Summary Basis of Decision for Prevnar ® 13
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:
Prevnar® 13
Pneumococcal 13-valent Conjugate Vaccine
(Diphtheria CRM197 Protein), suspension
Wyeth Canada
Submission control no: 122881
Date issued: 2010-11-15
Foreword
Health Canada's Summary Basis of Decision (SBD) documents outline the scientific and regulatory considerations that factor into Health Canada regulatory decisions related to drugs and medical devices. SBDs are written in technical language for stakeholders interested in product-specific Health Canada decisions, and are a direct reflection of observations detailed within the evaluation reports. As such, SBDs are intended to complement and not duplicate information provided within the Product Monograph.
Readers are encouraged to consult the 'Reader's Guide to the Summary Basis of Decision - Drugs' to assist with interpretation of terms and acronyms referred to herein. In addition, a brief overview of the drug submission review process is provided in the Fact Sheet entitled 'How Drugs are Reviewed in Canada'. This Fact Sheet describes the factors considered by Health Canada during the review and authorization process of a drug submission. Readers should also consult the 'Summary Basis of Decision Initiative - Frequently Asked Questions' document.
The SBD reflects the information available to Health Canada regulators at the time a decision has been rendered. Subsequent submissions reviewed for additional uses will not be captured under Phase I of the SBD implementation strategy. For up-to-date information on a particular product, readers should refer to the most recent Product Monograph for a product. Health Canada provides information related to post-market warnings or advisories as a result of adverse events (AE).
For further information on a particular product, readers may also access websites of other regulatory jurisdictions. The information received in support of a Canadian drug submission may not be identical to that received by other jurisdictions.
Other Policies and Guidance
Readers should consult the Health Canada website for other drug policies and guidance documents. In particular, readers may wish to refer to the 'Management of Drug Submissions Guidance'.
1 Product and submission information
Brand name:
Manufacturer/sponsor:
Medicinal ingredient:
International non-proprietary Name:
Strength:
Each polysaccharide is directly conjugated to the Corynebacterium diphtheriae protein carrier (CRM197)
Dosage form:
Route of administration:
Drug identification number(DIN):
- 02335204
Therapeutic Classification:
Non-medicinal ingredients:
Submission type and control no:
Control Number: 122881
Date of Submission:
Date of authorization:
2 Notice of decision
On December 21, 2009, Health Canada issued a Notice of Compliance to Wyeth Canada for the vaccine product Prevnar® 13 [Pneumococcal 13-valent Conjugate Vaccine (Diphtheria CRM197 Protein)].
Prevnar® 13 is an active immunizing agent, and contains 13 drug substances composed of pneumococcal polysaccharide serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F each of which is separately conjugated to a non-toxic diphtheria CRM197 carrier protein.
All conjugated drug substances are compounded, and then polysorbate 80 and aluminum phosphate are added to formulate the vaccine.
Prevnar® 13 is indicated for active immunization of infants and children from 6 weeks through 5 years of age against Streptococcus pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F, causing invasive pneumococcal disease (including sepsis, meningitis, bacteraemic pneumonia, pleural empyema and bacteraemia). The vaccine functions by triggering an immune response to the polysaccharide antigens contained within the vaccine. The boosting of the polysaccharide antigens results in an enhanced antibody response, induces immune memory, and elicits booster responses upon re-exposure in infants and young children.
The market authorization was based on quality, non-clinical, and clinical information submitted. The immunogenicity of the vaccine was demonstrated through an immunological comparison between Prevnar® 13 and Prevnar® (7-valent) in two pivotal studies (004 and 006) and a post-hoc analysis from one non-pivotal (3005) study. All three studies were multi-centre, randomized, double-blind, controlled studies. Within these studies, a total of 2,087 infants and young children received Prevnar® 13 and a total of 878 infants and young children received Prevnar® (7-valent). For 7 common serotypes in both vaccines (serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F), the results show that immunological non-inferiority was demonstrated by enzyme-linked-immuno-sorbent serologic assay (ELISA) for all 7 serotypes in study 3005, all except 6B in study 006, and all except for 6B and 9V in study 004, each of which missed non-inferiority margin at the lower bound of the 95% confidence interval for the difference between groups. The clinical relevance of these differences is not known. In line with the World Health Organization (WHO) recommendations, Health Canada will also evaluate post-approval pharmacovigilance and relevant clinical studies, to further support this product and its approved release specifications.
Prevnar® 13 is presented as a suspension for injection. Prevnar® 13 should be given intramuscularly using the pre-filled syringe (0.5 mL) and administered according to the vaccination schedule outlined in the dosing guidelines provided in the Product Monograph.
Prevnar® 13 is contraindicated for patients who are hypersensitive to any of the components of the vaccine, including diphtheria toxoid. In addition, safety and immunogenicity data on Prevnar® 13 are not available for children in specific groups at higher risk for invasive pneumococcal disease [for example, children with congenital or acquired splenic dysfunction, human immunodeficiency virus (HIV) infection, malignancy, or nephrotic syndrome]. Children in these groups may have a reduced antibody response to active immunization due to impaired immune responsiveness. Vaccination in high-risk groups should be considered on an individual basis.
Prevnar® 13 should be administered under the conditions stated in the Product Monograph taking into consideration the potential risks associated with the administration of this drug product. Detailed conditions for the use of Prevnar® 13 are described in the Product Monograph.
Priority Review Status was granted for the evaluation of Prevnar 13 as it appeared to provide promising evidence of clinical efficacy for a serious, life-threatening, and severely debilitating disease that is not adequately managed by a drug marketed in Canada through the inclusion of emerging serotypes in children, specifically against the serotypes 3, 6A, and 19A.
Based on the Health Canada review of data on quality, safety, and efficacy, Health Canada considers that the benefit/risk profile of Prevnar® 13 is favourable for the active immunization of infants and children from 6 weeks through 5 years of age against Streptococcus pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F, causing invasive pneumococcal disease (including sepsis, meningitis, bacteraemic pneumonia, pleural empyema and bacteraemia).
3 Scientific and Regulatory Basis for Decision
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
General Information
The Prevnar® 13 vaccine is an active immunizing agent that contains 13 drug substances composed of the pneumococcal polysaccharide serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F. Polysaccharides from each of these serotypes are separately conjugated to a non-toxic diphtheria carrier protein (CRM197).
Prevnar® 13 helps protect infants and children against diseases such as meningitis, sepsis or bacteraemia, and bacteraemic pneumonia caused by thirteen strains of the bacteria Streptococcus pneumoniae. The vaccine functions by triggering an immune response to the polysaccharide antigens contained within the vaccine. The boosting of the polysaccharide antigens results in an enhanced antibody response, induces immune memory, and elicits booster responses upon re-exposure in infants and young children.
Manufacturing Process and Process Controls
Pneumococcal 13-valent conjugate vaccine is a sterile solution of saccharides of the capsular antigens of Streptococcus (S.) pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F individually conjugated by reductive amination to non-toxic diphtheria CRM197 protein. The polysaccharides are chemically activated, and then covalently linked to the protein carrier CRM197 to form the glycoconjugate. The individual conjugates are compounded, and then polysorbate 80 and aluminum phosphate are added.
The manufacturing of the polysaccharides from the thirteen S. pneumoniae serotypes involves fermentation and harvest, purification, dispensing, storage, and shipping.
In-process testing is performed to monitor the manufacturing process of the pneumococcal polysaccharides. The descriptions of these tests and validation of these methods were provided. The materials used in the manufacture of the drug substances are considered suitable for their intended use. The manufacturing process is considered to be adequately controlled within justified limits.
Characterization
Detailed characterization studies were performed to provide assurance that all of the active ingredients consistently exhibit the desired characteristic structure and biological activity.
Appropriate tests are adequately controlling the levels of product- and process-related impurities.
Control of Drug Substance
The drug substance specifications and analytical methods used for quality control are considered acceptable. The specifications were selected to ensure the identity, purity, safety, and quality of the produced polysaccharides.
Batch analysis results were reviewed and all results comply with the specifications and demonstrate consistent quality of the batches produced.
The proposed packaging components are considered acceptable.
Stability
Based on the stability data submitted, the proposed shelf-life, storage, and shipping conditions for the drug substance are supported and considered to be satisfactory.
3.1.2 Drug Product
Description and Composition
Prevnar® 13 [Pneumococcal 13-valent Conjugate Vaccine (Diphtheria CRM197 Protein)] is a sterile, white, liquid suspension of capsular polysaccharide antigens of S. pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F, with each saccharide individually conjugated to a non-toxic diphtheria CRM197 carrier protein. Each 0.5-mL dose contains 2.2 µg of saccharide for each serotype with the exception of serotype 6B for which 4.4 µg of saccharide is included. The vaccine is formulated in succinate buffer containing sodium chloride and polysorbate 80, and contains aluminum phosphate, as an adjuvant. Prevnar® 13 is provided in a single-dose, pre-filled syringe (0.5 mL), in a package of 10, without needles.
All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of the active ingredients with the excipients is demonstrated by the stability data presented on the proposed commercial formulation.
Pharmaceutical Development
Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review.
Manufacturing Process and Process Controls
The method of manufacturing is considered acceptable and the process is considered adequately controlled within justified limits. All manufacturing equipment, in-process manufacturing steps and detailed operating parameters were adequately described in the submitted documentation and are considered acceptable.
Control of Drug Product
Prevnar® 13 is tested to verify that its identity, assay, antigenicity, appearance, pH, sterility, endotoxin content, volume (injection and extractable), protein (total and bound), polysaccharide content, and degradation products are within acceptance criteria.
Validation reports submitted for all analytical procedures used for in-process and release testing of the drug product is considered satisfactory.
Data from final batch analyses were reviewed and are considered to be acceptable according to the specifications of the drug product.
Stability
Based on the real-time, long-term, and accelerated stability data submitted, the proposed 24-month shelf-life at 2 to 8°C for Prevnar® 13 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.
3.1.3 Facilities and Equipment
An On-Site Evaluation (OSE) of the facilities involved in the manufacture and testing of Prevnar® 13 has been successfully conducted by the Biologics and Genetic Therapies Directorate, Health Canada.
The design, operations and controls of the facilities and equipment that are involved in the production of Prevnar® 13 are considered suitable for the activities and products manufactured. All sites are compliant with Good Manufacturing Practices.
3.1.4 Adventitious Agents Safety Evaluation
Raw materials of animal and recombinant DNA origin used in the manufacturing process are adequately tested to ensure freedom from adventitious agents. The excipients used in the final product formulation are not from animal or human origin.
3.1.5 Conclusion
The Chemistry and Manufacturing information submitted for Prevnar® 13 has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes.
3.2 Non-Clinical Basis for Decision
The composition of Prevnar® 13 used for the non-clinical studies was similar to the composition intended for human use.
3.2.1 Pharmacodynamics
No dedicated non-clinical pharmacodynamic studies were conducted with Prevnar®&nnbsp;13. The analysis of serum samples taken from the repeat-dose toxicity studies conducted in rats (adult and juvenile), rabbits, and monkeys demonstrated that the subcutaneous (SC) administration of Prevnar® 13 in rats and monkeys, and the intramuscular (IM) administration of Prevnar® 13 in rabbits induced immune response.
The safety pharmacology studies in rats and monkeys demonstrated that there were no effects of Prevnar® 13 on the central nervous system, the respiratory system, or the cardiovascular system, following a single SC injection of Prevnar® 13.
3.2.2 Pharmacokinetics
Non-clinical pharmacokinetic studies are not applicable to vaccines.
3.2.3 Toxicology
Single-Dose Toxicity
Single-dose toxicity was evaluated in rats (adult and juvenile), rabbits, and monkeys using data collected following the administration of the first dose in the repeat-dose toxicity studies. There was no mortality and no evidence of systemic toxicity in the animals that were administered a single dose of Prevnar® 13.
Repeat-Dose Toxicity
Prevnar® 13 was administered to rats, rabbits, and monkeys once every 2 or 3 weeks for a total of up to seven doses. No study-drug related adverse effects (AEs) were observed in either adult or juvenile animals in any of these studies with the exception of local injection site inflammatory reactions.
Genotoxicity
Genotoxicity studies were not conducted with Prevnar® 13 as it is composed of naturally occurring polysaccharides conjugated to a protein and is not capable of interacting with deoxyribonucleic acid (DNA) or generating metabolites capable of interacting with DNA. The omission of genotoxicity testing is consistent with both the World Health Organization (WHO) and European Medicines Agency (EMEA) guidances for the non-clinical safety assessment of vaccines.
Carcinogenicty
Carcinogenicity studies have not been conducted with Prevnar® 13 as the vaccine is intended to be administered infrequently, at doses that result in very low lifetime exposure. Prevnar® 13 is not expected to be carcinogenic. The omission of carcinogenicity testing is consistent with both the WHO and EMEA guidances for the non-clinical safety assessment of vaccines.
Reproductive and Developmental Toxicity
Prevnar® 13 is not intended for the vaccination of women of childbearing potential. The omission of fertility, embryo-foetal development, peri- and post-natal developmental toxicity studies is consistent with both the WHO and EMEA guidances for the non-clinical safety assessment of vaccines. However, a juvenile toxicity study was conducted in rats. The only effects were injection site reactions after the SC injection of Prevnar® 13.
Local Tolerance
A local tolerance study was conducted in rabbits to evaluate irritation following a single IM dose of Prevnar® 13. Following administration, there were no clinical signs and no evidence of injection-site irritation, effects on body weight or food consumption, or macroscopic or microscopic lesions related to Prevnar® 13, with or without the aluminum phosphate adjuvant.
3.2.4 Conclusion
Prevnar® 13 induced an immune response and was well-tolerated in the animals studied. There were no pharmacological/toxicological issues within the submission which would preclude approval of the requested product indication.
3.3 Clinical basis for decision
Prevnar® 13 is indicated for the active immunization of infants and children from 6 weeks through 5 years of age against S. pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F, causing invasive pneumococcal disease (including sepsis, meningitis, bacteraemic pneumonia, pleural empyema, and bacteraemia).
The immunologic potential of Prevnar® 13 was assessed through the analysis of immunogenicity and is described in section 3.3.1 Clinical Efficacy.
The clinical program was based on World Health Organization (WHO) recommendations (WHO Technical Report Series Number 927, 2005, Annex 2 and WHO recommendations to assure the quality, safety and efficacy of pneumococcal conjugate vaccines, 2009, WHO/BS/09.2108) stating that the approval of any new pneumococcal conjugate vaccine against invasive pneumococcal disease (IPD) can be based on the demonstration of immunological non-inferiority to the licensed 7-valent pneumococcal conjugate vaccine Prevnar®.
The WHO has recommended a serum anti-capsular polysaccharide antibody concentration of 0.35 µg/mL measured one month after the primary infant series as a single antibody reference concentration to estimate the efficacy of new pneumococcal conjugate vaccines against IPD. This recommendation is based upon the observed correlation between immunogenicity and IPD efficacy from three placebo-controlled trials with either 7-valent Prevnar® or the investigational 9-valent pneumococcal conjugate vaccine. This reference concentration is only applicable on a population basis and cannot be used to predict protection against IPD on an individual basis.
The WHO recommendations also require demonstration of functionality of the elicited antibodies. Opsonophagocytosis (antibody mediated killing of the bacteria) is recognized as the main mechanism of protection against pneumococcal disease, which can be measured by an opsonophagocytosis activity assay (OPA). The OPA measures the ability of vaccine-elicited antibodies to opsonize and promote killing of Pneumococcus bacteria. The percentage of subjects with an OPA titre >1:8 is used for comparison between vaccines. In addition to meeting the OPA criteria, the ability to induce immune memory is also required.
The recommended antibody threshold is only a reference and it should not be regarded as a definitive immunological correlate of protection. However, it is generally agreed that all other relevant parameters, including geometric mean concentrations (GMCs) as measured by enzyme-linked immunosorbent assay (ELISA), geometric mean titers (GMTs) as measured by OPA, reverse cumulative distribution curves (RCD), and a demonstration of the induction of immune memory following the administration of a booster dose, should also be taken into consideration.
3.3.1 Clinical Efficacy
In line with WHO recommendations for the approval of new pneumococcal conjugate vaccines, no clinical efficacy data were submitted to support the indication of IPD for Prevnar® 13; only immunological data were provided for Prevnar® 13 in comparison with the licensed 7-valent Prevnar®.
Prevnar® 13 contains the seven serotypes (4, 6B, 9V, 14, 18C, 19F, and 23F) which are included in the 7-valent Prevnar®, as well as six additional serotypes (serotypes 1, 3, 5, 6A, 7F, 19A). Besides 6 new serotypes, serotype 19F conjugate in Prevnar® 13 is modified compared with 7-valent Prevnar®. In addition, 0.02% polysorbate 80 (P80) and succinate buffer are included in the final formulation of Prevnar® 13, and not included in 7-valent Prevnar®.
This drug submission included fifteen clinical studies with different vaccination schedules and concomitantly administered routine childhood vaccines. Only two studies (Studies 004 and 006) evaluated the non-inferiority of Prevnar® 13 against 7-valent Prevnar® in terms of the percentage of subjects achieving WHO recommended serotype-specific IgG antibody level (0.35 µg/mL) measured 1 month after the primary infant series. The serotype-specific IgG antibody concentrations were measured, as recommended by the WHO, by enzyme-linked immunosorbent assay (ELISA), which included pre-adsorption of sera with pneumococcal C polysaccharide (C-PS) and serotype 22F polysaccharide.
Immune Response Following the Primary Infant Series
Study 004 and Study 006
Studies 004 and 006 were Phase III multicentre, active-controlled, double-blind studies. In Study 004, 332 subjects received Prevnar® 13 and 331 subjects received 7-valent Prevnar®. In Study 006, 300 subjects received Prevnar® 13 and 303 subjects received 7-valent Prevnar®. The vaccination schedule in Study 004 was a 3-dose primary infant series at 2, 4, and 6 months of age. In Study 006, the vaccination schedule was a 3-dose primary infant series at 2, 3, and 4 months of age.
Non-inferiority of Prevnar® 13 against 7-valent Prevnar® was evaluated in terms of the percentage of responders measured 1 month after the primary infant series. Responders are defined as subjects who achieve a serum anti-capsular polysaccharide immunoglobulin G (IgG) antibody concentration of 0.35 µg/mL by ELISA. Non-inferiority for a given serotype was declared if the lower limit of the 95% confident interval (CI) for the difference of percentage of responders between Prevnar® 13 and 7-valent Prevnar® was greater than -10%. For all 7 common serotypes, the percentage of responders to each serotype in the Prevnar® 13 group was compared with the percentage of responders to the same serotype in the 7-valent Prevnar® group. The non-inferiority criterion was met for all 7 common serotypes, except for serotypes 6B and 9V in Study 004 and serotype 6B in Study 006. For the 6 additional new serotypes, the percentage of responders to each serotype in the Prevnar® 13 group was compared with the lowest response rate among all of the 7 common serotypes in the 7-valent Prevnar® group. The non-inferiority criterion was met for the 6 new additional serotypes in Prevnar® 13, except for serotype 3. The clinical relevance of these observed differences is not known.
The ELISA GMCs of the pneumococcal anti-capsular polysaccharide IgG antibodies elicited by Prevnar® 13 were also compared to 7-valent Prevnar® following the primary infant series. Non-inferiority for a given serotype was declared if the lower limit of the 95% CI for the ratio of GMC between groups (Prevnar® 13 to 7-valent Prevnar® reference) was greater than 0.5. The 7-valent Prevnar® reference value was the corresponding GMC in the 7-valent Prevnar® group for the 7 common serotypes, or was the lowest GMC among the 7-valent Prevnar® group for the 6 additional serotypes. The non-inferiority criterion was met for all serotypes except for serotype 3. However, for the 7 common serotypes, the ELISA GMCs elicited by Prevnar® 13 were generally lower than those elicited by 7-valent Prevnar®, that is (i.e.), the ratio of GMC between groups (Prevnar® 13 to 7-valent Prevnar®) was less than 1 (ranged from 0.60 to 0.88) for all 7 common serotypes.
OPA antibody titres were measured in a randomly selected subset of subjects (approximately 100 subjects per group in each study). More than 90% of the evaluated subjects achieved an OPA antibody titre ≥1:8 one month after the primary infant series of Prevnar® 13 or 7-valent Prevnar®.
Other Clinical Studies (007, 008, 500, 501, 3007, 3008, 011, 009, 3000 and 3005)
The immune responses to each pneumococcal serotype in Prevnar® 13 were also evaluated in other Phase III studies with different vaccination schedules of pneumococcal vaccine (3-doses or 2-doses primary infant series) and different routine childhood concomitant vaccines. However, no comparison against 7-valent Prevnar® was provided. Generally, the percentage of responders was lower for serotypes 6B, 23F, 3, 5 and 6A compared to other serotypes.
Three-dose Primary Infant Series versus Two-dose Primary Infant Series
By comparing the results obtained from different studies, the immune response induced by the 2-dose primary infant series was lower than that induced by the 3-dose primary infant series, in terms of the percentage of responders 1 month after the infant series, especially for the serotypes 6B and 23F.
The immunogenicity results following the 2-dose infant series in the Prevnar® 13 group have not been compared to the 7-valent Prevnar® group. The currently available data are not considered sufficient to support the 2-dose primary infant schedule for Prevnar® 13.
Immune Response Following the Toddler Dose
The immune responses elicited by Prevnar® 13 were assessed following the toddler dose in the two pivotal studies (004 and 006), and four additional Phase III studies (007, 008, 500 and 501). However, only Studies 004 and 006 compared Prevnar® 13 to 7-valent Prevnar®.
Study 004 and Study 006
In terms of the percentage of responders and ELISA GMCs one month after the toddler dose, the non-inferiority criteria were met (same criteria as for primary infant series) for all 13 serotypes, except for serotype 3.
As observed after the primary infant series, for the 7 common serotypes, the ELISA GMCs elicited by Prevnar® 13 were generally lower than those elicited by 7-valent Prevnar®, i.e., the ratio of GMC between groups (Prevnar® 13 to 7-valent Prevnar® reference) was less than 1 (ranged from 0.65 to 0.93) for all 7 common serotypes, except for 19F. However, the GMC fold rises by comparing the GMCs before and after the toddler dose were at least 3.8-fold for all 13 serotypes in Prevnar® 13 recipients, with the exception with serotype 3 in Study 006.
OPA antibody titres were also evaluated in a randomly selected subset of subjects (approximately 100 subjects per group in each study) after the toddler dose. The percentage of subjects achieving an OPA antibody titre ≥1:8 after the toddler dose was high (>90%) in the Prevnar® 13 group. For the 7 common serotypes, the OPA GMTs were lower in the Prevnar® 13 group than in the 7-valent Prevnar® group, that is (i.e.), the ratio of GMT between groups (Prevnar® 13 to 7-valent Prevnar® reference) was less than 1, except for serotype 19F.
Studies 007, 008, 500, 501 and 009
The immune responses to each pneumococcal serotype in Prevnar® 13 were also evaluated in other Phase III studies one month after the toddler dose. However, no comparison against 7-valent Prevnar® was provided.
In the primary infant series, the subjects were administered either two doses (Studies 007 and 500) or three doses (Studies 008, 501 and 009) of Prevnar® 13. The results showed that one month after toddler dose, the percentage of responder was at least 92.2% for all 13 serotypes, except for the serotype 3 in Study 007 (88.2%).
Unique observation for Serotype 3
See the table below. The decrease of GMC values for serotype 3 after the toddler dose compared to that after the primary infant series were observed in some of the studies listed below. In addition, Study 008 showed that 1 toddler dose of Prevnar® 13 after 3 doses 7-valent Prevnar® of the primary infant series induced higher GMC compared with after 4 doses of Prevnar® 13. The clinical relevance of these observations is not known.
| Study | Group* | Geometric Mean Concentrations (GMC) for the serotype 3 | ||
|---|---|---|---|---|
| After infant series | Before toddler dose | After toddler dose | ||
| 004 | 13vPnC | 0.49 | 0.15 | 0.94 |
| 006 | 13vPnC | 1.55 | 0.25 | 1.02 |
| 009 | 13vPnC with P80 | 1.50 | 0.14 | 1.09 |
| 13vPnC | 1.62 | 0.18 | 1.16 | |
| 007 | 13vPnC | 0.63 | 0.14 | 0.98 |
| 008 | 13vPnC/13vPnC | 1.25 | 0.2 | 0.99 |
| 7vPnC/13vPnC | - | 0.1 | 1.32 | |
| 500 | 13vPnC | 1.15 | 0.25 | 1.22 |
| 501 | 13vPnC | 0.97 | - | 1.07 |
* 13vPnC = Prevnar® 13, 7vPnC = 7-valent Prevnar®,
* 13vPnC/13vPnC = 3 doses of Prevnar® 13 in the primary infant series plus 1 toddler dose of Prevnar® 13
* 7vPnC/13vPnC = 3 doses of 7-valent Prevnar® in the primary infant series plus 1 toddler dose of Prevnar® 13
* All Prevnar® 13 used in the trials contained no P80 except for the one specified.
Formulation Bridging Study
A formulation bridging study (Study 009) was submitted as the Prevnar® 13 formulation used in the two pivotal studies (Study 004 and 006) and seven additional Phase III studies (Studies 007, 008, 500, 501, 3007, 3008 and 011) did not contain polysorbate 80 (P80), and P80 is included in the final market formulation.
Non-inferiority of Prevnar® 13 with P80 against Prevnar® 13 without P80 was evaluated in terms of the percentage of responders measured 1 month after the primary infant series. Responders are defined as subjects who achieve a serum anti-capsular polysaccharide IgG antibody concentration of 0.35 µg/mL by ELISA. Non-inferiority for a given serotype was declared if the lower limit of the 95% CI for the difference of percentage of responders between Prevnar® 13 with P80 and Prevnar® 13 without P80 was greater than -10%.
In terms of the percentage of responders, non-inferiority criterion was met for all serotypes except for the serotype 6B and 23F after the primary infant series. After the toddler dose, the percentage of responders was high (≥95.1%) for all serotypes in the Prevnar® 13 with P80 group.
The ELISA GMCs were lower in the Prevnar® 13 with P80 group compared to the Prevnar® 13 without P80 group for all 13 serotypes, i.e., the ratio of GMC between groups (Prevnar® 13 with P80 to Prevnar® 13 without P80) was <1, although the non-inferiority criterion, the lower limit of the 95% CI for the ratio of GMC (Prevnar® 13 with P80 to Prevnar® 13 without P80) was greater than 0.5, was met.
Manufacturing Scale Bridging Studies
Two studies (Studies 3000 and 3005) compared the immune responses induced by the manufacturing scale lot and by the pilot scale lot of Prevnar® 13. All Prevnar® 13 lots studied in these two studies contained P80. Study 3000 compared one manufacturing lot to one pilot lot of Prevnar® 13. Study 3005 compared one manufacturing lot to two pilot lots of Prevnar® 13. The percentage of responders and the ELISA GMCs were similar between the manufacturing lot group and the pilot lot group after the primary infant series. The 95% CI of the percentage of responder was overlapped for each serotype between the manufacturing lot group and pilot lot group. The 95% CI of ELISA GMC was overlapped as well between the manufacturing lot group and pilot lot group. The immunogenicity results after the toddler dose were not provided, as well as the data for the lot consistency at the manufacturing scale level (commercial product level) were not provided.
Catch-up Schedule Study
The catch-up schedule study (Study 3002) evaluated the immune response induced by the following catch-up schedules of Prevnar® 13 in older infants and children: total 3 doses for subjects 7 to <12 months of age; total 2 doses for subjects 12 to <24 months of age; and 1 dose for subjects ≥24 months of age through to 5 years of age.
The proportion of responders was high in each of the catch-up groups (>92.7% for all serotypes) except for the serotype 14 (88.1%) in the 24-72 months 1-dose group. The ELISA GMCs were generally lower compared to the subjects who received 3-infant doses plus 1-toddler dose in Studies 004 and 006.
Switch from 7-valent Prevnar® to Prevnar® 13 (Study 008)
One study (Study 008) evaluated the immune response after the vaccine transition from 7-valent Prevnar® to Prevnar® 13. Three groups were involved in Study 008:
- 13v/13v: approximately 200 subjects received 3 infant doses of Prevnar® 13 and one toddler dose of Prevnar® 13
- 7v/7v: approximately 100 subjects received 3 infant doses of 7-valent Prevnar® and one toddler dose of 7-valent Prevnar®
- 7v/13v: approximately 100 subjects received 3 infant doses of 7-valent Prevnar® and one toddler dose of Prevnar® 13
The 3 infant doses of 7-valent Prevnar® were given at 2, 3, and 4 months of age; and the toddler dose was given at 12 months of age.
For the 7 common serotypes, ≥97.9% of 13v/13v recipients, ≥97.6% of 7v/7v recipients, and ≥97.3% of 7v/13v recipients achieved antibody concentrations ≥0.35 μg/mL one month after the toddler dose.
For the 6 additional serotypes (listed in the table below), the antibody response induced by a single toddler dose of Prevnar® 13 after 3 infant doses of 7-valent Prevnar® was lower than that induced by 4 doses of Prevnar® 13, except for the serotype 3. However, Study 008 was not powered as a non-inferiority test.
| Serotype | 13v/13v group | 7v/13v group | ||
|---|---|---|---|---|
| Response rate (%) | GMC (95% CI) | Response rate (%) | GMC (95% CI) | |
| 1 | 100 | 4.1 (3.7, 4.5) | 95.5 | 1.8 (1.5, 2.2) |
| 3 | 94.8 | 1.0 (0.9, 1.1) | 93.8 | 1.3 (1.1, 1.5) |
| 5 | 100 | 3.3 (3.0, 3.7) | 90.1 | 1.1 (1.0, 1.3) |
| 6A | 100 | 6.1 (5.5, 6.8) | 89.9 | 2.6 (2.0, 3.4) |
| 7F | 100 | 4.5 (4.1, 5.0) | 100 | 3.7 (3.2, 4.3) |
| 19A | 100 | 9.5 (8.5, 10.6) | 100 | 5.3 (4.6, 6.2) |
Co-administration of Paediatric Vaccines with Prevnar®13
The immune response rates to the following concomitant vaccines: diphtheria, tetanus, pertussis, haemophilus influenzae type B, polio, hepatitis B, measles, mumps, rubella, varicella, and meningococcal C were comparable between the Prevnar® 13 group and the 7-valent Prevnar® group. The overall results showed no evidence of interference of immune responses to these concomitant vaccine antigens.
3.3.2 Clinical Safety
The safety of Prevnar® 13 was assessed in thirteen controlled clinical studies. Approximately 15,000 doses were given to 4,729 healthy infants ranging in age from 6 weeks to 16 months. In all studies, Prevnar® 13 was co-administered with routine paediatric vaccines. Safety data was also obtained from a catch-up study which enrolled 354 children (7 months to 5 years of age) that received at least one dose of Prevnar® 13.
No specific safety concerns were identified from the adverse events (AEs) reported.
The incidence and intensity of solicited local AEs (tenderness, induration, erythema) were generally similar between the Prevnar® 13 and the 7-valent Prevnar® groups, although some statistically significant differences were observed. The differences were small; some were reportedly higher in the Prevnar® 13 group and some higher in the 7-valent Prevnar® group, therefore, these statistically significant differences are not considered to be clinically important. Solicited systemic AEs (fever, decreased appetite, irritability, increased sleep, decreased sleep) and the usage of antipyretic medication were also reported at a similar incidence in both Prevnar® 13 and 7-valent Prevnar® groups. There were no differences in overall unsolicited AEs (upper respiratory infections, bronchiolitis, conjunctivitis, diarrhea, pyrexia, rhinitis, nasopharyngitis, and gastroenterits) reported at any time period during the study.
During the thirteen controlled clinical studies, 4 infants died out of 7,489. All four cases were attributed to Sudden Infant Death Syndrome (SIDS). Three cases occurred in the Prevnar® 13 group (4,729 infants) and one case in the 7-valent Prevnar® group (2,760 infants). None of deaths were assessed by the investigator as causally related to vaccination.
The investigator assessed fever and febrile convulsion as the most common serious adverse events (SAEs) related to Prevnar® 13. SAEs were reported in 11 (0.1%) of the 7,489 subjects; 6 (0.1%) were in the Prevnar® 13 group (4,729 subjects) and 5 (0.2%) were in the 7-valent Prevnar® group (2,760 subjects). Of these 11 SAEs, there were 3 cases of febrile convulsions and 4 cases of fever. Out of the 4 cases with fever, 1 subject had diffuse body rash, 1 subject had respiratory distress, and 1 subject had tense fontanelle. The remaining related SAE cases were crying (1), bronchitis (1), infantile spasms (1) and nephroblastoma (1).
The most frequently reported reasons for discontinuation of the study among the Prevnar® 13 recipients were fever/febrile convulsion and allergic reactions. One case of pneumonia and one case of meningitis were reported.
3.3.3 Additional Issues
As part of the marketing authorization for Prevnar® 13, Health Canada requested that the sponsor agree to several commitments to be addressed post-market. Commitments include (but are not limited to) providing complete information and results from the following studies/activities:
- IPD effectiveness study
- IPD surveillance programme
- Studies in special populations, such as the Alaska Native population, pre-mature infants, bone-marrow transplant patients, HIV-infected patients, and patients with sickle cell disease
- Acute otitis media surveillance study
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
Priority Review Status was granted for the evaluation of Prevnar® 13 as it appeared to provide promising evidence of clinical efficacy for a serious, life-threatening, and severely debilitating disease that is not adequately managed by a drug marketed in Canada. IPD caused by Streptococcus pneumoniae is a major cause of morbidity and mortality worldwide, especially among children younger than 2 years, for whom the age-associated risk of disease is highest. Available data showed not only the prominence of serotype 19A as the leading cause of IPD in this age group, but also the importance of the other serotypes included in Prevnar® 13. The most important of the new serotypes added to the Prevnar® 13 vaccine are serotypes 19A, 6A, and 3, which caused 29.2%-40.9% of cases of paediatric IPD (depending on age and region) in Canada in 2007.
In line with the WHO recommendation, no clinical study has evaluated the clinical protection provided by Prevnar® 13 against IPD. However, immunogenicity results for Prevnar® 13 were provided in comparison with the licensed 7-valent Prevnar® vaccine. Non-inferiority (percentage of subjects with antibody concentrations >0.35 µg/mL by ELISA) was demonstrated for Prevnar® 13 for all 7 serotypes which are included in both vaccines, except for serotypes 6B and 9V. For the six additional serotypes in Prevnar® 13, the majority of vaccinees reached the required antibody threshold. In addition, Prevnar® 13 elicited functional antibodies to all vaccine serotypes as measured by OPA.
Prevnar® 13 (with the additional serotypes 1, 3, 5, 6A, 7F, and 19A) is expected to provide increased coverage of serotypes responsible for IPD.
However, the following observations were made:
- Results from the two pivotal studies (Studies 004 and 006) and from the post-hoc analysis of Study 3005 showed that Prevnar® 13 elicited generally lower antibody levels than 7-valent Prevnar® for both ELISA GMC and OPA GMT, after the infant series and after the toddler dose.
- Study 009 showed that the final formulation of Prevnar® 13 formulated with P80 elicited generally lower antibody levels than the formulation of Prevnar® 13 without P80 which was used in Studies 004 and 006.
The clinical relevance of these lower immune responses is unknown, but suggests the possibility of a higher rate of breakthrough of pneumococcal disease and shorter-term efficacy.
No clinical data were provided for high-risk populations, for example, Aboriginal and immune-compromised subjects. It remains to be demonstrated that Prevnar® 13 can provide optimal protection in these populations.
The submitted data suggest that Prevnar® 13 is generally well-tolerated. The safety profile of Prevnar® 13 is comparable to 7-valent Prevnar® and no significant safety issues were identified. Co-administration with eight paediatric vaccines was assessed. No negative interference in terms of immune response to these concomitant vaccine antigens and safety was observed.
The above limitations and potential risks will be addressed by the post-marketing commitments, and by providing clear guidance in the Product Monograph explaining the optimal use for better protection against IPD.
3.4.2 Recommendation
Based on the Health Canada review of data on quality, safety, and immunogenicity, Health Canada considers that the benefit/risk profile of Prevnar® 13 is favourable for active immunization of infants and children from 6 weeks through 5 years of age against Streptococcus pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F, causing invasive pneumococcal disease (including sepsis, meningitis, bacteraemic pneumonia, pleural empyema and bacteraemia). The 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.
4 Submission Milestones
Submission Milestones: Prevnar® 13
| Submission Milestone | Date |
|---|---|
| Pre-submission meetings: Control #117543, 125924 | 2008-01-31 - 2009-01-15 |
| Request for priority status | |
| Filed: | 2009-01-28 |
| Approval issued by Director, Centre for Biologics Evaluation: | 2009-02-25 |
| Submission filed: Control #12288 | 2009-03-18 |
| Screening | |
| Screening Acceptance Letter issued: | 2009-04-17 |
| Review | |
| On-Site Evaluation: | 2009-08-24 |
| On-Site Evaluation: | 2009-09-08 |
| Quality Evaluation complete: | 2009-12-17 |
| Clinical Evaluation complete: | 2009-12-16 |
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| PREVNAR 13 | 02335204 | PFIZER CANADA ULC | CORYNEBACTERIUM DIPHTHERIAE CRM-197 PROTEIN 34 MCG / 0.5 ML PNEUMOCOCCAL POLYSACCHARIDE SEROTYPE 1 2.2 MCG / 0.5 ML PNEUMOCOCCAL POLYSACCHARIDE SEROTYPE 14 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 23F 2.2 MCG / 0.5 ML PNEUMOCOCCAL POLYSACCHARIDE SEROTYPE 3 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 9V 2.2 MCG / 0.5 ML |