Summary Basis of Decision for Supemtek

Review decision

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


Product type:

Drug

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

Recent Activity for Supemtek

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.

The following table describes post-authorization activity for Supemtek, a product which contains the medicinal ingredients recombinant haemagglutinin protein strains A (H1N1), A (H3N2), B (Victoria), and B (Yamagata). For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the list of abbreviations that are found in PAATs.

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

Updated: 2023-08-25

Drug Identification Number (DIN):

DIN 02510936 – solution for intramuscular administration

Each 0.5‑mL dose contains:

  • Recombinant Haemagglutinin Protein – Strain A (H1N1) – 45 mcg
  • Recombinant Haemagglutinin Protein – Strain A (H3N2) – 45 mcg
  • Recombinant Haemagglutinin Protein – Strain B (Victoria) – 45 mcg
  • Recombinant Haemagglutinin Protein – Strain B (Yamagata) – 45 mcg

Post-Authorization Activity Table (PAAT)

Activity/submission type, control number Date submitted Decision and date Summary of activities
NC # 272984 2023-03-02 Issued NOL 2023-06-02 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes to the drug product manufacturing process. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 272239 2023-02-08 Issued NOL 2023-05-16 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to change a drug substance manufacturing facility from single-product to multi-product. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 274900 2023-05-01 Issued NOL 2023-05-09 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to update the PM and mock-up labels for the annual 2023-2024 influenza strain update. The submission was considered acceptable, and an NOL was issued.
NC # 272077 2023-02-02 Issued NOL 2023-05-04 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for the addition of a new Working Cell Bank. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 271501 2023-01-17 Issued NOL 2023-04-24 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for an alternative drug substance quality control test site, and changes to drug substance testing method and stability protocols. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 268883 2022-10-20 Issued NOC 2023-04-05 Submission filed as a Level I – Supplement to update the inner and outer labels and package insert. The submission was reviewed and considered acceptable, and an NOC was issued.
Drug product (DIN 02510936) market notification Not applicable Date of first sale: 2022-10-03 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
SNDS # 266531 2022-07-28 Issued NOC 2022-09-26 Submission filed as a Level I – Supplement to implement the 2022-2023 viral strains. The submission was reviewed and considered acceptable, and an NOC was issued.
NC # 264278 2022-05-13 Issued NOL 2022-09-02 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to transfer the quality control testing activities to a new facility. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 259885 2022-01-06 Issued NOC 2022-07-25 Submission filed as a Level I – Supplement for the addition of a drug product manufacturing facility. The submission was reviewed and considered acceptable, and an NOC was issued.
NC # 264411 2022-05-19 Issued NOL 2022-07-15 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to change a drug substance manufacturing facility from single-product to multi-product. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 263892 2022-04-29 Issued NOL 2022-05-10 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to update the PM and mock-up labels for the 2022-2023 influenza strain update. The submission was considered acceptable, and an NOL was issued.
SNDS # 258111 2021-10-29 Issued NOC 2022-04-19 Submission filed as a Level I – Supplement for labelling updates to the PM (Part III: Consumer Information) and to migrate the PM to the 2020 format. The submission was reviewed and considered acceptable, and an NOC was issued.
NDS # 235672 2020-01-31 Issued NOC 2021-01-14 NOC issued for New Drug Submission.
Summary Basis of Decision (SBD) for Supemtek

Date SBD issued: 2021-05-07

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

Quadrivalent Recombinant Influenza Vaccine (recombinant haemagglutinin protein strains A [H1N1], A [H3N2], B [Victoria], and B [Yamagata])

Drug Identification Number (DIN):

  • DIN 02510936 - 45 µg each of recombinant haemagglutinin protein strains A (H1N1), A (H3N2), B (Victoria), and B (Yamagata), solution for intramuscular administration

Sanofi Pasteur Ltd.

New Drug Submission Control Number: 235672

 

On January 14, 2021, Health Canada issued a Notice of Compliance to Sanofi Pasteur Limited for the vaccine Supemtek.

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 Supemtek is favourable for active immunization for the prevention of influenza disease caused by influenza A subtype viruses and type B virus lineages contained in the vaccine. Supemtek is approved for use in persons 18 years of age and older.

 

1 What was approved?

 

Supemtek, an active immunizing agent, was authorized for active immunization for the prevention of influenza disease caused by influenza A subtype viruses and type B virus lineages contained in the vaccine. Supemtek is approved for use in persons 18 years of age and older.

No data are available at this time to authorize an indication for pediatric use. Based on the data reviewed by Health Canada, the safety and immunogenicity of Supemtek in geriatric patients (≥50 years of age) has been established; therefore, Health Canada has authorized an indication for geriatric use.

Supemtek is contraindicated for patients who are hypersensitive to this vaccine or to any component of the vaccine.

Supemtek was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Supemtek (quadrivalent recombinant influenza vaccine) is presented as a solution for intramuscular injection. It contains four medicinal ingredients: recombinant haemagglutinin protein strains A (H1N1), A (H3N2), B (Victoria), and B (Yamagata). In addition to the medicinal ingredients, the solution contains sodium chloride, monobasic sodium phosphate, dibasic sodium phosphate and polysorbate 20. Supemtek does not contain adjuvant, egg proteins, antibiotics, or preservatives; there is no gelatin added as a stabilizer in Supemtek.

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

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

 

2 Why was Supemtek approved?

 

Health Canada considers that the benefit-risk profile of Supemtek is favourable for active immunization for the prevention of influenza disease caused by influenza A subtype viruses and type B virus lineages contained in the vaccine. Supemtek is approved for use in persons 18 years of age and older.

Influenza is a highly infectious, contagious, acute viral respiratory disease that tends to spread rapidly in seasonal epidemics. The overall burden of influenza in terms of morbidity and mortality is high with the heaviest impact in older adults, as well as in young children and in individuals with underlying compromising conditions. Vaccination is the most effective measure to prevent influenza and to reduce the impact of disease burden.

A variety of influenza vaccines are available for the prevention of seasonal influenza disease, including inactivated vaccines produced by inactivating and purifying influenza virus grown in eggs or mammalian Madin-Darby Canine Kidney (MDCK) cells. Most of these products are split or subunit vaccines containing 15 µg of haemagglutinin (HA) per antigen and are available in either trivalent or quadrivalent formulations. Supemtek is the first recombinant influenza vaccine available in Canada.

Supemtek has been shown to be efficacious for the prevention of influenza disease caused by the influenza A subtype viruses and type B virus lineages contained in the vaccine. The market authorization was primarily based on the results of three studies: Study PSC12 (conducted in subjects ≥50 years of age) and Studies PSC16 and PSC04 (conducted in subjects 18 to 49 years of age). Study PSC04 was conducted with the trivalent recombinant vaccine (RIV3) but is considered relevant as both vaccines are manufactured using the same process and have overlapping compositions.

Study PSC12 was a Phase III, randomized, observer-blind, active-controlled, multicentre study conducted to evaluate the efficacy, immunogenicity, and safety of Supemtek (quadrivalent recombinant vaccine [RIV4]) in older, medically-stable adults (≥50 years of age with a mean age of 62.5 years). The pre-specified primary objective was met as Supemtek demonstrated non-inferiority relative to another influenza vaccine (Fluarix Tetra - IIV4) in protecting against reverse transcription polymerase chain reaction (RT-PCR)‑confirmed protocol-defined influenza-like illness. The relative vaccine efficacy (rVE) of Supemtek over IIV4 against RT-PCR-positive influenza was 30% (95% confidence interval [CI]: 10, 47%). Supemtek also met the rVE criterion for non-inferiority for several exploratory analyses.

Studies PSC16 and PSC04 were submitted to support the indication for subjects 18 to 49 years of age. In Study PSC16, Supemtek demonstrated non-inferior immunogenicity as compared to IIV4 against 3 of the 4 antigens present in the vaccine. Non-inferior immunogenicity against the B/Victoria antigen was not demonstrated, and may be partly due to antigenic differences between the B/Victoria recombinant HA and the egg-grown B/Victoria antigen used in the haemagglutination inhibition assay. In addition, Study PSC04 provided efficacy data for RIV3, and support the use of Supemtek in adults 18 to 49 years of age.

Safety data were provided from two studies (PSC12 and PSC16). Study PSC16 provided data from 1,330 subjects aged 18 to 49 years, of whom 998 received Supemtek. Study PSC12 provided data from 8,672 subjects ≥50 years of age, of whom 4,328 received Supemtek. In total, 5,326 subjects received a single dose of Supemtek. To evaluate safety, both studies collected solicited local and systemic adverse events (AEs) for 7 days, unsolicited adverse events for 28 days, and both serious adverse events and medically attended adverse events for 6 months post-vaccination.

In both Study PSC12 and Study PSC16, the local and systemic reactions recorded for both vaccines are not unexpected for influenza vaccines in terms of nature, frequency and severity. The reactogenicity and AE rates were generally comparable between Supemtek and IIV4 groups. The most frequently reported solicited local AEs in Supemtek recipients were tenderness, followed by local pain. The most frequently reported solicited systemic AEs in Supemtek recipients were headache, fatigue, and joint and muscle pain. There were no serious adverse events considered to be causally related to Supemtek. Overall, the rates of unsolicited AEs and medically attended adverse events were similar between the two groups in both studies. In addition, safety data from studies with RIV3 and post-market experiences with RIV3 and Supemtek did not identify special safety concerns.

A Risk Management Plan (RMP) for Supemtek was submitted by Sanofi Pasteur Limited to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product. The sponsor agreed to several commitments to be addressed post-market. Commitments include (but are not limited to) providing special analyses regarding anaphylactic reactions/hypersensitivity, pericarditis, Guillain-Barré Syndrome, neuritis, convulsion, encephalomyelitis/transverse myelitis, thrombocytopenia, syncope and vasculitis as Adverse Events of Special Interest (AESI) in clinical studies.

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

A Look‑alike Sound‑alike brand name assessment was performed and the proposed name Supemtek was accepted.

Overall, the benefits of Supemtek seen in the pivotal studies are similar to the comparator and are considered to outweigh the potential risks. Supemtek has an acceptable safety profile based on the non-clinical data and clinical studies. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Supemtek Product Monograph to address the identified safety concerns.

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

 

3 What steps led to the approval of Supemtek?

 

Submission Milestones: Supemtek

Submission Milestone Date
Pre-submission meeting 2019-12-06
Screening  
Screening Acceptance Letter issued 2020-03-20
Review  
Review of Risk Management Plan complete 2020-11-25
Quality Evaluation complete 2021-01-13
Clinical/Medical Evaluation complete 2021-01-13
Biostatistics Evaluation complete 2021-01-13
Labelling Review complete 2021-01-13
Notice of Compliance issued by Director General, Biologics and Genetic Therapies Directorate 2021-01-14

 

The Canadian regulatory decision on the quality, non-clinical, and clinical review of Supemtek was based on a critical assessment of the data package submitted to Health Canada. The foreign reviews completed by the European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) were used as added references.

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

 

4 What follow-up measures will the company take?

 

Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations.

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

  • Anaphylactic reactions/hypersensitivity, pericarditis, Guillain-Barré Syndrome, neuritis, convulsion, encephalomyelitis/transverse myelitis, thrombocytopenia, syncope and vasculitis are included as Adverse Events of Special Interest (AESI) in the ongoing Phase IV Study VAP00003. One case of pericarditis was reported in one clinical study in a patient treated with RIV3 and the other events are recognized Adverse Events Following Immunization (AEFIs). Therefore, it is recommended that special analyses of these events be presented in Periodic Benefit‑Risk Evaluation Reports.

 

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

 

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

AnchorThe PAAT for Supemtek is found above.

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

 

6 What other information is available about drugs?

 

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

 

7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical Basis for Decision

 

Clinical Pharmacology

Annual influenza vaccination is recommended as the circulating strains of influenza virus change from year to year and immunity declines in the year following vaccination.

Supemtek is a quadrivalent recombinant influenza vaccine (RIV4) that contains recombinant haemagglutinin (HA) proteins of the four strains of influenza virus specified by health authorities for inclusion in the annual seasonal vaccine. These proteins function as antigens which induce a humoral immune response, measured by haemagglutination inhibition (HI) antibodies, known to protect against influenza infection. Using the recombinant production technology, the HA proteins in Supemtek have identical primary structures to the HA in the wild type virus strains selected for seasonal vaccines.

As is customary for vaccines, conventional pharmacology studies were not performed with Supemtek. Dose selection was based on pharmacodynamics determined by the measured humoral immune response. The immunogenicity of recombinant haemagglutinin (rHA) vaccine products was evaluated in a number of Phase I and II clinical studies, including mono- and bivalent rHA formulations. Immunogenicity was predominantly measured utilizing assays of HI antibody titers and, in some studies, neutralizing antibody titers and immunoglobulin G antibody titers. The doses of rHA evaluated in the early trials were multiples of 15 µg in order to compare with licensed influenza vaccines.

Two Phase II clinical trials were conducted to establish the optimal dose of rHA in comparison to licensed, egg-grown, inactivated influenza vaccine. The first trial was conducted in adults 65 years of age and older, due to the recognized medical need for influenza vaccines with improved efficacy in this age group. This trial evaluated rHA doses of 15 µg, 45 µg, and 135 µg of each antigen compared with trivalent inactivated vaccine (IIV3). Immunogenicity was determined by geometric mean HI titers to each antigen before and approximately 28 days following a single injection. In the second dose‑finding, placebo-controlled study in adults 18 to 49 years of age, doses of 15 and 45 µg rHA for influenza A/H1 and influenza B were evaluated because a dose-response relationship for these antigens had not been apparent in the earlier study. For the influenza A/H3 antigen, the dose of 45 µg was used as it had been established as the optimal dose in the earlier study.

Both studies yielded HI immunogenicity data that were published in peer-reviewed journals and, together with other early phase studies of rHA, served to identify the rHA dose level of 45 µg per antigen that was developed in the original trivalent formulation of RIV3. No additional dose-finding work was performed for Supemtek, as the 45 µg dose had been established as safe and effective for RIV3.

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

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

Clinical Efficacy

The clinical efficacy of Supemtek (RIV4) was supported by the results of three studies conducted in subjects 18 years of age and older in the United States:

  • Study PSC12 was designed with the primary objective of demonstrating that Supemtek conferred efficacy that was non-inferior to that provided by the comparator (Fluarix Tetra [IIV4]) in adults ≥50 years of age.
  • Study PSC16 was designed with the primary objective of demonstrating that Supemtek could induce HI immune responses to the four rHA antigens that were non-inferior to those of the comparator (Fluarix Tetra [IIV4]) in adults 18 to 49 years of age.
  • Study PSC04 was submitted to provide additional data to support the efficacy in adults from 18 to 49 years of age. This study was conducted with a trivalent recombinant influenza vaccine (RIV3) and is relevant to Supemtek as both vaccines were manufactured using the same process and have overlapping compositions.

Fluarix Tetra (IIV4) was used as the active comparator in Study PSC12 and PSC16. It is not currently approved in Canada, but is approved in the United States and Europe. Fluarix Tetra is an acceptable comparator due to the availability of efficacy, immunogenicity, and safety data for both Fluarix Tetra and Fluarix. In addition, there are similarities between Fluarix Tetra and FluLaval Tetra (approved in Canada), in terms of manufacturing processes and immunogenicity profiles.

Study PSC12

Study PSC12 was a Phase III, randomized, observer-blind, active-controlled, multicentre study conducted during the 2014-2015 influenza season. The purpose of the study was to evaluate the efficacy, immunogenicity, and safety of Supemtek in older, medically stable adults ≥50 years of age (mean age 62.5 years). A total of 8,963 subjects were enrolled and randomized 1:1 to receive a single dose (0.5 mL) of Supemtek (number of subjects [n] = 4,474) or IIV4 (n = 4,489) administered intramuscularly on study Day 0. Among randomized subjects, 58% were female, 80% were white, 18% were black/African-American, 2% were of other races, and 5% were of Hispanic/Latino ethnicity. Among randomized subjects, 60% were 50 to 64 years of age and 40% were ≥65 years of age.

Efficacy

Reverse-transcription polymerase chain reaction (RT-PCR)-confirmed influenza was assessed by active and passive surveillance for influenza-like illness (ILI) beginning 2 weeks post-vaccination until the end of the influenza season, approximately 6 months post- vaccination. Influenza-like illness was defined as having at least one symptom (no specified duration) in each of two categories of respiratory and systemic symptoms. Respiratory symptoms included sore throat, cough, sputum production, wheezing, and difficulty breathing. Systemic symptoms included fever >99°F (>37 °C) measured orally, chills, fatigue, headache, and myalgia. A nasopharyngeal swab sample was collected for RT-PCR testing from subjects with an episode of ILI. Reflex viral culture was performed on RT-PCR-positive samples.

The primary efficacy endpoint of Study PSC12 was protocol-defined, RT-PCR-confirmed ILI beginning at least 14 days post-vaccination and caused by any influenza strain. Non-inferiority to the comparator was established if the lower bound of the two-sided 95% confidence interval (CI) for vaccine efficacy was greater than the non-inferiority margin of -0.20.

The relative vaccine efficacy (rVE) of Supemtek over IIV4 against RT-PCR-positive influenza was 30% (95% CI: 10%, 47%), meeting the non-inferiority criterion for the primary efficacy endpoint.

Post-hoc analyses of relative vaccine efficacy according to influenza type A or B were performed, and the majority of laboratory-confirmed cases of ILI were caused by A/H3N2. The results show a trend towards non-inferior rVE for Supemtek against influenza A, but not against influenza B, where the number of cases were fewer and 95% CIs were wider. In addition, the efficacy of Supemtek relative to IIV4 included culture-confirmed (regardless of "match") protocol-defined ILI, for which the rVE was 43%.

Immunogenicity

The immunogenicity of Supemtek as compared to IIV4 was evaluated as a secondary endpoint. Pre- and post-vaccination (Day 28), HI titers from a subset of subjects (314 Supemtek and 300 IIV4 recipients) were analyzed. The immunogenicity of the four Supemtek antigens was compared to the corresponding IIV4 antigens using Day 28 post-vaccination HI geometric mean titer (GMT) ratios and seroconversion rate (SCR) differences for a total of eight secondary immunogenicity endpoints.

The pre-specified success criteria for establishing non-inferior immunogenicity of Supemtek as compared to IIV4 were as follows for all four vaccine antigens:

  • The upper bound of the two-sided 95% CI for the GMT ratio (IIV4/Supemtek) ≤1.5
  • The upper bound of the two-sided 95% CI for the SCR difference (IIV4 - Supemtek) ≤10%

The study results showed that Supemtek met the GMT ratio success criterion for the A/H1N1, A/H3N2 and B/Yamagata antigens, but failed to meet the GMT ratio success criterion for the B/Victoria antigen. The SCR success criterion was met for the A/H3N2 and B/Yamagata antigens but was not met for the A/H1N1 and B/Victoria antigens.

Study PSC16

Immunogenicity

Study PSC16 was a Phase III, observer-blind, randomized, comparator-controlled study conducted in the 2014-2015 influenza season. The study was designed to evaluate the safety and immunogenicity of Supemtek compared to IIV4 in healthy adults 18 to 49 years of age. A total of 1,350 subjects were enrolled, randomized 3:1, and vaccinated with a single dose (0.5 mL) of Supemtek (n = 998) or IIV4 (n = 332). Subjects were predominantly female (65%), white (60%), black/African American (37%), and of non-Hispanic/Latino ethnicity (84%), with a mean age of 33.5 years. Of the 1,350 subjects enrolled, 1,292 subjects (969 Supemtek and 323 IIV4 recipients) were evaluable for immune responses (Immunogenicity Population). The study had eight co-primary endpoints: Day 28 HI SCRs and GMTs for each of the four antigens contained in the study vaccines.

Post-vaccination immunogenicity was evaluated from serum samples obtained from subjects 28 days after administration of a single dose of study vaccine. Haemagglutination inhibition (HI) GMTs were determined for the two vaccine groups for each vaccine antigen. Immunogenicity was compared by calculating the difference in SCRs and the ratios of GMTs of Comparator to Supemtek. Seroconversion was defined as either a pre-vaccination HI titer of <1:10 and a post-vaccination HI titer of ≥1:40, or a pre-vaccination HI titer of ≥1:10 and a minimum 4-fold rise in post-vaccination HI titer, at Day 28.

The pre-specified success criteria for establishing the non-inferior immunogenicity of Supemtek as compared to IIV4 were the same as those defined for Study PSC12. The data showed that the antibody response to Supemtek met the non-inferior success criteria for the GMT ratio and SCR difference co-primary endpoints for the A/H1N1, A/H3N2 and B/Yamagata vaccine antigens but failed to meet the success criteria for the B/Victoria antigen.

Study PSC04

Efficacy

Study PSC04 was conducted for the trivalent recombinant influenza vaccine (RIV3). It was a Phase III randomized, observer-blind, placebo-controlled, efficacy, immunogenicity and safety study in 4,648 healthy adults aged 18 to 49 years (mean age 32.5 years) during the 2007-2008 influenza season. Among enrolled subjects, 59% were female, 67% were white, 19% were African-American, 2% were Asian, <1% were of other races, and 11% were of Latino/Hispanic ethnicity. Subjects were randomized 1:1 to receive a single dose of RIV3 (n = 2,344) or saline placebo (n = 2,304).

Culture-confirmed influenza was assessed by active and passive surveillance for ILI beginning 2 weeks post-vaccination until the end of the influenza season, approximately 7 months post-vaccination.

The primary efficacy endpoint was defined as ILI meeting the case definition of Centers for Disease Control-defined influenza-like illness (CDC-ILI) with a positive culture for an influenza virus strain antigenically resembling a strain represented in RIV3. The CDC-ILI definition is fever of ≥100 °F (≥37.8 °C) measured orally, accompanied by cough, sore throat, or both, on the same or consecutive days. Attack rates and vaccine efficacy, defined as the reduction in the influenza rate for RIV3 relative to placebo, were calculated for the total vaccinated cohort (n = 4,648).

The pre-defined success criterion for the primary efficacy analysis was that the lower bound of the 95% CI of vaccine efficacy (VE) should be at least 40%. The primary efficacy criterion was not met. Vaccine efficacy against antigenically matched culture-confirmed CDC-ILI could not be determined reliably because 96% of the influenza isolates obtained from subjects were not antigenically matched to the strains represented in the vaccine.

A pre-specified exploratory analysis of protection against culture-confirmed CDC- ILI due to any virus strain demonstrated a VE of 44.6% (95% CI: 18.8, 62.6). In a post hoc exploratory analysis, the VE of RIV3 against culture-confirmed ILI due to any virus strain regardless of antigenic match was 44.8% (95% CI: 24.4, 60.0).

Indication

The New Drug Submission for Supemtek was filed by the sponsor with the following indication, which Health Canada subsequently approved:

  • Supemtek vaccine is indicated for active immunization for the prevention of influenza disease caused by influenza A subtype viruses and type B virus lineages contained in the vaccine. Supemtek is approved for use in persons 18 years of age and older.

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

Clinical Safety

Safety data in support of the authorization of Supemtek were obtained from two studies (Study PSC12 and PSC16) conducted with Supemtek (RIV4) described in the Clinical Efficacy section above.

Study PSC16 provided data from 1,330 subjects aged 18 to 49 years, of whom 998 received Supemtek. Study PSC12 provided data from 8,672 subjects aged ≥50 years of age, of whom 4,328 received Supemtek. In total, 5,326 subjects received a single dose of Supemtek. The mean age of subjects in the studies was 33.6 years in the 18 to 49 years group and 62.6 years in the ≥50 years group. To evaluate safety, both studies collected solicited local and systemic adverse events (AEs) for 7 days, unsolicited AEs for 28 days, and both serious adverse events (SAEs) and medically attended adverse events (MAEs) for 6 months post-vaccination.

Overall, the safety profiles of Supemtek and the comparator (IIV4) were comparable. In Study PSC16 (18 to 49 years), the most common reactions occurring after vaccine administration were injection site reactions, with 48% of subjects who received Supemtek reporting tenderness and 37% reporting pain. Comparably, of study participants who received IIV4, 47% reported tenderness and 36% reported pain. In Study PSC12 (≥50 years), the most common reaction was injection site tenderness, reported by 34% and 37% of those receiving Supemtek or IIV4, respectively. The majority of local solicited AEs were mild to moderate in both vaccine groups. In both studies, the most frequently reported solicited systemic AEs were headache, fatigue, joint and muscle pain for both Supemtek and IIV4 groups. Overall, the rates of unsolicited AEs and MAEs were similar between the two groups in both studies. There were no SAEs considered causally related to Supemtek.

Safety data were also submitted from Study PSC04 which included data from 4,648 subjects 18 to 49 years of age randomized to receive RIV3 (n = 2,344) or placebo (n = 2,304). In addition, a summary of a post-market study (PSC13) was provided during the review of this submission, to evaluate the safety of RIV3 compared with trivalent standard-dose, inactivated influenza vaccine (IIV3) in Kaiser Permanente Northern California (KPNC) members. These studies did not identify special safety concerns regarding the use of RIV3 in adults.

Special Populations

There is limited data available from the use of Supemtek in pregnant women. One animal study performed with RIV3 did not indicate direct or indirect harmful effects with respect to pregnancy, embryo-foetal development or early post-natal development. The National Advisory Committee on Immunization (NACI) recommends influenza vaccination for all pregnant women at any stage of pregnancy.

It is not known if Supemtek vaccine is excreted in breastmilk.

Drug Interactions

Supemtek should not be mixed with another vaccine in the same syringe or vial. No data to assess the concomitant administration of Supemtek with other vaccines are available. If Supemtek is to be given at the same time as another injectable vaccine(s), the vaccine(s) should be administered at different injection sites.

Overall Analysis of Safety

Overall, post-market experiences with Supemtek and RIV3 did not identify any safety signals. Appropriate warnings and precautions are in place in the approved Supemtek Product Monograph to address the identified safety concerns.

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

 

 

 

7.2 Non-Clinical Basis for Decision

 

Non-clinical studies conducted with Supemtek were not submitted. The non-clinical assessment was primarily based on data obtained with the trivalent recombinant influenza vaccine (RIV3, Flublok). The main difference between RIV3 and Supemtek is the total recombinant haemagglutinin (rHA) content (RIV3 - 135 µg rHA protein/dose versus Supemtek - 180 µg rHA protein/dose) due to the addition of another lineage B recombinant haemagglutinin. Health Canada considered the RIV3 non-clinical package adequate to support the authorization of Supemtek based on the fact that RIV3 has a similar manufacturing process, has no novel excipients or process residuals, and has no post-licensure safety concerns in the United States. The trivalent vaccine RIV3 is not approved for use in Canada, but is approved in the United States.

A series of non-clinical immunogenicity studies were conducted in laboratory animals (primarily mice) during the development of RIV3. In all studies, RIV3 or monovalent rHA induced a serological response as measured by enzyme-linked immunosorbent assay (ELISA), haemagglutination-inhibition (HI) or virus neutralization.

Toxicity studies were performed mostly in rabbits or rats, and consisted of local tolerance studies, single-dose toxicity studies, a repeat-dose toxicity study, and safety pharmacology studies. All these studies were conducted with RIV3 administered intramuscularly or subcutaneously at a dose corresponding to 300‑times the human dose based on a mg/kg basis. No adverse systemic effects were observed in the non-clinical safety studies (including toxicology, cardiovascular, respiratory and central nervous system endpoints), and the RIV3-related effects were limited to transient local inflammation at the injected area observed in the intramuscular local tolerance and repeat-dose toxicity studies following subcutaneous administration.

To support the vaccination of women of child-bearing potential, a developmental and reproductive toxicology (DART) study was performed with RIV3. The study was designed to evaluate potential adverse maternal and developmental effects when administered to female rats twice prior to mating and once during gestation. The study did not indicate harmful effects with respect to pregnancy, embryo-foetal development or early post-natal development, at a RIV3 dose of approximately 300 times the human dose (on a mg/kg basis).

The results of the non-clinical studies as well as the potential risks to humans have been included in the Supemtek Product Monograph. In view of the intended use of Supemtek, there are no pharmacological/toxicological issues within this submission which preclude authorization of the product.

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

 

 

7.3 Quality Basis for Decision

 

Characterization of the Drug Substance

Detailed characterization studies were performed to provide assurance that all four medicinal ingredients (recombinant haemagglutinin [rHA] proteins) consistently exhibit the desired characteristic structure and biological activity. The rHA proteins were adequately characterized to control identity, glycosylation and higher order conformation. Functionality was tested by adequate methods which demonstrated the appropriate antigenic activity of the rHA proteins.

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 and Process Controls of the Drug Substance and Final Product

Supemtek is a quadrivalent recombinant influenza vaccine (RIV4) and is formulated to contain 180 µg haemagglutinin (HA) per 0.5 mL dose in the recommended ratio of 45 µg HA of each of the four influenza strains selected by the World Health Organization for each year's seasonal vaccine (A/H3N2, A/H1N1, B/Yamagata-like, B/Victoria-like). In addition, the solution contains the following excipients: sodium chloride, monobasic sodium phosphate, dibasic sodium phosphate, and polysorbate 20. Cell product derived and culture derived residuals (baculovirus and Spodoptera frugiperda cell proteins, baculovirus and cellular deoxyribonucleic acid [DNA], and Triton X-100) are removed during purification of the drug substance. It is supplied as a sterile, preservative-free solution in a pre-filled syringe.

The drug substance consists of purified HA proteins produced in a continuous insect cell line (expresSF+) infected with recombinant baculoviruses containing the HA‑encoding gene. The master cell bank (MCB) and the two working cell bank (WCB) lots derived from it have been characterized in line with International Conference for Harmonisation (ICH) guidelines. Testing of the MCB and end of production cells is in line with European Pharmacopeia (Ph. Eur.) requirements.

Each of the four HAs is expressed in this cell line using the baculovirus vector Autographa californica nuclear polyhedrosis virus (AcNPV). The master virus bank (MVB) was generated from a master parent linear baculovirus vector. The HA gene for each influenza strain included in the seasonal vaccine is added to the MVB to create the working virus bank (WVB). The WVBs are subsequently tested to ensure identity, potency and correct assembly of the WVB. After construction of the WVB, the correct sequence is then verified by comparison with the sequence of a reference virus.

The rHA antigens are full length, uncleaved glycoproteins with molecular weights of approximately 65 kDa. The rHA antigens assemble into complexes of 4 or 5 rHA trimers. In addition, rosette-like micelle structures are observed by electron microscopy, providing further support for the formation of rHA multimer complexes. The glycosylation pattern of the rHA proteins examined is consistent with that expected from recombinant proteins produced in insect cells.

Upstream manufacturing includes culturing of expresSF+ cells, baculovirus infection and expansion and protein production. Recombinant baculoviruses are expanded in parallel in expresSF+ cells from the WVB through to the working virus stock (WVS). The WVS is used for inoculation of the working volume culture. Downstream processing includes centrifugation, extraction of recombinant HA from the cell pellet, followed by clarification of the crude extract by depth filtration, capture and purification of HA protein by column chromatography, DNA removal and ultrafiltration. The purified monovalent bulk HAs are blended during final formulation, filtered and filled into single-dose pre-filled syringes.

The materials used in the manufacture of Supemtek (including biological-sourced materials) are considered suitable and/or meet standards appropriate for their intended use. The manufacturing process is considered to be adequately controlled within justified limits.

Control of the Drug Substance and Final Product

Each lot of Supemtek drug product is tested for appearance, identity, endotoxin, sterility, potency, total protein content, content uniformity, purity, total DNA, osmolality, pH, fill volume and Triton X-100 content. Established test specifications and validated analytical test methods are considered acceptable.

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

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

Stability of the Drug Substance and Final Product

Based on the stability data submitted, the proposed shelf life and storage conditions for the drug substance and final product were adequately supported and are considered to be satisfactory. The proposed 12 month shelf life at 2‑8 °C for Supemtek is considered acceptable when protected from light.

The container used for the storage and transport of the monovalent bulk is a single use bag. Stability studies were conducted to confirm the compatibility of the components in contact with the rHA. Information on leachables and extractables provided sufficient evidence to conclude that the extractable and leachable compounds in product contact materials will not negatively impact product quality.

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 test acceptance criteria.

The proposed packaging and components are considered acceptable.

Facilities and Equipment

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

Due to the coronavirus disease (COVID-19) pandemic and government‑imposed travel restrictions, on-site evaluations (OSEs) for the current submission were not feasible. In lieu of OSEs, a review of 11 foreign inspector reports provided by the sponsor and an in-depth review of the facilities section were performed. This information combined with supporting data in the submission were considered sufficient to support the final quality review recommendation.

All sites involved in production are compliant with Good Manufacturing Practices.

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 of animal or human origin.

No endogenous adventitious agents have been found in either the cell and virus master banks or working stocks. During routine manufacturing, each unprocessed bulk is tested for the presence of viral contaminants. Prior to infection, the production culture is additionally tested. The absence of infectious baculovirus is a requirement for release of the drug substance.

The capacity of the manufacturing process for effective virus clearance was evaluated in several studies. A baculovirus clearance study was also performed using spiked process intermediates to assess the clearance of baculovirus from the manufacturing process for both processes/facilities. These studies demonstrated adequate viral clearance of model viruses and baculovirus.

 

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