Summary Basis of Decision for Synflorix ™

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
SynflorixTM

Pneumococcal conjugate vaccine [Non-Typeable Haemophilus influenzae (NTHi) protein D, diphtheria or tetanus toxoid conjugates] adsorbed

GlaxoSmithKline Inc.

Submission control no: 119056

Date issued: 2009-06-16

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:

SynflorixTM

Manufacturer/sponsor:

GlaxoSmithKline Inc.

Medicinal ingredient:

  • Streptococcus (S.) pneumoniae polysaccharide from serotypes 1, 4, 5, 6B, 7F, 9V, 14 and 23F conjugated to Non-Typeable Haemophilus influenzae (NTHi) protein D (PD) carrier protein
  • S. pneumoniae polysaccharide from serotype 18C conjugated to tetanus toxoid (TT) carrier protein
  • S. pneumoniae polysaccharide from serotype 19F conjugated to diphtheria toxoid (DT) carrier protein

International non-proprietary Name:

Pneumococcal conjugate vaccine [Non-Typeable Haemophilus influenzae (NTHi) protein D, diphtheria or tetanus toxoid conjugates] adsorbed

Strength:

1 dose (0.5 mL) contains:
1 µg S. pneumoniae polysaccharide from serotype 11,
3 µg S. pneumoniae polysaccharide from serotype 41,
1 µg S. pneumoniae polysaccharide from serotype 51,
1 µg S. pneumoniae polysaccharide from serotype 6B1,
1 µg S. pneumoniae polysaccharide from serotype 7F1,
1 µg S. pneumoniae polysaccharide from serotype 9V1,
1 µg S. pneumoniae polysaccharide from serotype 141,
3 µg S. pneumoniae polysaccharide from serotype 18C2,
3 µg S. pneumoniae polysaccharide from serotype 19F3,
1 µg S. pneumoniae polysaccharide from serotype 23F1

Dosage form:

Suspension

Route of administration:

Intramuscular

Drug identification number(DIN):

  • 02320541

Therapeutic Classification:

Active Immunizing Agent

Non-medicinal ingredients:

Aluminium phosphate, sodium chloride, and water for injection

Submission type and control no:

New Drug Submission, Control Number: 119056

Date of Submission:

2007-12-19

Date of authorization:

2008-12-11
1 conjugated to protein D (derived from NTHi) carrier protein
2 conjugated to tetanus toxoid carrier protein
3 conjugated to diphtheria toxoid carrier protein
2 Notice of decision

On December 11, 2008, Health Canada issued a Notice of Compliance to GlaxoSmithKline Inc. for the vaccine product, SynflorixTM [pneumococcal conjugate vaccine (Non-Typeable Haemophilus influenzae (NTHi) protein D, diphtheria or tetanus toxoid conjugates) adsorbed].

SynflorixTM is an active immunizing agent, and contains many drug substances:

  • Pneumococcal polysaccharide serotypes 1, 4, 5, 6B, 7F, 9V, 14, and 23F conjugated to protein D (PD) carrier protein derived from NTHi;
  • Pneumococcal polysaccharide serotype 18C conjugated to tetanus toxoid (TT) carrier protein;
  • Pneumococcal polysaccharide serotype 19F conjugated to diphtheria toxoid (DT) carrier protein.

All drug substances are individually adsorbed onto aluminum phosphate.

SynflorixTM is indicated for active immunization of infants and children from 6 weeks up to 2 years of age against Streptococcus pneumoniae serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F and invasive disease caused by these serotypes (including sepsis, meningitis, bacteraemic pneumonia, pleural empyema and bacteraemia). Theoretically, the carrier proteins (PD, TT, and DT) provide T-cell help to B-cells to produce a boostable antibody response of high affinity to the polysaccharide antigens.

The market authorization was based on quality, non-clinical, and clinical information submitted. No clinical study evaluated the efficacy of SynflorixTM against invasive pneumococcal disease (IPD). Instead, the authorization was based on World Health Organization (WHO) recommendations stating that the approval of any new pneumococcal conjugate vaccine against IPD can be based on the demonstration of immunological non-inferiority to the licensed conjugate vaccine Prevnar® by measuring the total amount of anticapsular immunoglobulin G (IgG). The WHO also recommends demonstration of functionality of the vaccine-elicited antibodies by verifying their ability to opsonise and promote the killing of pneumococcus bacteria. Immunological non-inferiority of SynflorixTM to Prevnar® was demonstrated by enzyme-linked immunosorbent assay (ELISA) for all serotypes included in both vaccines, except for 6B and 23F. For serotypes 6B and 23F, respectively, 65.9% and 81.4% of the SynflorixTM vaccinees reached the non-inferiority threshold one month after the third primary dose (versus 79.0% and 94.1% for Prevnar®). The percentage of vaccinees reaching the threshold for the three additional serotypes (1, 5, and 7F) in SynflorixTM was respectively 97.3%, 99.0% and 99.5%. Additionally, SynflorixTM elicited functional antibodies to all vaccine serotypes as measured by an opsonophagocytic activity assay (OPA). Antibody persistence 8 to 12 months after the last primary dose was similar or higher in SynflorixTM vaccinees as compared to Prevnar® vaccinees for all serotypes, except serotype 14.

SynflorixTM is presented as a suspension for injection. SynflorixTM should be administered intramuscularly as separate 0.5 mL doses according to the schedule outlined in the dosing guidelines available in the Product Monograph.

SynflorixTM is contraindicated for patients who are hypersensitive to any of the components of the vaccine. SynflorixTM 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 SynflorixTM are described in the Product Monograph.

Based on the Health Canada review of data on quality, safety, and efficacy, Health Canada considers that the benefit/risk profile of SynflorixTM is favourable for active immunization of infants and children from 6 weeks up to 2 years of age against Streptococcus pneumoniae serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F, and invasive disease caused by these serotypes (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

SynflorixTM is a conjugate vaccine, adsorbed, and an active immunizing agent. It is composed of ten active ingredients: the Streptococcus (S.) pneumoniae polysaccharide serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F, each conjugated to a carrier protein (protein D, tetanus toxoid or diphtheria toxoid). SynflorixTM is indicated for the active immunization of infants and children from 6 weeks to 2 years of age against invasive disease caused by the S. pneumoniae serotypes mentioned above (including sepsis, meningitis, bacteraemic pneumonia, pleural empyema and bacteraemia).

S. pneumoniae is a primary cause of invasive pneumococcal disease (IPD), which manifests as bacteraemia, bacteraemic pneumonia, and meningitis. IPD is a severe illness that can result in significant morbidity and mortality, predominantly in children. The carrier proteins within SynflorixTM enhance protection by providing T-cell help to B-cells to produce a boostable antibody response to the S. pneumoniae polysaccharide antigens, thereby promoting defence against bacterial tract infections caused by S. pneumoniae.

Manufacturing Process and Process Controls

The individual polysaccharides, tetanus toxoid, and diphtheria toxoid are prepared from fermentation, inactivation, and purification of isolates. Protein D is a 40kD cell surface protein originally derived from Non-Typeable Haemophilus Influenzae (NTHi) and now produced by recombinant deoxyribonucleic acid (DNA) technology. Capsular polysaccharide from each S. pneumoniae serotype included in the vaccine is conjugated to one of the carrier proteins and adsorbed onto aluminium phosphate as a monovalent preparation prior to mixing into the final vaccine formulation.

The manufacturing process and the conjugation procedure for each of the ten conjugates were evaluated. The materials used in the manufacture of the drug substances are considered to be suitable for their intended use. Consecutive batches of each process manufactured intermediate were assessed according to pre-established specifications with satisfactory results. The manufacturing process is considered to be adequately controlled within justified limits.

Characterization

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

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

Control of Drug Substance

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

The proposed packaging components are considered acceptable.

Stability

Based upon the 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

SynflorixTM conjugate vaccine, adsorbed, is composed of ten active ingredients: the S. pneumoniae polysaccharide serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F, each conjugated to a carrier protein (PD, TT, or DT). It is a preservative-free liquid suspension, adjuvanted with aluminium phosphate. In addition, each vial of product contains the following excipients: sodium chloride and water for injection. The volume per nominal dose is 0.5 mL. SynflorixTM is supplied in the following presentations for intramuscular injection:

  • Monodose: 0.5 mL of suspension in a pre-filled syringe (type I glass) for one dose with a plunger stopper (rubber butyl) with or without needles – pack sizes of 1 or 10;
  • Monodose: 0.5 mL of suspension in a vial (type I glass) for one dose with a stopper (rubber butyl) – pack sizes of 1, 10 or 100;
  • Two-dose: 1 mL of suspension in a vial (type I glass) for two doses with a stopper (rubber butyl) – pack size of 100.

The storage conditions are 2 to 8°C for vials and syringes. A formulation overage is applied in order to guarantee an effective injectable dose of 0.5 mL (target fill volume for monodose presentation in syringes is 0.57 mL and for monodose presentation in vials is 0.65 mL; target fill volume for two-dose presentation in vials is 1.18 mL).

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

Information was provided to describe the rationale for the selection of the serotypes included in the vaccine as well as for the choice of the different carrier proteins and the serotype dosages. Pre-clinical and clinical data were also provided to demonstrate the need for the vaccine to be adjuvanted.

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

Pharmaceutical development data, including development of the container closure system, are considered acceptable. Data provided include the composition of SynflorixTM, the rationale for the choice of formulation, the manufacturing process (including packaging), information on the batches used in in vitro studies for characterization, and discussion on the effect of formulation change on the safety and/or efficacy of SynflorixTM. Studies that justified the type and proposed concentration of excipients for use in the drug product were also reviewed and are considered to be acceptable.

Manufacturing Process and Process Controls

The final bulk is formulated, mixed, aseptically filled into glass vials or glass syringes, closured with rubber stoppers, labelled and packaged using conventional pharmaceutical equipment and facilities.

All manufacturing equipment, in-process manufacturing steps, and detailed operating parameters were adequately described in the submitted documentation and are found to be acceptable. The manufacturing process is considered to be adequately controlled within justified limits.

Control of Final Product

SynflorixTM is tested to verify that its identity, pH, sterility, endotoxin content, fill volume, protein and polysaccharide content, levels of degradation products, drug-related impurities, bacterial endotoxins, and microbiological impurities are within acceptance criteria. To ensure quality, tests are conducted to measure the free polysaccharide content in the supernatant of the adsorbed monobulks as well as the completeness of adsorption (% unbound conjugate in supernatant of adsorbed monobulks).

The test specifications and analytical methods are considered acceptable; the shelf-life and the release limits for individual and total degradation products are within acceptable limits.

Data from final batch analyses were reviewed and are considered to be acceptable according to the specifications of the drug product. Through Health Canada’s lot release testing and evaluation program, consecutively manufactured final product lots were tested, evaluated, and found to meet the specifications of the drug product and demonstrate consistency in manufacturing.

Stability

Based on the real-time, long-term, and accelerated stability data submitted, the proposed 36-month shelf-life at 2 to 8°C for SynflorixTM is considered acceptable.

In addition, a transport test was conducted to assess a potential cold chain break during transportation. All lots met the specifications and there was no major impact of the cold chain interruption.

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 of the facilities involved in the manufacture and testing of SynflorixTM was successfully conducted by the Biologics and Genetic Therapies Directorate, Health Canada. The design, operations and controls of the facility and equipment that are involved in the production of SynflorixTM are considered suitable for the activities and products manufactured.

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 quality information submitted was approved and a request for several post-approval commitments was made.

The Chemistry and Manufacturing information submitted for SynflorixTM 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

3.2.1 Immunogenicity

Several 11-valent related Phase II formulations were developed that contained the same serotypes as SynflorixTM in addition to serotype 3. The vaccines also differed in carrier protein. Primary pharmacodynamic studies demonstrated that the 10-valent vaccine SynflorixTM and a similar 11-valent vaccine were immunogenic in mice and guinea pigs. Immunology studies in rabbits were also performed using one of the 11-valent Phase II vaccines.

In all animal species tested, the vaccines induced polysaccharide-specific immunoglobulin G (IgG) to all serotypes contained in the vaccine. Additionally, the sera of immunized mice and guinea pigs had functional (opsonophagocytic) activity in vitro against several test serotypes. The intramuscular injection route of administration was used to evaluate immunogenicity in animals. Serum antibody levels to each of the serotypes were analysed using an enzyme-linked immunosorbent assay (ELISA).

Two immunogenicity studies in mice demonstrated the enhancing effect of the adjuvant (aluminium phosphate) on the antibody response for most of the serotypes.

Non-clinical studies were also conducted to assess the effect of protein D, the carrier protein from Haemophilus influenzae. A juvenile chinchilla otitis media model was used to demonstrate that passive inoculation with the sera of children administered SynflorixTM or the 11-valent vaccine conferred protection against otitis media caused by NTHi. The passively transferred sera provided approximately 34% protection against otitis media, and there were no significant differences between the two vaccines.

3.2.2 Toxicology

No toxicology studies have been performed with the final formulation of SynflorixTM; however, toxicology studies were performed with the similar 11-valent formulated vaccines. From a toxicological standpoint, the 11-valent formulations can be considered to be representative of SynflorixTM as they contain higher amounts of antigen, carrier proteins, or residues than SynflorixTM. Results show that the 11-valent formulations were well tolerated and that there was no evidence of toxicity other than injection site reactions which were reversible over time.

Acute and Repeat-dose Toxicity

Acute and repeat-dose toxicity studies were conducted in rabbits. A full human dose of several 11-valent vaccines showed no systemic toxicity or target organ toxicity, providing overall evidence that the vaccine was safe and well tolerated in the studied animal species.

Reproductive and Developmental Toxicity

No studies on reproductive or developmental toxicity have been performed. This vaccine is not intended for women of child-bearing potential.

Carcinogenicity and Mutagenicity

Carcinogenicity and mutagenicity studies are normally not necessary for vaccines.

A series of studies was conducted to evaluate the toxicity, mutagenicity, and sensitization potential of a by-product produced from the conjugation of the polysaccharide serotypes to their respective carrier proteins. Based on the results of these studies, the residual amounts of process-specific impurities are considered to be of no toxicological concern.

Local Tolerance

Local tolerance was assessed by intramuscular injection administration in rabbits. Microscopic examination of vaccine-treated animals showed characteristics of a compact local inflammatory process. The inflammatory response was found to be comparable to that observed in other toxicity studies conducted with other aluminium-based adjuvants. Data from repeat-dose toxicity studies indicated that the local inflammatory reaction was reversible over time with no observed necrosis.

3.2.3 Summary and Conclusion

The vaccine formulations used in the toxicology studies were immunogenic, well tolerated and without evidence of toxicity, with the exception of injection site reactions that were reversible over time. The toxicity studies conducted with the comparable 11-valent formulated vaccines are considered to be representative of SynflorixTM. There were no special safety concerns identified in the non-clinical studies.

3.3 Clinical basis for decision

SynflorixTM is indicated for the active immunization of infants and children from 6 weeks up to 2 years of age against S. pneumoniae serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F, and 23F, and invasive disease caused by these serotypes.

The immunologic potential of SynflorixTM was assessed through the analysis of immunogenicity and are 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) stating that the approval of any new pneumococcal conjugate vaccine against IPD can be based on the demonstration of immunological non-inferiority to the licensed conjugate vaccine Prevnar®. This is assessed by measuring the total amount of anticapsular IgG with an ELISA. According to these recommendations, the primary endpoint for demonstration of immunological non-inferiority is the percentage of subjects reaching a predetermined antibody threshold one month after three primary doses of the pneumococcal conjugate vaccine. As serotype specific thresholds were not identified, the WHO recommended the use of a single antibody threshold for all serotypes. This threshold was derived from a pooled analysis of three efficacy trials conducted with pneumococcal conjugate vaccines. Based on the results of the second generation ELISA available at that time, the WHO recommended using the percentage of subjects with an antibody concentration ≥0.35 µg/mL as a primary endpoint for the demonstration of non-inferiority to Prevnar®.

To increase specificity, third generation ELISAs were developed. These ELISAs include a pre-adsorption step with pneumococcal type 22F polysaccharide and the use of purified capsular polysaccharide for coating to improve the specificity of the pneumococcal-polysaccharide ELISA. The WHO recommendations state that third generation ELISAs must be bridged to second generation ELISAs. In bridging experiments carried out by the sponsor, an antibody concentration of 0.2 µg/mL in the third generation ELISA was shown to be equivalent to the 0.35 µg/mL WHO reference threshold. Therefore, the 0.2 µg/mL threshold was used for the demonstration of immunological non-inferiority as compared to Prevnar® in a head-to-head comparative study.

Also in line with WHO recommendations, the clinical program involved verification of the functionality of the elicited antibodies. Opsonophagocytosis (antibody mediated killing of bacteria) is recognized as the main mechanism of protection against pneumococcal disease. This is tested in vitro using an opsonophagocytosis activity assay (OPA) that is capable of measuring the ability of the vaccine-elicited antibodies to opsonize and promote the killing of pneumococcus bacteria. Furthermore, demonstration that the vaccine induces immune memory was 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 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

There were no clinical protection data provided to support the indication of SynflorixTM for IPD; only immunological data were provided for SynflorixTM in comparison with the licensed vaccine Prevnar®. This is in keeping with WHO recommendations for the approval of new pneumococcal conjugate vaccines as outlined above.

The clinical program for the authorization of SynflorixTM was extensive, involving 11 clinical studies. These included support from 7 completed primary vaccination studies (number [n] = 3545), 5 completed booster studies (n = 2086), and 1 catch-up study (n = 450). Some of the booster studies were extensions of the primary vaccination studies. Inclusion criteria for subjects in these studies consisted of being born following a gestation period of 36 to 42 weeks with freedom of obvious health problems as established by medical history and clinical examination. The studies included various primary vaccination schedules including 2-3-4, 2-4-6, and 3-4-5 months of age with some including a booster dose. In addition, for the study conducted in catch-up vaccination groups, the dosing schedules for infants and toddlers were as follows: subjects 7 to 11 months of age received 2 doses of SynflorixTM at an interval of 4 weeks, followed by a third dose in their second year of life and subjects 12 to 23 months of age received 2 doses of SynflorixTM at an interval of 8 weeks.

Immunogenicity

In a pivotal, randomized, controlled, multi-centric study conducted in Europe, 1235 infants were vaccinated with SynflorixTM and 415 were vaccinated with Prevnar®. The subjects were vaccinated according to a 2-3-4 months of age vaccination schedule. The co-primary objectives were as follows:

  • To demonstrate lot-to-lot consistency of three consecutive lots of SynflorixTM in terms of the immune response induced against each of the ten pneumococcal serotypes and the carrier protein, protein D.
  • To demonstrate that SynflorixTM, when administered as a three-dose primary vaccination course is non-inferior to Prevnar® for the immune response against at least seven of the pneumococcal serotypes included in the vaccine.

Several secondary objectives for the pivotal study were also outlined including the demonstration that SynflorixTM, when co-administered with a diphtheria-tetanus-acellular pertussis (DTPa)-combined vaccine as a three-dose primary vaccination course is non-inferior to Prevnar®. The immunogenicity of the DTPa-combined vaccine was also analysed to determine if it was altered when co-administered with SynflorixTM.

The first co-primary objective of lot-to-lot consistency was met.

The second co-primary objective of the demonstration of immunological non-inferiority of SynflorixTM to Prevnar® was assessed one month following the third primary dose of each vaccine. For the seven serotypes common to both vaccines, SynflorixTM generally induced lower immune responses than Prevnar® in terms of GMCs. Nevertheless, the co-primary objective was considered to be met as the upper limits of the 96.5% confidence intervals (CIs) for the difference between the groups (Prevnar® minus SynflorixTM or the aggregate response minus SynflorixTM) in terms of the percentage of subjects with pneumococcal antibody concentrations ≥0.2 µg/mL were below the pre-defined limit for non-inferiority of 10% for eight serotypes (1, 4, 5, 7F, 9V, 14, 18C, and 19F). Non-inferiority was not reached for serotypes 6B and 23F; the upper limit of the 96.5% CIs for the difference between the groups was 18.3% for serotype 6B and 16.1% for serotype 23F.

Further to the immunogenicity data for SynflorixTM, the functionality of the antibodies elicited by the vaccine was also tested. SynflorixTM stimulated the production of functional antibodies to all vaccine serotypes. One month following the third primary dose, the OPA GMTs were lower (no overlap of the CIs) for serotypes 4, 6B, 14, 18C, and 23F, and higher for serotype 19F, in the SynflorixTM group compared to those in the Prevnar® group. However, the observed difference between groups (Prevnar® minus SynflorixTM) in terms of the percentage of subjects with opsonophagocytic activity ≥8 was below 5% for all pneumococcal serotypes common to both vaccines. The degree of opsonophagocytic activity for antibodies to serotypes 1 and 5 was lower than the responses to other serotypes, especially after the primary course. This suggests that lower efficacy for these serotypes may exist prior to the booster dose which induces an anamnestic response. The clinical relevance of this observation is unknown as in studied populations, the vast majority of serotype 1 and 5 IPD cases occur after one year of age.

A further pivotal study was conducted to assess the immunogenicity of SynflorixTM as compared to Prevnar® when given as a fourth (booster) dose between the ages of 12 to18 months in children who were previously vaccinated with SynflorixTM or Prevnar® as infants in the pivotal study described above. The administration of a booster of SynflorixTM elicited an anamnestic antibody response as measured by ELISA and OPA for the ten serotypes included in the vaccine. With the exception of serotype 19F, the magnitude of the ELISA antibody GMCs and OPA GMTs post-booster of SynflorixTM was lower in SynflorixTM-primed subjects than in Prevnar®-primed subjects for the remaining common serotypes.

Throughout the studies conducted, SynflorixTM was evaluated in three-dose primary vaccination schedules of 2-3-4, 3-4-5, and 2-4-6 months of age. Overall, the immunogenicity of SynflorixTM was comparable across the three-dose schedules; however, it appears that the highest antibody concentrations were measured for all serotypes in studies using the 2-4-6 months of age schedule. The immune persistence results (before a booster dose at 11 and 18 months of age) were generally similar between SynflorixTM and Prevnar® groups for all serotypes.

The co-administration of SynflorixTM with other common paediatric vaccines (Meningitec®, NeisVac-C®, InfanrixTM-hexa, RotarixTM, and Priorix®-tetra) was assessed and did not result in significant negative interference in terms of immune response.

Pneumococcal Otitis Media Efficacy Trial (POET)

Efficacy data was also submitted from a study [Pneumococcal Otitis Media Efficacy Trial (POET)] conducted with a related 11-valent pneumococcal vaccine. Data from the POET study was the only clinical protection data submitted to support the authorization of SynflorixTM. Results of the study show that a related 11-valent vaccine is effective for the prevention of acute otitis media (AOM) episodes caused by the vaccine pneumococcal serotypes, especially serotypes 6B and 23F. This suggests that the vaccine produces a functioning immune response. These results provide indirect but valuable data for the potential efficacy of SynflorixTM for IPD, especially taking into account the many uncertainties in considering only immune correlates. The sponsor did not apply for an indication for Acute Otitis Media.

3.3.2 Clinical Safety

The 11 clinical studies introduced in section 3.3.2 Clinical Efficacy, were also used to evaluate the safety of SynflorixTM. In addition, safety results from studies with the 11-valent formulations (n >4000) were submitted as supportive evidence for the safety profile of SynflorixTM.

In one of the pivotal studies, safety and reactogenicity were evaluated by examining subjects for:

  • Occurrence of fever with rectal temperature >39.0°C, within 4 days after at least one vaccination;
  • Occurrence of solicited local or general adverse events (AEs) within 4 days after each vaccination;
  • Occurrence of unsolicited AEs within 31 days after each vaccination;
  • Occurrence of serious adverse events (SAEs) throughout the whole study period.

Throughout the study, no specific safety concerns were identified. The observed incidence of solicited and unsolicited AEs was similar for SynflorixTM and Prevnar®. The most common adverse reactions after primary vaccination were redness at the injection site and irritability which occurred after all doses. The majority of these reactions were of mild to moderate severity and were not long lasting.

In the booster study, the observed incidence of solicited and unsolicited (local and general) AEs was within the same range in all three groups (subjects who were primed with SynflorixTM and boosted with SynflorixTM or subjects who were primed with Prevnar® and boosted with Prevnar® or SynflorixTM). The observed incidence of injection site reactions was higher after the booster vaccination with SynflorixTM than after a primary vaccine dose, but remained within the same range as those reported at the DTPa-based booster injection site. Prior to administration of the booster dose, follow-up was conducted at 8 to 14 months after completion of the primary doses. At this time, no SAEs were assessed by investigators to be causally related to vaccination. The data from the booster study did not identify any safety concerns after the booster dose of SynflorixTM, as compared with Prevnar®.

No increase in the incidence or severity of the AEs was seen with subsequent doses of the primary vaccination series. An increase in reactogenicity was reported after booster vaccination compared to doses of the primary course for SynflorixTM. The incidence of solicited local and general AEs reported within 4 days after each vaccination dose of SynflorixTM was within the same range as after vaccination with Prevnar®.

In primary vaccination studies, two (out of 4,145) SynflorixTM vaccinees (receiving 12,137 doses) experienced SAEs with a fatal outcome. These SAEs included one case of sudden infant death syndrome (SIDS) and one case of brain neoplasm. One (out of 1,072) Prevnar® vaccinees died due to muscular atrophy. None of the fatal serious cases were assessed by the investigator as causally related to vaccination. No fatal AEs were reported in the completed booster and catch-up immunization studies.

Five of the 4,145 subjects (0.1%) receiving primary vaccination with SynflorixTM and two of the 1,072 Prevnar® vaccinees (0.2%) experienced an SAE that was assessed by the investigator as causally related to vaccination. In booster studies, four of 3,725 subjects (0.1%) receiving a booster dose of SynflorixTM and none of the 449 Prevnar® vaccinees reported an SAE that was assessed by the investigator as causally related to vaccination. In most cases, SynflorixTM was co-administered with a DTPa-based combined vaccine, therefore, it is difficult to determine if the SAEs were related to SynflorixTM. The SAEs reported that were considered to be causally related to vaccinations (including SynflorixTM) included: crying/anxiety, fever, swelling, and febrile convulsions. One case of nephrotic syndrome was also reported.

SynflorixTM should not be administered to subjects with known hypersensitivity to any component of the vaccine. As with other vaccines, the administration of SynflorixTM should be postponed in subjects suffering from acute severe febrile illness. However, the presence of a minor infection, such as a cold, should not result in the deferral of vaccination.

The potential risk of apnea and the need for respiratory monitoring for 48 to 72 hours should be considered when administering the primary immunization series to very premature infants (born ≤28 weeks of gestation) and particularly for those with a previous history of respiratory immaturity. As the benefit of vaccination is high in this group of infants, vaccination should not be withheld or delayed.

Co-administration of SynflorixTM with monovalent or combination paediatric vaccines was assessed and did not result in significant negative interference in terms of safety.

Overall, the submitted safety data suggest that SynflorixTM is generally well tolerated. The safety profile of SynflorixTM was comparable to Prevnar® with no new significant safety issues. The total number of subjects who received SynflorixTM was relatively small; therefore, conformation of the acceptable safety profile of SynflorixTM is expected from large post-marketing clinical studies.

3.3.3 Additional Issues

As part of the marketing authorization for SynflorixTM, 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 Canadian Aboriginal population, pre-term infants, and HIV-infected children.

3.4 Benefit/Risk Assessment and Recommendation

3.4.1 Benefit/Risk Assessment

In line with the WHO recommendation, no clinical study has specifically evaluated the clinical protection provided by SynflorixTM vaccine against Invasive Pneumococcal Disease. However, SynflorixTM was shown to induce immune responses to all ten serotypes. Compared to the licensed 7-valent vaccine (Prevnar®), non-inferiority was demonstrated for all serotypes common to both vaccines, with the exception of serotypes 6B and 23F. For the three novel serotypes contained in SynflorixTM, the majority of vaccinees also reached the required antibody threshold. In addition, SynflorixTM elicited functional antibodies to all vaccine serotypes as measured by OPA. Boostability of the ELISA and OPA responses confirmed priming of the immune system against all vaccine serotypes. Adequate priming of the immune system by SynflorixTM was confirmed by the administration of a plain polysaccharide vaccine booster in the second year of life.

In order to estimate the overall impact of vaccination with SynflorixTM on IPD in the absence of IPD efficacy data with the vaccine, an estimate of the overall impact of SynflorixTM was developed by the sponsor. The estimate took into account the serotype-specific effectiveness values for Prevnar®, the distribution of serotypes causing IPD in individual countries, and serotype-specific immunological differences between SynflorixTM and Prevnar® observed in direct comparative studies. Based on these estimates, the impact of SynflorixTM vaccine on overall IPD is anticipated to be similar to that of Prevnar® (for example (e.g.), in Canada), or somewhat better (e.g. in countries that reported more IPD due to serotypes 1, 5, and 7F). SynflorixTM is expected to provide increased coverage of the serotypes responsible for IPD.

In terms of risks, SynflorixTM is generally less immunogenic than Prevnar®, especially for serotypes 6B and 23F. Secondly, the OPA results for two of the three new serotypes included in SynflorixTM were low (serotypes 1 and 5). Furthermore, the immune response elicited against 6B and 23F after the two-dose catch-up schedule in children aged 12 to 23 months is comparable to the response elicited after three doses in infants. In contrast to infants, however, the need for a booster dose after two doses in children aged 12 to 23 months has not been established. The clinical relevance of 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 (e.g. Natives and immune-compromised subjects). The potential exists that SynflorixTM cannot provide optimal protection in these populations.

The submitted data suggest that SynflorixTM is generally well tolerated and that its safety profile is comparable to Prevnar® with no new significant safety issues identified. The co-administration of SynflorixTM with monovalent or combination paediatric vaccines was assessed and did not result in significant negative interference in terms of immune response and safety.

The limitations and potential risks described above have been addressed by post-marketing commitments and by the production of accurate study results and guidance explaining optimal use for better protection in the Product Monograph.

3.4.2 Recommendation

Based on the Health Canada review of data on quality, safety and efficacy, Health Canada considers that the benefit/risk profile of SynflorixTM is favourable for the active immunization of infants and children from 6 weeks up to 2 years of age against Streptococcus pneumoniae serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F and invasive disease caused by these serotypes (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: SynflorixTM

Submission MilestoneDate
Pre-submission meeting:2007-04-12
Submission filed:2007-12-19
Screening
Submission received in Regulatory Affairs Division (RAD):2008-01-04
Screening Acceptance Letter issued:2008-02-15
Review
On-Site Evaluation (Belgium):2008-10-24
On-Site Evaluation (Hungary):2008-11-14
Quality Evaluation complete:2008-12-10
Clinical Evaluation complete:2008-12-10
Labelling Review complete:2008-12-10
Notice of Compliance issued by Director General:2008-12-11

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