Summary Basis of Decision for Prevnar 20
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:
Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Prevnar 20 is located below.
Recent Activity for Prevnar 20
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 decisions were negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.
Summary Basis of Decision (SBD) for Prevnar 20
Date SBD issued: 2022-08-31
The following information relates to the new drug submission for Prevnar 20.
Pneumococcal 20-valent conjugate vaccine (diphtheria cross-reactive material 197 [CRM197] protein)
Drug Identification Number (DIN):
- DIN 02527049 - 0.5 mL suspension containing 2.2 mcg of each of pneumococcal serotypes 1, 3, 4, 5, 6A, 7F, 8, 9V, 10A, 11A, 12F, 14, 15B, 18C, 19A, 19F, 22F, 23F, and 33F polysaccharides and 4.4 mcg of pneumococcal serotype 6B polysaccharide, each conjugated to diphtheria CRM197 protein (approximately 51 mcg/0.5 mL); intramuscular administration
Pfizer Canada ULC
New Drug Submission Control Number: 253111
On May 9, 2022, Health Canada issued a Notice of Compliance to Pfizer Canada ULC for the vaccine Prevnar 20.
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 Prevnar 20 is favourable for active immunization for the prevention of pneumonia and invasive pneumococcal disease (including sepsis, meningitis, bacteremic pneumonia, pleural empyema and bacteremia) caused by Streptococcus pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15B, 18C, 19A, 19F, 22F, 23F, and 33F in adults 18 years of age and older.
1 What was approved?
Prevnar 20 (pneumococcal 20-valent conjugate vaccine [diphtheria CRM197 protein]), an active immunizing agent, was authorized for active immunization for the prevention of pneumonia and invasive pneumococcal disease (including sepsis, meningitis, bacteremic pneumonia, pleural empyema and bacteremia) caused by Streptococcus pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15B, 18C, 19A, 19F, 22F, 23F, and 33F in adults 18 years of age and older.
Clinical efficacy for the prevention of pneumonia was studied with the previously authorized vaccine Prevnar 13 for the 13 shared serotypes, but not for the additional 7 serotypes present in Prevnar 20 (8, 10A, 11A, 12F, 15B, 22F, and 33F). Prevnar 20 may not prevent disease caused by Streptococcus pneumoniae serotypes that are not contained in the vaccine.
The safety and immunogenicity of Prevnar 20 in individuals younger than 18 years of age have not been established.
Of the 4,263 adults in the three Phase III studies of the clinical development program who received Prevnar 20, 668 (15.7%) were 65 through 69 years of age, 398 (9.3%) were 70 through 79 years of age, and 72 (1.7%) were 80 years of age and older. Prevnar 20 has been shown to be safe and immunogenic in the geriatric population regardless of prior pneumococcal vaccination (i.e., in individuals who were naïve to pneumococcal vaccines or who were previously vaccinated with Prevnar 13, the 23-valent pneumococcal polysaccharide vaccine [Pneumovax 23], or both).
p>Prevnar 20 is presented as a suspension supplied in a single-dose prefilled syringe. The suspension contains capsular polysaccharide antigens of Streptococcus pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15B, 18C, 19A, 19F, 22F, 23F, and 33F. Each polysaccharide is individually conjugated to a carrier protein, the non-toxic variant of diphtheria toxin cross-reactive material 197 (CRM197). In addition to the medicinal ingredients, the suspension contains aluminum phosphate, polysorbate 80, sodium chloride, succinic acid, and water for injection.The use of Prevnar 20 is contraindicated in individuals who are hypersensitive to the active substance or to any component of the vaccine, including diphtheria toxoid.
The vaccine was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with its administration. The Prevnar 20 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 Prevnar 20 approved?
Health Canada considers that the benefit-risk profile of Prevnar 20 is favourable for active immunization for the prevention of pneumonia and invasive pneumococcal disease (including sepsis, meningitis, bacteremic pneumonia, pleural empyema and bacteremia) caused by Streptococcus pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15B, 18C, 19A, 19F, 22F, 23F, and 33F in adults 18 years of age and older.
Streptococcus pneumoniae is a gram-positive bacterium, commonly referred to as pneumococcus. Infections caused by Streptococcus pneumoniae are responsible for substantial morbidity and mortality, particularly among young children, elderly adults, and individuals with immune deficiencies. The virulence of Streptococcus pneumoniae is primarily mediated by its polysaccharide capsule, which is the basis for classification of the pneumococci into over 100 known serotypes. Certain serotypes are much more likely than others to be associated with clinically apparent infections, to cause severe invasive infections, and some have acquired resistance to one or more classes of antibacterial agents. Two types of pneumococcal vaccines are available for clinical use: pneumococcal polysaccharide vaccine and pneumococcal conjugate vaccine. Both types of vaccine contain capsular polysaccharides from pneumococcal serotypes that commonly cause invasive disease. A 23-valent pneumococcal polysaccharide vaccine (Pneumovax 23) contains unconjugated pneumococcal capsular polysaccharides from 23 serotypes and has been available since the 1980s. Pneumococcal conjugate vaccines consist of pneumococcal capsular polysaccharides covalently linked (conjugated) to a protein, which modifies the immune response to the polysaccharides from a T-cell independent response to a T-cell dependent response. Formulations of pneumococcal conjugate vaccines authorized for use in Canada are the 10-valent Synflorix, the 13-valent Prevnar 13, and the 15-valent Vaxneuvance.
Prevnar 20 is a pneumococcal 20-valent conjugate vaccine. It is modelled after Prevnar 13 and contains the same 13 serotype-specific capsular polysaccharides included in Prevnar 13 (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F), and 7 additional serotype-specific capsular polysaccharides (8, 10A, 11A, 12F, 15B, 22F, and 33F), which are present in Pneumovax 23 as unconjugated polysaccharides. Each polysaccharide in Prevnar 20 is conjugated to a carrier protein, the non-toxic variant of diphtheria toxin cross-reactive material 197 (CRM197).
The market authorization of Prevnar 20 was based on data derived from three Phase III safety and immunogenicity clinical trials: the pivotal Study 1007 and the supportive Study 1006 and Study 1008 (detailed in the Immunogenicity section). There were no clinical efficacy studies conducted with Prevnar 20; however, the previously demonstrated clinical efficacy of Prevnar 13 for the prevention of pneumonia is relevant to Prevnar 20. The immunogenicity data derived from the three Phase III safety and immunogenicity clinical trials were used to infer Prevnar 20 efficacy. Immunity to Streptococcus pneumoniae is mediated by antibodies against the serotype-specific polysaccharides. These antibodies trigger complement-mediated phagocytosis, a process by which white blood cells ingest and kill the bacteria.
The clinical trials were conducted in adults of different age groups, including individuals who were naïve to pneumococcal vaccines (Study 1007 and Study 1008) or who were previously vaccinated with Prevnar 13, Pneumovax 23, or both (Study 1006). Each study enrolled healthy adults and immunocompetent adults with stable underlying conditions, including chronic cardiovascular disease, chronic pulmonary disease, renal disorders, diabetes mellitus, chronic liver disease, and medical risk conditions and behaviours (e.g., smoking) that are known to increase the risk of serious pneumococcal pneumonia and invasive pneumococcal disease. In each study, immune responses elicited by Prevnar 20 and the control pneumococcal vaccines were measured by serotype-specific opsonophagocytic activity (OPA) assays before and one month after vaccination. The OPA assays assess in vitro the levels of serum antibodies against Streptococcus pneumoniae that trigger complement-mediated phagocytosis of the bacteria by cultured white blood cells.
The pivotal Study 1007 was a Phase III, randomized, double-blind, non-inferiority, multicentre trial conducted in 3,889 adults (18 years of age and older) with no history of pneumococcal vaccination. Participants were enrolled into one of three cohorts based on their age at the time of enrollment. In the main cohort (Cohort 1), there were 2,997 participants 60 years of age and older randomized in a ratio of 1:1 to receive a single dose of Prevnar 20 followed by a single dose of saline placebo one month later, or a single dose of Prevnar 13 followed by a single dose of Pneumovax 23 one month later. The other two cohorts included adults younger than 60 years of age: 445 participants 50 to 59 years of age (Cohort 2) and 447 participants 18 to 49 years of age (Cohort 3). These participants were randomized in a ratio of 3:1 to receive Prevnar 20 or Prevnar 13.
In participants 60 years of age and older (Cohort 1), the immune responses to all 13 matched serotypes elicited by Prevnar 20 were non-inferior to the immune responses to the same serotypes elicited by Prevnar 13 one month after vaccination. In addition, the immune responses to 6 out of the 7 additional serotypes induced by Prevnar 20 were non-inferior to the immune responses to these same serotypes induced by Pneumovax 23 one month after vaccination. The immune response to serotype 8 missed the prespecified statistical non-inferiority criterion; however, it was within the range of immune responses observed for the 13 serotypes in the Prevnar 13 group.
In participants aged 50 to 59 years (Cohort 2) and 18 to 49 years (Cohort 3), Prevnar 20 elicited immune responses to the 20 vaccine serotypes one month after vaccination. The immune responses were non-inferior to those observed in adults 60 to 64 years of age.
The safety profile of Prevnar 20 (detailed in the Clinical Safety section) is based on data from the three Phase III safety and immunogenicity clinical trials. In total, 4,263 adult participants received Prevnar 20, 3,639 of whom were naïve to pneumococcal vaccines, 253 had previously received Pneumovax 23, 246 had previously received Prevnar 13, and 125 had previously received both Pneumovax 23 and Prevnar 13. In the three Phase III clinical trials, the safety profile of Prevnar 20 was evaluated based on the following endpoints: solicited local reactions (redness, swelling, and pain at the injection site) occurring within 10 days after vaccination; solicited systemic events (fever, headache, fatigue, muscle pain, and joint pain) occurring within 7 days after vaccination; adverse events occurring within 1 month after vaccination; serious adverse events occurring within 6 months after vaccination; and newly diagnosed chronic medical conditions occurring within 6 months after vaccination. The most frequently reported solicited adverse reactions (in over 10% of participants who received Prevnar 20) were vaccination-site pain/tenderness, muscle pain, fatigue, headache, and joint pain. Overall, the serious adverse events reported were consistent with diseases and conditions observed in adults of different age groups, and none were considered to be related to the study vaccines. In all three Phase III trials, Prevnar 20 demonstrated a tolerability and safety profile similar to that of Prevnar 13.
A Risk Management Plan (RMP) for Prevnar 20 was submitted by Pfizer Canada ULC to Health Canada. 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. Upon review, the RMP was considered to be acceptable. Of note, as part of additional pharmacovigilance activities, the sponsor is expected to provide results from an ongoing Phase IV, real-world study (Study B7471015) in the United States, designed to evaluate the effectiveness of Prevnar 20 against vaccine-type radiologically confirmed community-acquired pneumonia in adults 65 years of age and older. The sponsor is also expected to provide results from ongoing Phase III studies, including a safety and immunogenicity trial with Prevnar 20 co-administered with a seasonal inactivated influenza vaccine in adults 65 years of age and older, as well as results from pediatric trials to be evaluated for a potential extension of the indication to the pediatric population.
The submitted inner and outer labels, package insert, and Patient Medication Information section of the Prevnar 20 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 Prevnar 20 was accepted.
Overall, based on the submitted non-clinical and clinical information, Prevnar 20 has been shown to have a favourable benefit-risk profile in adults. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Prevnar 20 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 issued 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 Prevnar 20?
The review of the New Drug Submission (NDS) for Prevnar 20 was based on a critical assessment of the data package submitted to Health Canada. The reviews completed by the European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) were used as added references as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada. The Canadian regulatory decision on the Prevnar 20 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: Prevnar 20
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting | 2020-12-09 |
| New Drug Submission filed | 2021-05-25 |
| Screening | |
| Screening Acceptance Letter issued | 2021-07-13 |
| Review | |
| Non-clinical evaluation completed | 2022-04-07 |
| Clinical/medical evaluation completed | 2022-04-07 |
| Review of Risk Management Plan completed | 2022-04-11 |
| Labelling review completed | 2022-04-14 |
| Quality evaluation completed | 2022-04-25 |
| Notice of Compliance issued by Director General, Biologic and Radiopharmaceutical Drugs Directorate | 2022-05-09 |
4 What follow-up measures will the company take?
Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations.
6 What other information is available about drugs?
Up-to-date information on drug products can be found at the following links:
- See MedEffect Canada for the latest advisories, warnings and recalls for marketed products.
- See the Notice of Compliance (NOC) Database for a listing of the authorization dates for all drugs that have been issued an NOC since 1994.
- See the Drug Product Database (DPD) for the most recent Product Monograph. The DPD contains product-specific information on drugs that have been approved for use in Canada.
- See the Notice of Compliance with Conditions (NOC/c)-related documents for the latest fact sheets and notices for products which were issued an NOC under the Notice of Compliance with Conditions (NOC/c) Guidance Document, if applicable. Clicking on a product name links to (as applicable) the Fact Sheet, Qualifying Notice, and Dear Health Care Professional Letter.
- See the Patent Register for patents associated with medicinal ingredients, if applicable.
- See the Register of Innovative Drugs for a list of drugs that are eligible for data protection under C.08.004.1 of the Food and Drug Regulations, if applicable.
7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical basis for decision
Clinical Pharmacology
Prevnar 20 contains 20 serotype-specific pneumococcal capsular polysaccharides, each of them conjugated to a carrier protein, the non-toxic variant of diphtheria toxin cross-reactive material 197 (CRM197), which modifies the immune response to the polysaccharide from a T-cell independent response to a T-cell dependent response. The T-cell dependent response leads to both an enhanced antibody response and generation of memory B cells, allowing for an anamnestic (booster) response on re-exposure to bacterial polysaccharide.
Vaccination with Prevnar 20 induces serum antibody production and immunologic memory against the serotypes contained within the vaccine. The levels of circulating antibodies that correlate with protection against pneumococcal disease have not been clearly defined.
The pharmacodynamics of Prevnar 20 was assessed through evaluations of immunogenicity (see Immunogenicity). Pharmacokinetic studies to demonstrate absorption, distribution, metabolism, and excretion of Prevnar 20 were not conducted, and are typically not required for vaccines.
No data are currently available regarding concomitant use of Prevnar 20 with other vaccines. The sponsor is expected to provide results of a currently ongoing clinical trial evaluating Prevnar 20 co-administered with seasonal inactivated influenza vaccine.
For further details, refer to the Prevnar 20 Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Efficacy
No clinical endpoint efficacy studies were conducted with Prevnar 20. The immunogenicity data derived from three Phase III safety and immunogenicity clinical trials (Study 1007, Study 1006, and Study 1008) were used to infer Prevnar 20 efficacy.
Immunogenicity
Three Phase III safety and immunogenicity clinical trials were conducted in adults of different age groups, including individuals who were naïve to pneumococcal vaccines (Study 1007 and Study 1008) or who were previously vaccinated with Prevnar 13, Pneumovax 23, or both (Study 1006). Prevnar 13 is a 13-valent pneumococcal polysaccharide conjugate vaccine, whereas Pneumovax 23 is a 23-valent unconjugated polysaccharide vaccine. Prevnar 20 contains the same 13 serotype-specific polysaccharide antigens as those present in Prevnar 13 and 7 additional serotype-specific polysaccharide antigens which are included in Pneumovax 23.
Each study included healthy adults and immunocompetent adults with stable underlying conditions, including chronic cardiovascular disease, chronic pulmonary disease, renal disorders, diabetes mellitus, chronic liver disease, and medical risk conditions and behaviours (e.g., smoking) that are known to increase the risk of serious pneumococcal pneumonia and invasive pneumococcal disease.
In each study, immune responses elicited by Prevnar 20 and the control pneumococcal vaccines were measured by serotype-specific opsonophagocytic activity (OPA) assays. The serotype-specific OPA assays measure functional serum antibodies against Streptococcus pneumoniae that trigger complement-mediated phagocytosis. The OPA titer is calculated as the reciprocal of the test serum dilution resulting in a 50% reduction in the number of bacterial colony-forming units, when compared with the control without test serum.
Pivotal study (Study 1007)
Study 1007 was a Phase III, randomized, double-blind, non-inferiority, multicentre study conducted in 3,889 adults (18 years of age and older) with no history of pneumococcal vaccination. Among the study participants, 60% were women, 84.2% were White, 12.3% were Black, and 12.9% were current smokers. The primary objectives of the study were to evaluate the safety and immunogenicity of Prevnar 20.
Participants were enrolled into one of three cohorts based on their age at the time of enrollment.
In the main cohort (Cohort 1), there were 2,997 participants 60 years of age and older randomized in a ratio of 1:1 to receive a single dose of Prevnar 20 (Vaccination 1) followed by a single dose of saline placebo (Vaccination 2) one month later, or a single dose of Prevnar 13 (Vaccination 1) followed by a single dose of Pneumovax 23 (Vaccination 2) one month later.
The other two cohorts included adults younger than 60 years of age: 445 participants 50 to 59 years of age (Cohort 2) and 447 participants 18 to 49 years of age (Cohort 3). These participants were randomized in a ratio of 3:1 to receive Prevnar 20 or Prevnar 13.
Serotype-specific OPA geometric mean titers (GMTs) were measured before the first vaccination and one month after each vaccination. In Cohort 1, the immune responses (i.e., OPA GMTs one month after vaccination) induced by Prevnar 20 were declared non-inferior to the immune responses induced by a control vaccine (Prevnar 13 or Pneumovax 23) for each serotype if the lower bound of the two-sided 95% confidence interval (CI) for the GMT ratio (Prevnar 20/Prevnar 13; Prevnar 20/Pneumovax 23) was greater than 0.5. A linear regression model that included terms for age, corresponding baseline OPA titer, sex, smoking status, and vaccine group was used to calculate the serotype-specific OPA GMT ratios and CIs.
Similarly, the OPA GMTs from the participants 50 to 59 years of age (Cohort 2) and from the participants 18 to 49 years of age (Cohort 3) were declared non-inferior to those from participants aged 60 to 64 years from Cohort 1 for each Prevnar 20 serotype, if the lower bound of the two-sided 95% CI for the serotype-specific OPA GMT ratio exceeded 0.5.
In participants 60 years of age and older (Cohort 1), the immune responses to all 13 matched serotypes elicited by Prevnar 20 were non-inferior to the immune responses to the same serotypes elicited by Prevnar 13 one month after vaccination. In addition, the immune responses to 6 out of the 7 additional serotypes induced by Prevnar 20 were non-inferior to the immune responses to these same serotypes induced by Pneumovax 23 one month after vaccination. The immune response to serotype 8 missed the prespecified statistical non-inferiority criterion because the lower bound of the 95% CI for the OPA GMT ratio was 0.49. However, the observed geometric mean fold rise (GMFR) in OPA titers of 22.1 for serotype 8 from before vaccination to one month after vaccination in the Prevnar 20 group was within the range of the observed GMFRs in OPA titers (5.8 to 42.6) for the 13 serotypes in the Prevnar 13 group. Also, the percentage of participants who had at least a 4-fold or greater rise in OPA titers for serotype 8 from baseline to one month after Prevnar 20 (77.8%) fell within the range of percentages (54.0% to 84.0%) observed for the 13 serotypes in the Prevnar 13 group. Furthermore, the proportion of participants with OPA titers at or above the lower limit of quantitation (LLOQ) at one month after vaccination for serotype 8 in the Prevnar 20 group (92.9%) was within the range of proportions (76.0% to 96.6%) observed for the 13 serotypes in the Prevnar 13 group.
In participants aged 50 to 59 years (Cohort 2) and 18 to 49 years (Cohort 3), Prevnar 20 elicited immune responses to all 20 vaccine serotypes one month after vaccination. The immune responses were non-inferior to those observed in adults 60 to 64 years of age.
Supportive studies
Study 1006
Study 1006 was a Phase III, randomized, open-label study designed to describe the safety and immunogenicity of Prevnar 20 in adults 65 years of age or older with prior pneumococcal vaccination (Pneumovax 23, Prevnar 13, or Prevnar 13 followed by Pneumovax 23). Among 873 participants, 54.4% were women, 92.4% were White, 5.4% were Black, and 6.3% were current smokers. The median age of participants at vaccination ranged from 68 to 69 years across the vaccine groups. Pneumococcal serotype-specific OPA titers were measured one month after vaccination. Analyses of results were descriptive, as no formal hypothesis testing was conducted for any safety or immunogenicity endpoint.
Participants were enrolled in one of three cohorts based on their prior pneumococcal vaccination status and randomized to receive a single dose of Prevnar 20 or control vaccine (Prevnar 13 or Pneumovax 23), as follows:
- Cohort A: 375 participants who had received only Pneumovax 23 1 to 5 years prior to vaccination in this study were randomized (2:1) to receive Prevnar 20 or Prevnar 13.
- Cohort B: 373 participants who had received only Prevnar 13 at least 6 months prior to vaccination in this study were randomized (2:1) to receive Prevnar 20 or Pneumovax 23.
- Cohort C: 125 participants who had received Prevnar 13 followed by Pneumovax 23 (Pneumovax 23 received at least 1 year prior to vaccination in this study) were assigned to receive Prevnar 20 only.
At baseline, OPA GMTs for the 13 serotypes of Prevnar 13 were generally numerically highest in Cohort C followed by Cohort B, and lowest in Cohort A. Baseline OPA GMTs for the seven additional serotypes were generally numerically highest in participants in Cohort C, followed by participants in Cohort A, and lowest in Cohort B.
Immune responses to all 20 vaccine serotypes were observed one month after Prevnar 20 in all three cohorts, regardless of prior pneumococcal vaccination. The OPA GMTs to the 13 vaccine serotypes shared with Prevnar 13 tended to be numerically higher in the participants who had previously received Prevnar 13 only, followed by those who had previously received both Prevnar 13 and Pneumovax 23, and slightly lower among those who had previously received Pneumovax 23 only. The participants who were naïve to the seven additional serotypes in Prevnar 20 (i.e., those who had received only Prevnar 13) had the highest fold rise in OPA titers for those additional serotypes.
The results support the recommendation included in the Prevnar 20 Product Monograph that if the sequential use of Pneumovax 23 is considered appropriate, Prevnar 20 should be given first.
Study 1008
Study 1008 was a Phase III, randomized, double-blind study, which aimed to describe the safety and immunogenicity of three different lots of Prevnar 20 in pneumococcal vaccine-naïve adults 18 to 49 years of age. Among 1,708 participants, 65.3% were women, 72.7% were White, and 18.5% were Black. The median age at vaccination was 36 years (range of 18 to 49 years). Participants received a single dose of Prevnar 20 (488 participants received Lot 1; 489 participants received Lot 2; and 486 participants received Lot 3). In the safety control group, 245 participants received Prevnar 13. Pneumococcal serotype-specific OPA titers were measured one month after vaccination. The study demonstrated that the three different lots of Prevnar 20 elicited equivalent immune responses for the 20 vaccine serotypes.
Indication
The New Drug Submission for Prevnar 20 was filed by the sponsor with the following indication:
- Prevnar 20 (pneumococcal 20-valent conjugate vaccine [diphtheria CRM197 protein]) is indicated for active immunization for the prevention of pneumonia and invasive pneumococcal disease (including sepsis, meningitis, bacteremic pneumonia, pleural empyema and bacteremia) caused by Streptococcus pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15B, 18C, 19A, 19F, 22F, 23F, and 33F in adults 18 years of age and older.
Health Canada revised the proposed indication to include a caveat statement reflecting the fact that clinical efficacy for the prevention of pneumonia was studied with Prevnar 13 for the shared 13 serotypes, but not for the additional 7 serotypes that are present in Prevnar 20. Another caveat statement was included to state that the vaccine may not prevent disease caused by Streptococcus pneumoniae serotypes that are not contained in the vaccine. Accordingly, Health Canada approved the following indication:
- Prevnar 20 (pneumococcal 20-valent conjugate vaccine [diphtheria CRM197 protein]) is indicated for active immunization for the prevention of pneumonia and invasive pneumococcal disease (including sepsis, meningitis, bacteremic pneumonia, pleural empyema and bacteremia) caused by Streptococcus pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15B, 18C, 19A, 19F, 22F, 23F, and 33F in adults 18 years of age and older.
- Clinical efficacy for the prevention of pneumonia was studied with Prevnar 13 for the shared serotypes, but not for the additional serotypes 8, 10A, 11A, 12F, 15B, 22F, and 33F.
- Prevnar 20 may not prevent disease caused by Streptococcus pneumoniae serotypes that are not contained in the vaccine.
For more information, refer to the Prevnar 20 Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Safety
In the three Phase III clinical trials (described in the Immunogenicity section), the safety profile of Prevnar 20 was evaluated based on the following endpoints: solicited local reactions (redness, swelling, and pain at the injection site) occurring within 10 days after vaccination; solicited systemic events (fever, headache, fatigue, muscle pain, and joint pain) occurring within 7 days after vaccination; adverse events occurring within 1 month after vaccination; serious adverse events occurring within 6 months after vaccination; and newly diagnosed chronic medical conditions occurring within 6 months after vaccination.
Pivotal study
In the pivotal study (Study 1007), across the three age cohorts, similar proportions of participants reported solicited local reactions and systemic events after Prevnar 20 or Prevnar 13. The most frequently reported local reaction was pain at injection site (reported by 55.4%, 72.5%, and 81.2% of participants who received Prevnar 20 in Cohort 1, Cohort 2, and Cohort 3, respectively). Most local reactions were mild or moderate in severity. The median day of onset for local reactions was between Day 1 (the day of vaccination) and Day 2.5. Local reactions generally resolved with a median duration of 1 to 2 days. Muscle pain was the most frequently reported systemic event (reported by 39.1%, 49.8%, and 66.6% of participants who received Prevnar 20 in Cohort 1, Cohort 2, and Cohort 3, respectively). The median day of onset for systemic events was between Day 1 (the day of vaccination) and Day 2, and systemic events generally resolved with a median duration of 1 to 2 days.
The most frequently reported adverse reactions occurring within 1 month after vaccination and considered to be related to the study vaccine were injection site adverse events (<1% after Prevnar 20). Twenty participants (12 subjects who received Prevnar 20 and 8 subjects who received Prevnar 13) in Cohort 1 (subjects 60 years of age and older) discontinued participation in the study due to an adverse event. Reasons for discontinuation that were considered related to Prevnar 20 included anxiety, bronchial hyperreactivity, headache, myalgia, palpitations, and vaccination site adverse events (erythema, pain, pruritus, and swelling). No participants in Cohort 2 or Cohort 3 withdrew from the study due to an adverse event.
No serious adverse events or newly diagnosed chronic medical conditions were considered related to the study vaccines. The serious adverse events and newly diagnosed chronic medical conditions reported in the study were consistent with the medical events or conditions that might develop in adults of the respective age groups (65 years of age or older; 50 to 59 years of age; 18 to 49 years of age).
Supportive studies
In Study 1006, the proportions of participants who reported solicited local reactions occurring within 10 days or systemic events occurring within 7 days after administration of Prevnar 20 were generally similar across cohorts regardless of prior pneumococcal vaccination. These proportions were also generally similar to those observed in the corresponding control groups (Prevnar 13 and Pneumovax 23). Across the three cohorts and all vaccine groups, local reactions were of mild or moderate severity, had a median onset day of Day 1 (the day of vaccination) or Day 2, and generally resolved within 1 to 2 days. The most frequently reported local reaction was pain at injection site (50.2% to 61.2% after Prevnar 20, 43.0% after Prevnar 13, and 56.3% after Pneumovax 23). In all vaccine groups, most systemic events were mild or moderate in severity, with a median onset day between Day 1 (the day of vaccination) and Day 3.5, and generally resolved after 1 to 2 days. Muscle pain was the most frequently reported systemic event (32.0% to 37.6% after Prevnar 20, 31.4% after Prevnar 13, and 46.0% after Pneumovax 23). The proportions of participants who reported any adverse event occurring within 1 month after vaccination and considered to be related to the study vaccine were low (≤2.4%) in all vaccine groups. The most frequently reported vaccine-related adverse events were injection site adverse events (<1%). One participant in Cohort A reported severe adverse events of injection site pruritus and injection site warmth that were considered related to Prevnar 20 vaccination. None of the serious adverse events occurring within 6 months after vaccination were considered related to the study vaccine, and no deaths were reported during the study. Overall, the serious adverse events and newly diagnosed chronic medical conditions reported in the study were consistent with the medical events or conditions that might develop in individuals of this age group (adults 65 years of age or older).
In Study 1008, the proportions of participants who reported solicited local reactions occurring within 10 days or systemic events occurring within 7 days after Prevnar 20 were similar across the three different lots of Prevnar 20 and similar compared to those in the Prevnar 13 control group. Most local reactions across all vaccine groups were mild or moderate in severity. Local reactions and systemic events were of mild or moderate severity with a median onset day between Day 1 (the day of vaccination) and Day 2, and they generally resolved after 1 to 2 days in all vaccine groups. The most frequently reported local reaction across all vaccine groups was pain at injection site (78.7% after Prevnar 20; 75.7% after Prevnar 13). The most frequently reported systemic event across all vaccine groups was muscle pain (62.1% after Prevnar 20; 60.5% after Prevnar 13). The proportions of participants with adverse events occurring within 1 month and within 6 months after vaccination were low (<1%) and similar across all three lots of Prevnar 20 and the Prevnar 13 control. Two participants had severe adverse events that occurred within 1 month after vaccination and were considered related to the study vaccines (migraine in a participant who received Lot 1 of Prevnar 20, and musculoskeletal and neck pain in a participant who received Prevnar 13). The proportion of participants who reported at least one serious adverse event occurring within 6 months after vaccination was low (0.7% after Prevnar 20; 0% after Prevnar 13). No serious adverse events occurring within 6 months after vaccination were considered related to the study vaccine, and no deaths were reported during the study. Overall, the serious adverse events and newly diagnosed chronic medical conditions reported in the study were consistent with the medical events or conditions that might develop in individuals of this age group (adults 18 to 49 years of age).
For more information, refer to the Prevnar 20 Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.2 Non-Clinical Basis for Decision
The immunogenicity of Prevnar 20 (20-valent pneumococcal conjugate vaccine) was evaluated in one pivotal study in rabbits. Two supportive studies conducted in mice and rats evaluated the immunogenicity of the seven additional serotypes contained in Prevnar 20 (serotypes 8, 10A, 11A, 12F, 15B, 22F, and 33F).
In rabbits, one month after vaccination with Prevnar 20, immunogenicity responses to each of the 20 serotypes assessed by immunoglobulin G (IgG) concentrations and opsonophagocytic antibody (OPA) titres varied between serotypes. No comparable trends were observed between serotype-specific IgG concentrations and OPA titres, except for the serotype 33F, which elicited low increases in both IgG concentrations (120-fold) and OPA titres (28-fold), and for the serotype 11A, which elicited the same fold increases for both IgG and OPA (approximately 1,400-fold for each). Other serotypes with low increases in OPA titres included serotypes 1 (27-fold), 3 (72-fold), and 14 (42-fold), despite high increases in IgG concentrations (379-fold, 1,542-fold, and 457-fold, respectively).
A repeat-dose toxicity study was conducted in rabbits with Prevnar 20 administered intramuscularly at the intended clinical dose (low dose) and at twice the clinical dose (high dose) once every two weeks for a total of five doses over the course of 59 days. Local inflammatory reactions (mild or moderate erythema and small firm masses) were observed at the injection sites. The local findings were reversible. No clinical evidence of systemic toxicity was found. Post-mortem examinations revealed adverse microscopic findings in the heart (degeneration/necrosis of cardiomyocytes and interstitial fibrosis) that were not considered to be vaccine-related adverse events following additional evaluations by an external pathology working group. This conclusion was supported by the analysis of pooled data from six additional repeat-dose toxicity studies in rabbits. The heart lesions were believed to be associated with the handling and procedures performed on the animals.
A pivotal fertility and developmental study was conducted in female rabbits administered the intended clinical dose of Prevnar 20 or control saline intramuscularly four times: twice prior to mating (17 days and 4 days prior to mating) and twice during gestation (on gestation days 10 and 24). Clinical signs reported for the dams were unremarkable, without any indication of maternal systemic toxicity. There were no vaccine-related effects on the mating performance or fertility in female rabbits, nor on the embryo-fetal or postnatal survival, growth or development in the F1 offspring.
In a local tolerance study, conducted in rabbits that received a single clinical dose of Prevnar 20, only transient incidence of mild erythema, edema and/or a mass at the injection site were observed on Day 2 after injection.
The conclusions of the non-clinical studies as well as the potential risks to humans have been included in the Prevnar 20 Product Monograph. In view of the intended use of Prevnar 20, there are no pharmacological or toxicological issues within this submission to preclude authorization of the product.
For more information, refer to the Prevnar 20 Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.3 Quality Basis for Decision
The development of the Prevnar 20 manufacturing process leveraged prior knowledge and experience (e.g., process parameters and ranges, in-process tests) from the previously authorized vaccine Prevnar 13. Consequently, the review of the quality component of the New Drug Submission for Prevnar 20 focused on the additional seven serotypes introduced in this vaccine.
Characterization of the Drug Substance
Prevnar 20 is a pneumococcal 20-valent conjugate vaccine. It is modelled after Prevnar 13 and contains the same 13 serotype-specific capsular polysaccharides included in Prevnar 13 (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F) and 7 additional serotype-specific capsular polysaccharides (8, 10A, 11A, 12F, 15B, 22F, and 33F). Each polysaccharide is covalently linked to a carrier protein, the non-toxic variant of diphtheria toxin cross-reactive material 197 (CRM197).
Detailed characterization studies were performed to provide assurance that the medicinal ingredients in Prevnar 20 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.
Manufacturing Process of the Drug Substance and Drug Product and Process Controls
The seven additional pneumococcal polysaccharides (also referred to as drug substance intermediates) are manufactured from Streptococcus pneumoniae serotypes 8, 10A, 11A, 12F, 15B, 22F, and 33F.
The carrier protein CRM197 is a non-toxic variant of diphtheria toxin isolated from cultures of Corynebacterium diphtheriae strain C7 (β197).
The manufacturing processes and controls 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 individual glycoconjugates are purified by a series of chemical and physical methods and compounded to formulate Prevnar 20. Each 0.5 mL dose of the vaccine is formulated to contain approximately 2.2 mcg of each of Streptococcus pneumoniae serotypes 1, 3, 4, 5, 6A, 7F, 8, 9V, 10A, 11A, 12F, 14, 15B, 18C, 19A, 19F, 22F, 23F and 33F polysaccharides, 4.4 mcg of 6B polysaccharide, 51 mcg CRM197 carrier protein, 100 mcg polysorbate 80, 295 mcg succinic acid, 4.4 mg sodium chloride, and 125 mcg aluminum as aluminum phosphate adjuvant.
The materials used in the manufacturing process of Prevnar 20 are considered suitable and meet standards appropriate for their intended use. Process validation studies have demonstrated that the manufacturing process, when operating within the predefined process controls, consistently produces drug substance and drug product that conform to all predefined acceptance criteria.
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. Analytical procedures are validated and in compliance with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines.
Prevnar 20 is a Schedule D (biologic) drug and is, therefore, subject to Health Canada's Lot Release Program before sale as per the 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 shelf life of 24 months for Prevnar 20, when stored at 2 °C to 8 °C, 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 involved in the production are considered suitable for the activities and products manufactured.
Based on risk assessment scores determined by Health Canada, on-site evaluations of the drug substance and drug product manufacturing facilities were not deemed necessary.
The sites involved in production are compliant with good manufacturing practices.
Adventitious Agents Safety Evaluation
The risk of introducing endogenous and exogenous contaminants in Prevnar 20 is mitigated by adequate control measures incorporated in the manufacturing process of the vaccine.
Bioburden and sterility controls are in place at the appropriate stages of the vaccine manufacturing process to ensure that any adventitious agents are removed. The sponsor has demonstrated, via aseptic media-fill simulations, that aseptic processing is maintained throughout the manufacturing process. The sterility of the final product is appropriately controlled.
The materials of animal origin used in the manufacturing process are properly sourced and tested as per the relevant guidelines on minimizing the risk of transmitting animal spongiform encephalopathy agents via medicinal products.
There is no living mammalian cell substrate involved in the manufacturing process of Prevnar 20 and, consequently, there is no potential for the propagation of animal viruses. The risk of viral adventitious agents is considered negligible.
The excipients used in the final product formulation are not of animal or human origin.
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| PREVNAR 20 | 02527049 | PFIZER CANADA ULC | CORYNEBACTERIUM DIPHTHERIAE CRM-197 PROTEIN 51 MCG / 0.5 ML PNEUMOCOCCAL POLYSACCHARIDE SEROTYPE 1 2.2 MCG / 0.5 ML PNEUMOCOCCAL POLYSACCHARIDE SEROTYPE 10A 2.2 MCG / 0.5 ML PNEUMOCOCCAL POLYSACCHARIDE SEROTYPE 11A 2.2 MCG / 0.5 ML PNEUMOCOCCAL POLYSACCHARIDE SEROTYPE 12F 2.2 MCG / 0.5 ML PNEUMOCOCCAL POLYSACCHARIDE SEROTYPE 14 2.2 MCG / 0.5 ML PNEUMOCOCCAL POLYSACCHARIDE SEROTYPE 15B 2.2 MCG / 0.5 ML PNEUMOCOCCAL POLYSACCHARIDE SEROTYPE 18C 2.2 MCG / 0.5 ML PNEUMOCOCCAL POLYSACCHARIDE SEROTYPE 19A 2.2 MCG / 0.5 ML PNEUMOCOCCAL POLYSACCHARIDE SEROTYPE 19F 2.2 MCG / 0.5 ML PNEUMOCOCCAL POLYSACCHARIDE SEROTYPE 22F 2.2 MCG / 0.5 ML PNEUMOCOCCAL POLYSACCHARIDE SEROTYPE 23F 2.2 MCG / 0.5 ML PNEUMOCOCCAL POLYSACCHARIDE SEROTYPE 3 2.2 MCG / 0.5 ML PNEUMOCOCCAL POLYSACCHARIDE SEROTYPE 33F 2.2 MCG / 0.5 ML PNEUMOCOCCAL POLYSACCHARIDE SEROTYPE 4 2.2 MCG / 0.5 ML PNEUMOCOCCAL POLYSACCHARIDE SEROTYPE 5 2.2 MCG / 0.5 ML PNEUMOCOCCAL POLYSACCHARIDE SEROTYPE 6A 2.2 MCG / 0.5 ML PNEUMOCOCCAL POLYSACCHARIDE SEROTYPE 6B 4.4 MCG / 0.5 ML PNEUMOCOCCAL POLYSACCHARIDE SEROTYPE 7F 2.2 MCG / 0.5 ML PNEUMOCOCCAL POLYSACCHARIDE SEROTYPE 8 2.2 MCG / 0.5 ML PNEUMOCOCCAL POLYSACCHARIDE SEROTYPE 9V 2.2 MCG / 0.5 ML |