningitis, bacteremic pneumonia, pleural empyema and bacteremia) caused by Streptococcus pneumoniae serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F, and 33F).

 

1 What was approved?

 

Vaxneuvance, an active immunizing agent, was authorized for the active immunization of adults 18 years of age and older for the prevention of invasive disease (including sepsis, meningitis, bacteremic pneumonia, pleural empyema and bacteremia) caused by Streptococcus pneumoniae (S. pneumoniae) serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F, and 33F).

Vaxneuvance may not prevent disease caused by S. pneumoniae serotypes that are not contained in the vaccine.

The safety and effectiveness of Vaxneuvance in individuals younger than 18 years of age have not yet been established.

The efficacy and safety of Vaxneuvance have been studied in the geriatric population. Of the 4,344 individuals aged 50 years and older who received Vaxneuvance, 2,470 (56.9%) were 65 years and older, and 479 (11.0%) were 75 years and older.

Vaxneuvance (pneumococcal 15‑valent conjugate vaccine [CRM197 protein], adsorbed) is presented as a suspension for intramuscular injection. Each 0.5 mL dose contains 32 mcg of total pneumococcal polysaccharide (2.0 mcg each of polysaccharide serotypes 1, 3, 4, 5, 6A, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F, and 33F, and 4.0 mcg of polysaccharide serotype 6B) conjugated to 30 mcg of CRM197 carrier protein. In addition to the medicinal ingredients, the suspension contains aluminum (as aluminum phosphate adjuvant), L‑histidine, polysorbate 20, sodium chloride, and water for injection.

The use of Vaxneuvance is contraindicated in individuals with a history of a severe allergic reaction (e.g., anaphylaxis) to any component of the vaccine or any diphtheria toxoid-containing vaccine.

The drug product was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with its administration. The Vaxneuvance Product Monograph is available through the Drug Product Database.

For more information about the rationale for Health Canada's decision, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

 

2 Why was Vaxneuvance approved?

 

Health Canada considers that the benefit-risk profile of Vaxneuvance is favourable for the active immunization of adults 18 years of age and older for the prevention of invasive disease (including sepsis, meningitis, bacteremic pneumonia, pleural empyema and bacteremia) caused by Streptococcus pneumoniae (S. pneumoniae) serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F, and 33F).

Vaxneuvance may not prevent disease caused by S. pneumoniae serotypes that are not contained in the vaccine.

Invasive pneumococcal disease (IPD), caused by the bacterium S. pneumoniae, is a serious and life-threatening condition that can result in significant morbidity and mortality in adults 18 years of age and older. Pneumonia with secondary bacteremia, bacteremia, and meningitis are the most common forms of IPD. Bacteremic pneumococcal pneumonia is the most common presentation among adults and is a common complication following influenza. The case fatality rate of bacteremic pneumococcal pneumonia is 5% to 7% and is higher among elderly persons. The risk is greatest in immunocompetent adults with certain risk factors and in immunocompromised adults.

There are currently 92 S. pneumoniae serotypes recognized worldwide, 15 of which cause the majority of disease. In Canada, approximately 50 different serotypes are identified each year. Three pneumococcal vaccines are currently marketed and available for use in Canada; however, S. pneumoniae continues to be a major cause of vaccine-preventable disease worldwide, and pneumococcal disease remains an unmet medical need despite the significant public health impact of currently available pneumococcal vaccines.

Two S. pneumoniae serotypes, 22F and 33F, are not included in any currently authorized pneumococcal conjugate vaccines and have increased in frequency in several regions and countries. As of 2017, serotypes 22F and 33F were among the 10 leading serotypes associated with IPD in adults 65 years of age and older and in children 5 years of age and younger. Serotypes 22F and 33F are associated with serious clinical outcomes (including meningitis, bacteremia, sepsis, bacteremic pneumonia, and septic arthritis) as demonstrated by their relatively high degree of invasiveness in comparison to other serotypes not currently covered by authorized pneumococcal conjugate vaccines.

Vaxneuvance is a 15‑valent pneumococcal conjugate vaccine composed of capsular polysaccharides derived from the 13 S. pneumoniae serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F) contained in Prevnar 13 (a 13‑valent pneumococcal conjugate vaccine currently authorized in Canada) as well as two additional pneumococcal serotypes (22F and 33F).

The clinical immunogenicity and safety of Vaxneuvance were supported by the results of seven clinical studies. Four principal Phase III studies (the pivotal Study P019V114 and studies P016V114, P017V114, and P020V114) provided the main data in support of the effectiveness of Vaxneuvance. These studies were conducted in 14 countries with participants who were 18 years of age and older without prior history of pneumococcal vaccination (pneumococcal vaccine-naïve). In each study, immunogenicity endpoints were used to infer the effectiveness of Vaxneuvance for the prevention of IPD. This approach relied on immunologic comparability to Prevnar 13 by evaluation of opsonophagocytic activity (OPA) titers analyzed using pre-specified non-inferiority criteria for the 13 common serotypes between the two vaccines. For the additional serotypes contained in Vaxneuvance, and for the shared serotype 3, pre-specified success criteria were used in superiority analyses to infer effectiveness.

The pivotal Study P019V114 was conducted in pneumococcal vaccine-naïve adults 50 years of age and older. The study success criteria for immunogenicity were met, as Vaxneuvance was shown to be non‑inferior to Prevnar 13 for the 13 shared serotypes and superior to Prevnar 13 for the two serotypes unique to Vaxneuvance, as well as shared serotype 3. Data from studies P016V114 and P020V114 provided further support in adults 50 years of age or older. In Study P016V114, serotype-specific pneumococcal immune responses to the 15 serotypes contained in Vaxneuvance were evaluated when Pneumovax 23 was given approximately 12 months after Vaxneuvance or Prevnar 13. The results of the study demonstrated comparable immune responses for all 15 serotypes between subjects administered Vaxneuvance or Prevnar 13, one year prior to receipt of Pneumovax 23. Study P020V114 provided lot-to-lot consistency data showing that all three lots of Vaxneuvance studied met equivalence criteria.

Study P017V114 enrolled participants 18 to 49 years of age and demonstrated that following the sequential administration of Pneumovax 23 six months after Vaxneuvance or Prevnar 13, immune responses were similar for all shared serotypes. The results of the four principal studies in addition to data from three further supportive clinical studies all demonstrated that Vaxneuvance elicited an immune response and met the pre-specified primary objectives for non-inferiority for the shared serotypes with Prevnar 13. In addition, the pivotal study demonstrated that Vaxneuvance elicited immune response that met the pre-specified primary objective for superiority to Prevnar 13 for the 2 serotypes unique to Vaxneuvance (serotypes 22F and 33F), and the secondary objective for superiority to Prevnar 13 for the shared serotype 3.

Safety data from the seven clinical studies also demonstrated an acceptable safety profile for Vaxneuvance. There were no serious adverse events (SAE) considered causally related to the vaccine. In the following populations, Vaxneuvance showed a similar safety profile with that observed in immunocompetent, pneumococcal vaccine-naïve adults:

  • Adults 18 to 49 years of age with risk factors for pneumococcal disease;
  • Adults ≥18 years of age considered immunocompromised due to human immunodeficiency virus (HIV) infection;
  • Adults ≥65 years of age with prior pneumococcal vaccination.

Vaxneuvance administered sequentially with Pneumovax 23 or concomitantly with quadrivalent influenza vaccine (Fluarix) showed a similar safety profile with that of Vaxneuvance in immunocompetent, pneumococcal vaccine-naïve adults.

Vaxneuvance was moderately more reactogenic following a single dose when compared to a single dose of Prevnar 13, however overall safety profiles were comparable across groups.

In the submitted clinical studies, no data were available in some special populations (e.g., pregnant and breastfeeding women). Such limitations are not unique to Vaxneuvance, and recommendations on the use of Vaxneuvance in these special populations have been clearly labelled in the Product Monograph for Vaxneuvance.

A Risk Management Plan (RMP) for Vaxneuvance was submitted by Merck Canada Inc. to Health Canada. At the time of Notice of Compliance issuance, there were no RMP-related issues that would preclude the authorization of Vaxneuvance. 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.

The submitted inner and outer labels, package insert and Patient Medication Information section of the Vaxneuvance Product Monograph meet the necessary regulatory labelling, plain language and design element requirements.

The sponsor submitted a brand name assessment that included testing for look‑alike sound‑alike attributes. Upon review, the proposed name Vaxneuvance was accepted.

Overall, Vaxneuvance has been shown to have a favourable benefit-risk profile and 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 Vaxneuvance 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 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 Vaxneuvance?

 

The review of the quality component of the New Drug Submission (NDS) for Vaxneuvance was based on a critical assessment of the data package submitted to Health Canada. The review completed by the United States Food and Drug Administration (FDA) was used as an added reference, as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada. The Canadian regulatory decision on the Vaxneuvance NDS was made independently based on the Canadian review.

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

 

Submission Milestones: Vaxneuvance

Submission Milestone Date
Pre-submission meeting 2020-07-09
New Drug Submission filed 2020-12-04
Screening  
Screening Acceptance Letter issued 2021-01-22
Review  
Review of Risk Management Plan completed 2021-10-18
Non-clinical evaluation completed 2021-10-29
Clinical/medical evaluation completed 2021-10-29
Quality evaluation completed 2021-11-01
Labelling review completed 2021-11-09
Biostatistics evaluation completed 2021-11-16
Notice of Compliance issued by Director General, Biologic and Radiopharmaceutical Drugs Directorate 2021-11-16

 

4 What follow-up measures will the company take?

 

As part of the marketing authorization for Vaxneuvance, Health Canada requested and the sponsor agreed to several commitments to be addressed post-market. In addition to requirements outlined in the Food and Drugs Act and Regulations, commitments include (but are not limited to) the submission of:

  • a Periodic Benefit‑Risk Evaluation Report (PBRER) every 6 months for the first year of market authorization including an analysis of the safety concerns discussed in the Risk Management Plan. Subsequent PBRER submission frequency will be determined following the review of the second PBRER.
  • a cumulative review of cases of Guillain-Barré syndrome (if any) in the PBRER.

 

5 What post-authorization activity has taken place for Vaxneuvance?

 

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 decisions were negative or positive. The PAAT will continue to be updated during the product life cycle.

The PAAT for Vaxneuvance 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?
7.1 Clinical Basis for Decision

 

Clinical Pharmacology

Vaxneuvance is a conjugated polysaccharide vaccine that protects against invasive disease and pneumonia caused by Streptococcus pneumoniae (S. pneumoniae). Vaxneuvance contains serotype-specific pneumococcal capsular polysaccharides each of which are conjugated to the carrier protein CRM197. Vaccination with Vaxneuvance elicits antibodies that enhance opsonization, phagocytosis, and killing of pneumococci to protect against pneumococcal disease. Vaxneuvance elicits a T‑cell‑dependent immune response. Carrier protein-specific helper T cells support specificity, functionality and maturation of serotype‑specific B cells.

Immune responses following natural exposure to S. pneumoniae or following pneumococcal vaccination can be determined through the measurements of opsonophagocytic activity (OPA) and immunoglobulin G (IgG) responses. Opsonophagocytic activity represents functional antibodies capable of opsonizing S. pneumoniae via pneumococcal capsular polysaccharides for presentation to phagocytic cells for engulfment and subsequent killing and are considered an important immunologic surrogate measure of protection against pneumococcal disease in adults. Opsonophagocytic activity titers are expressed as the reciprocal of the highest serum dilution that reduces survival of the pneumococci by at least 50%. A validated multiplexed OPA was used to measure serotype‑specific OPA titers for each of the 15 serotypes contained in Vaxneuvance.

The clinical pharmacology of Vaxneuvance was assessed through the analysis of immunogenicity described in the Clinical Efficacy section. Overall, the duration of effect of Vaxneuvance was evaluated up to 12 months postvaccination. Immune responses elicited by Vaxneuvance persisted up to 12 months postvaccination, as assessed by OPA geometric mean titers (GMTs) and IgG geometric mean concentrations (GMCs). Immune responses at 12 months postvaccination were comparable between Vaxneuvance and Prevnar 13 for the 13 shared serotypes and higher for the two serotypes unique to Vaxneuvance.

For further details, please refer to the Vaxneuvance Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

No clinical study evaluated the efficacy of Vaxneuvance against invasive pneumococcal disease (IPD). Instead, the authorization was based on World Health Organization recommendations stating that the approval of any new pneumococcal conjugate vaccine against invasive disease can be based on the demonstration of immunological non-inferiority to the authorized pneumococcal conjugate vaccine with the most shared serotypes.

The clinical immunogenicity and safety of Vaxneuvance were supported by the results of seven clinical studies. This included four principal Phase III studies (the pivotal Study P019V114 and Studies P016V114, P017V114, and P020V114) that provided the main data in support of the effectiveness of Vaxneuvance. These studies were conducted in 14 countries with participants who were 18 years of age and older without prior history of pneumococcal vaccination (pneumococcal vaccine-naïve). Additional supportive immunogenicity data were generated from two other Phase III studies (P018V114, P021V114) and from one Phase II study (P007V114).

In each of these studies, immunogenicity endpoints were used to infer the effectiveness of Vaxneuvance for the prevention of IPD. This approach relied on immunologic comparability to Prevnar 13 by evaluation of OPA titers analyzed using pre-specified non-inferiority criteria for the 13 common serotypes between the two vaccines. For the additional serotypes contained in Vaxneuvance, and for serotype 3, pre-specified success criteria were used in superiority analyses to infer effectiveness. Although there is no established immune correlate of protection for prevention of IPD in adults, opsonophagocytosis is considered the main mechanism of protection against pneumococci, and OPA measured in vitro reflects this mechanism of protection. The same approach was used to support the authorization of Prevnar 13 in Canada.

Six of the seven clinical studies (P007V114, P016V114, P017V114, P019V114, P020V114, and P021V114) were conducted across the Americas, Europe, and Asia Pacific, in healthy and immunocompetent adults across different age groups. Participants in these studies included individuals with or without prior pneumococcal vaccination, with stable underlying medical conditions (e.g., diabetes mellitus, renal disorders, chronic heart disease, chronic liver disease, chronic lung disease including asthma), and/or behavioral risk factors (e.g., smoking, increased alcohol use) known to increase the risk of pneumococcal disease. The mean age of the participants was 59 years and 56.0% were female. The racial distribution was as follows: 74.1% were White, 9.6% were Asian, 8.5% were American Indian or Alaska Native, 6.4% were Black or African American, and 17.6% were of Hispanic or Latino ethnicity. In each study, immunogenicity was assessed by serotype-specific OPA and IgG responses at 30 days postvaccination for primary immunogenicity evaluation.

Principal Studies

Pivotal Study P019V114

The pivotal Study P019V114 was the main study evaluating the effectiveness of Vaxneuvance in pneumococcal vaccine-naïve adults 50 years of age and older. This Phase III, multicentre, randomized, double-blind, active comparator-controlled study evaluated the safety, tolerability, and immunogenicity of Vaxneuvance in 1,202 healthy adults. The median age of participants was 66 years (range: 50 to 92 years), with approximately 69% over 65 years of age, and approximately 12% over 75 years of age. Among participants, approximately 57% were female, 68% were white, 25% were Asian, 6% were Black or African American, and 1% were other race. Participants were randomized in a 1:1 ratio to receive a single dose (0.5 mL) of either Vaxneuvance or Prevnar 13.

The primary immunogenicity objective of Study P019V114 was to compare the serotype-specific OPA geometric mean titers (GMTs) at 30 days postvaccination between the Vaxneuvance and Prevnar 13 groups. The study success criteria for immunogenicity were met, as Vaxneuvance was non‑inferior to Prevnar 13 for the 13 shared serotypes and was superior to Prevnar 13 for the two serotypes unique to Vaxneuvance. Specifically, the lower bounds of the two-sided 95% confidence interval (CI) of the OPA GMT ratio (Vaxneuvance/Prevnar 13) were greater than 0.5 for the shared serotypes and greater than 2.0 for the two unique serotypes. In addition, Vaxneuvance was superior to Prevnar 13 for the two serotypes unique to Vaxneuvance as assessed by the proportion of participants with a ≥4‑fold rise in serotype-specific OPA responses from pre-vaccination to 30 days postvaccination. The lower bounds of the two‑sided 95% CI of the difference (Vaxneuvance-Prevnar 13) between the proportions of participants with a ≥4‑fold rise were >0.1 for the two unique serotypes, and Vaxneuvance was superior to Prevnar 13 for shared serotype 3; specifically, the lower bounds of the two-sided 95% CI of the OPA GMT ratio (Vaxneuvance/Prevnar 13) was greater than 1.2.

Study P020V114

Study P020V114 was a Phase III, multicentre, randomized, double-blind, active comparator-controlled, lot-to-lot consistency study to evaluate the safety, tolerability, and immunogenicity of Vaxneuvance in 2,340 healthy adults 50 years of age or older.

The primary immunogenicity objective of the study was the comparison of serotype-specific OPA GMTs at 30 days postvaccination with Vaxneuvance across the three different lots. Immunogenicity analyses were conducted separately for each of the 15 pneumococcal serotypes contained in the vaccine. The primary immunogenicity analyses showed that all three lots of Vaxneuvance met equivalence criteria, as assessed by the serotype-specific OPA GMTs for the 15 serotypes in Vaxnuevance at 30 days postvaccination. Specifically, the bounds of the 95% CI of the GMT ratio for each pairwise Vaxneuvance lot-to-lot comparison of the OPA GMT ratio to be within 0.5 to 2.0.

Study P017V114

Study P017V114 was a Phase III, randomized, double-blind, active-controlled, multicentre study to evaluate the safety, tolerability, and immunogenicity of Vaxneuvance in immunocompetent and pneumococcal vaccine-naïve adults 18 to 49 years of age with or without risk factors for pneumococcal disease. A total of 1,515 adults were randomized in a 3:1 ratio to receive either Vaxneuvance (total number [n] = 1,135) or Prevnar 13 (n = 380), followed by Pneumovax 23 six months later. Demographic and baseline characteristics were generally comparable for vaccinated participants across intervention groups.

The primary immunogenicity objective was to evaluate the serotype-specific OPA GMTs at 30 days postvaccination with Vaxneuvance and Prevnar 13 within each vaccination group separately. This descriptive study showed that Vaxneuvance was immunogenic in pneumococcal vaccine-naïve, immunocompetent adults 18 to 49 years of age with or without risk factors for pneumococcal disease as assessed by OPA GMTs at 30 days postvaccination for all 15 serotypes contained in the vaccine, particularly for 22F and 33F. Serotype-specific OPA GMTs and IgG GMCs at 30 days postvaccination with pneumococcal conjugate vaccine were comparable for the 13 shared serotypes between Vaxneuvance and Prevnar 13. Following the sequential administration of Pneumovax 23 six months after Vaxneuvance, OPA GMTs for all shared serotypes were similar to those observed following sequential administration of Pneumovax 23 six months after Prevnar 13.

Study P016V114

Study P016V114 was Phase III, multicenter, randomized, double-blind, active comparator-controlled study to evaluate the safety and immunogenicity of a single dose of Vaxneuvance compared to Prevnar 13 when administered to healthy pneumococcal vaccine-naïve adults 50 years of age or older. In addition, the study was conducted to describe serotype-specific pneumococcal immune responses to the 15 serotypes contained in Vaxneuvance when Pneumovax 23 was given approximately 12 months after Vaxneuvance or Prevnar 13. A total of 652 adults were randomized in a 1:1 ratio to receive either Vaxneuvance (total number [n] = 327) or Prevnar 13 (n =325), followed by Pneumovax 23, approximately 12 months later.

The primary immunogenicity objective was to evaluate the serotype-specific OPA GMTs at 30 days postvaccination with Pneumovax 23 at Month 13 for participants administered Vaxneuvance compared with participants administered Prevnar 13, approximately 12 months prior to receipt of Pneumovax 23. The results demonstrated that serotype-specific OPA GMTs at 30 days postvaccination with Pneumovax 23 at Month 13 were comparable between participants administered Vaxneuvance or Prevnar 13, approximately 12 months prior to receipt of Pneumovax 23 for all 15 serotypes in Vaxneuvance. In addition, between-group comparisons of IgG GMCs at 30 days postvaccination with Pneumovax 23 (Month 13) were consistent with those observed in the primary analysis of OPA GMTs.

Supportive Studies

Study P021V114

Study P021V114 was a Phase III randomized, double-blind, placebo-controlled, multicenter study designed to evaluate the safety, tolerability, and immunogenicity of Vaxneuvance administered concomitantly with a quadrivalent influenza vaccine (QIV; Fluarix QIV) compared to sequential administration of QIV followed by Vaxneuvance one month later (non-concomitant study group). A total of 1,200 participants were randomized in a 1:1 ratio to receive either Vaxneuvance with concomitant QIV or Vaxneuvance with non‑concomitant QIV.

Key findings from the study showed that Vaxneuvance administered concomitantly with QIV met non‑inferiority criteria for the 15 serotypes in Vaxneuvance as assessed by serotype-specific OPA GMTs and by influenza strain‑specific hemagglutination inhibition (HAI) GMTs for all four influenza strains, at 30 days postvaccination with Vaxneuvance and/or QIV.

Study P018V114

Study P018V114 was a Phase III, multicenter, randomized, double-blind, active comparator-controlled study to evaluate the safety, tolerability, and immunogenicity of Vaxneuvance compared to Prevnar 13 in 302 adults 18 years of age or older infected with human immunodeficiency virus (HIV). In addition, the study was conducted to describe serotype-specific pneumococcal immune responses to the 15 serotypes contained in Vaxneuvance when Pneumovax 23 was given approximately 8 weeks after Vaxneuvance or Prevnar 13.

The study showed that Vaxneuvance elicited an immune response in HIV‑positive adults as assessed by OPA GMTs and IgG GMCs for all 15 serotypes contained in the vaccine at 30 days postvaccination with pneumococcal conjugate vaccine. After the sequential administration of Pneumovax 23, the OPA GMTs observed at 30 days after Vaxneuvance vaccination were compared between the two vaccination groups.

Study P007V114

Study P007V114 was a Phase II, multicenter, double-blind study of the safety, tolerability, and immunogenicity of Vaxneuvance compared to Prevnar 13 in healthy adults 65 years of age or older previously vaccinated with Pneumovax 23.

The primary immunogenicity objective of the study was to summarize the serotype-specific IgG responses measured at Day 1 and Day 30 postvaccination in participants who received Vaxneuvance and Prevnar 13, for the 13 shared pneumococcal serotypes contained in both vaccines and the two serotypes unique to Vaxneuvance. The OPA data support the findings of the primary analyses for the shared and unique serotypes; however, in the exploratory analyses, differences were observed in the proportion of participants in both study groups who achieved a ≥4-fold rise in OPA titers based on time since receipt of Pneumovax 23. In general, a greater proportion of participants 65 to 74 years of age achieved a ≥4-fold rise when a longer duration of time had elapsed since receipt of Pneumovax 23 (>3 years compared to >1 to 3 years).

Indication

The New Drug Submission for Vaxneuvance was filed by the sponsor with the following indication:

  • Active immunization for the prevention of invasive disease and pneumonia caused by Streptococcus pneumoniae serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F and 33F) in adults 18 years of age and older.

The proposed indication for the prevention of pneumococcal pneumonia for Vaxneuvance could not be granted because there was a lack of evidence that the antibody levels/responses observed in the clinical trials were indicative of prevention of non-bacteremic pneumonia. To ensure safe and effective use of the product, Health Canada approved the following indication

  • Active immunization of adults 18 years of age and older for the prevention of invasive disease (including sepsis, meningitis, bacteremic pneumonia, pleural empyema and bacteremia) caused by Streptococcus pneumoniae serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F and 33F).

Overall Analysis of Efficacy

The effectiveness of Vaxneuvance against IPD for all age groups was inferred from OPA antibody responses after a single dose of Vaxneuvance as compared to the corresponding OPA GMTs after a single dose of Prevnar 13. The effectiveness of Vaxneuvance in pneumococcal vaccine‑naïve adults 50 years of age and older was inferred by demonstrating the following:

  • non‑inferiority of OPA antibody responses for the 13 common serotypes after a single dose of Vaxneuvance to the corresponding OPA GMTs after a single dose of Prevnar 13; and
  • superiority of OPA antibody responses for unique serotypes 22F, 33F and the common serotype 3 after a single dose of Vaxneuvance, relative to the corresponding OPA GMTs after a single dose of Prevnar 13. This could offer additional clinical benefit relative to Prevnar 13.

In conclusion, the data provided from the clinical studies has established the benefit of vaccination with Vaxneuvance with respect to the prevention of disease caused by the 15 S. pneumoniae serotypes contained in the vaccine in adults 18 years of age and older. For more information, refer to the Vaxneuvance Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

Safety data in support of the authorization of Vaxneuvance were obtained from the seven clinical studies described in the Clinical Efficacy section.

Vaxneuvance had a generally comparable safety profile to Prevnar 13 when administered as a single dose to adults 18 years of age and older with or without prior pneumococcal vaccination (pneumococcal vaccine-naïve). In these subjects, the most frequently (≥5%) reported adverse events (AEs) were solicited AEs (i.e., those that were selected from a list of events that participants were asked to record). Pain, erythema, and swelling at the injection site, fatigue, headache, arthralgia, and myalgia occurred most frequently. In pneumococcal vaccine-naïve adults 50 years of age and older, the proportion of participants with solicited injection site pain was higher among those who received Vaxneuvance compared with Prevnar 13.

Safety data were integrated across three of the Phase III studies (the pivotal Study P019V114 and Studies P016V114 and P020V114) in pneumococcal vaccine-naïve adults 50 years of age and older. These studies were considered appropriate for integration because of similarities in study design and study population. In the integrated population of pneumococcal vaccine-naïve adults 50 years of age and older, 3,032 subjects received Vaxneuvance and 1,154 subjects received Prevnar 13. Across the three studies, the proportion of participants who experienced serious adverse events (SAEs) was low following vaccination with Vaxneuvance or Prevnar 13, and comparable across intervention groups. No SAEs were considered by the investigator to be vaccine‑related. Vaxneuvance showed a similar safety profile with that observed in immunocompetent, pneumococcal vaccine-naïve adults, in the following populations:

  • adults 18 to 49 years of age with risk factors for pneumococcal disease;
  • adults 18 years of age and older considered to be immunocompromised due to HIV infection; and
  • adults 65 years of age and older with prior pneumococcal vaccination.

Vaxneuvance administered sequentially with Pneumovax 23 or concomitantly with quadrivalent influenza vaccine showed a similar safety profile with that of Vaxneuvance in immunocompetent, pneumococcal vaccine-naïve adults.

To conclude, Vaxneuvance was moderately more reactogenic following a single dose when compared to a single dose of Prevnar 13, however, overall safety profiles were comparable across groups. In the submitted clinical studies, limited or no data were available in some special populations (e.g. pregnant and breastfeeding women). Such limitations are not unique to Vaxneuvance, and recommendations on the use of Vaxneuvance in these special populations have been clearly labelled in the Product Monograph for Vaxneuvance.

Appropriate warnings and precautions are in place in the approved Vaxneuvance Product Monograph to address the identified safety concerns. For more information, refer to the Vaxneuvance Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

 

 

7.2 Non-Clinical Basis for Decision

 

During the preclinical development of Vaxneuvance, a series of non‑clinical immunogenicity (primary pharmacodynamics) studies were conducted in laboratory animals, primarily in New Zealand white rabbits and infant rhesus monkeys. These studies demonstrated that all serotypes included in the vaccine were immunogenic in all three rabbit and two infant rhesus monkey studies.

Three repeat-dose toxicity studies in rats were performed to evaluate the preclinical safety of Vaxneuvance. One intramuscular embryo-fetal developmental and pre‑weaning toxicity study, and one intramuscular postnatal developmental toxicity study in rats were also conducted.

In the repeat-dose toxicity studies, vaccine administration resulted in findings consistent with an anticipated inflammatory response and local muscle and subcutaneous inflammation at the injection sites. An expected immunogenic finding of lymphoid hyperplasia or histiocytic infiltrate in the draining lymph nodes was noted. The symptoms were completely or partially resolved 28 days post dose. No other treatment-related findings were observed.

In embryo-fetal developmental and reproductive toxicology (DART) studies, vaccine administration did not have any effects on female reproductive potential and fetal/embryonic development. No impacts were observed on fertility parameters, ovarian and uterine examination and litter parameters, or natural delivery parameters. In postnatal studies, there were no fetal external, soft tissue, coronal or skeletal abnormalities, or body weight changes attributed to vaccine administration.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Vaxneuvance Product Monograph. In view of the intended use of Vaxneuvance, there are no pharmacological/toxicological issues within this submission which preclude authorization of the product. For more information, refer to the Vaxneuvance Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

 

7.3 Quality Basis for Decision

 

As described above, the review of the quality component of the New Drug Submission for Vaxneuvance was conducted as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.

Characterization of the Drug Substance

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

Results from process validation studies indicate that the processing steps adequately 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 and scaled up during development. The process changes introduced at each generation of the process were adequately described and comparatively addressed. Lot release, stability, and characterization data have also been used to support the comparability assessment.

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

Vaxneuvance conjugate vaccine, adsorbed, is composed of the following medicinal ingredients: pneumococcal polysaccharide serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F and 33F each conjugated to a CRM197 carrier protein. It is a preservative-free liquid suspension, adjuvanted with aluminum phosphate.

Drug Substance

The Vaxneuvance drug substance is composed of pneumococcal polysaccharide serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F and 33F individually conjugated to CRM197 carrier protein. Two drug substance intermediates (pneumococcal polysaccharides and CRM197) are utilized in the Vaxneuvance drug substance manufacturing process. Fourteen of the fifteen polysaccharide drug substance intermediates are already used as drug substance for Pneumovax 23, currently authorized in Canada. The manufacture of the novel serotype 6A was based on the manufacture of serotype 6B (currently included in Pneumovax 23), due to their similar polysaccharide structure. The manufacture of CRM197 is supported by extensive manufacturing/clinical experience.

The manufacturing processes and control for the monovalent bulk conjugate drug substances are similar to those already approved for other conjugate vaccines and are in line with World Health Organization recommendations. The available data support adequate control over drug substance quality/consistency.

Drug Product

The drug product manufacturing process begins with the thawing and dilution of monovalent bulk conjugates, which are then adsorbed onto aluminum phosphate adjuvant to produce the final bulk. The vaccine is then filled into single-dose syringes (0.5 mL per dose).

Changes to the manufacturing process made throughout the pharmaceutical development are considered acceptable upon review.

The materials used in the manufacture of Vaxneuvance (including biological-sourced materials) are considered suitable and/or meet standards appropriate for their intended use. The method of manufacturing and the controls used during the manufacturing process for both the drug substance and drug product are validated and considered to be adequately controlled within justified limits.

Control of the Drug Substance and Drug Product

The drug substance and drug product are tested against suitable reference standards to verify that they meet approved specifications and analytical procedures are validated and in compliance with International Council for Harmonisation (ICH) guidelines.

Each lot of Vaxneuvance drug product is tested for appearance, identity, total saccharide content, conjugated saccharide content, free saccharide, aluminum content, polysorbate 20 content, pH, recoverable volume, syringeability, syringe functionality, container closure integrity, endotoxin, and sterility. Established test specifications and validated analytical test methods are considered acceptable.

Through Health Canada's lot release testing and evaluation program, consecutively manufactured final product lots were tested using a subset of release methods. The testing process confirmed that the methods used in-house are acceptable for their intended use and positively supported the quality review recommendation.

Vaxneuvance is a Schedule D (biologic) drug and is, therefore, subject to Health Canada's Lot Release Program before sale as per Health Canada's Guidance for Sponsors: Lot Release Program for Schedule D (Biologic) Drugs.

Stability of the Drug Substance and Drug 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 for Vaxneuvance when stored at 2 to 8 ºC and protected from light 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 facility and equipment that are involved in the production are considered suitable for the activities and products manufactured.

An on-site evaluation (OSE) of the facilities involved in the manufacture and testing of the drug substances and drug product intermediate was recommended based on risk assessment scores determined by Health Canada. However, due to the coronavirus disease 2019 (COVID-19) pandemic, an OSE was not feasible. Following a thorough assessment of the information provided in the submission and additional information received during the review period, the risk was considered to be lower than what was originally assigned during the OSE determination process.

All sites involved in production are compliant with good manufacturing practices.

Adventitious Agents Safety Evaluation

Raw materials of animal origin used in the manufacturing process are adequately tested to ensure freedom from adventitious agents. These materials originate from sources with no or minimal risk of transmissible spongiform encephalopathy agents or other human pathogens. The excipients used in the drug product formulation are not of animal or human origin.

The manufacturing process of Vaxneuvance, including media and buffers used, does not support virus growth, therefore, there are no concerns with respect to viral safety.

 

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