Summary Basis of Decision for Shingrix

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 Shingrix is located below.

Recent Activity for Shingrix

The SBDs written for eligible drugs (as outlined in Frequently Asked Questions: Summary Basis of Decision [SBD] Project: Phase II) approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. The PAATs will be updated regularly with post-authorization activity throughout the product life cycle.

Post-Authorization Activity Table (PAAT) for Shingrix

Updated: 2024-08-23

 

The following table describes post-authorization activity for Shingrix, a product which contains the medicinal ingredient varicella zoster virus (VZV) glycoprotein E (gE). For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the List of abbreviations found in Post-Authorization Activity Tables (PAATs).

 

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

 

Drug Identification Number (DIN):

DIN 02468425 – 50 mcg/0.5 mL, varicella zoster virus (VZV) glycoprotein E (gE), suspension for intramuscular injection

 

Post-Authorization Activity Table (PAAT)

 

Activity/Submission Type, Control Number

Date Submitted

Decision and Date

Summary of Activities

SNDS # 280925

2023-11-09

Issued NOC 2024-06-10

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

NC # 286393

2024-04-26

Cancellation Letter Received 2024-05-10

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the drug product manufacturing process. The changes were not considered to be in scope of Level II NC but were considered to be Level III changes. The sponsor cancelled the submission.

NC # 282345

2023-12-21

Issued NOL 2024-04-03

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change involving a biological adjuvant. The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 280412

2023-10-27

Issued NOL 2024-02-23

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change involving a biological adjuvant. The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 279555

2023-09-29

Issued NOL 2023-12-07

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change to the drug substance purification process. The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 279527

2023-09-28

Issued NOL 2023-12-11

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes to the seed banks. The submission was reviewed and considered acceptable, and an NOL was issued.

SNDS # 265524

2022-06-23

Issued NOC 2022-11-15

Submission filed as a Level II – Supplement (Safety) to update the PM with new safety information. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Adverse Reactions and Clinical Trials sections of the PM, and corresponding changes were made to Part III: Patient Medication Information and to the package inserts. An NOC was issued.

NC # 257235

2021-10-01

Issued NOL 2021-12-15

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change involving a biological adjuvant. The submission was reviewed and considered acceptable, and an NOL was issued.

SNDS # 246933

2020-12-01

Issued NOC 2021-11-24

Submission filed as a Level I – Supplement to extend the indication of Shingrix to adults ≥18 years of age at increased risk of Herpes Zoster in order to address the unmet medical need for Herpes Zoster prevention in that population. The indication authorized was: Shingrix is indicated for the prevention of herpes zoster (HZ, or shingles) in adults 18 years of age or older who are or will be at increased risk of HZ due to immunodeficiency or immunosuppression caused by known disease or therapy. The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published.

SNDS # 253242

2021-05-31

Issued NOC 2021-10-25

Submission filed as a Level II – Supplement (Safety) to update the PM with new safety information. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions and Adverse Reactions sections of the PM, and corresponding changes were made to the package inserts. An NOC was issued.

NC # 254654

2021-07-09

Cancellation Letter Received 2021-08-19

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the specifications used to release a primary or functional secondary container closure component. Upon review, the changes were not considered to be in scope of Level II NC but were considered to be Level III changes. The sponsor cancelled the submission.

NC # 251598

2021-04-08

Issued NOL 2021-07-08

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

NC # 248731

2021-01-22

Issued NOL 2021-04-26

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for the qualification of new lots of reference standard against the approved reference standards. The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 247150

2020-12-03

Issued NOL 2021-03-01

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the drug product manufacturing process and changes in the control strategy of the drug product. The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 247152

2020-12-04

Issued NOL 2021-02-02

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

NC # 246096

2020-11-03

Issued NOL 2021-01-13

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

SNDS # 238487

2020-04-22

Issued NOC 2020-11-30

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

NC # 240475

2020-06-09

Issued NOL 2020-10-01

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

NC # 237084

2020-03-13

Issued NOL 2020-06-17

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

SNDS # 229162

2019-06-25

Issued NOC 2020-06-03

Submission filed as a Level I – Supplement to update the PM with new clinical data. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions; Adverse Reactions; Action and Clinical Pharmacology; and Clinical Trials sections of the PM, and corresponding changes were made to Part III: Patient Medication Information and to the package inserts. An NOC was issued.

NC # 238541

2020-04-16

Cancellation Letter Received 2020-04-30

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for the qualification of a new lot of reference standard against the approved reference standard. The changes were not considered to be in scope of Level II NC but were considered to be Level III changes. The sponsor cancelled the submission.

SNDS # 231069

2019-09-13

Issued NOC 2019-11-21

Submission filed as a Level I – Supplement to update the package insert to accommodate a smaller leaflet size. The submission was reviewed and considered acceptable, and an NOC was issued.

SNDS # 220565

2018-09-28

Issued NOC 2019-05-15

Submission filed as a Level I – Supplement for a change involving a drug product manufacturer/manufacturing facility. The submission was reviewed and considered acceptable, and an NOC was issued.

NC # 222616

2018-11-30

Issued NOL 2019-03-05

Submission filed as a Level II (90 day) Notifiable Change to update the PM with new safety information. As a result of the NC, modifications were made to the Adverse Reactions section of the PM, and corresponding changes were made to Part III: Patient Medication Information. The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 215573

2018-04-18

Issued NOL

2018-07-30

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to change a testing procedure for the drug substance. The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 216504

2018-05-22

Issued NOL

2018-05-29

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to make changes regarding the reference standard. The submission was considered acceptable, and an NOL was issued.

Drug product (DIN 02468425) market notification

Not applicable

Date of first sale: 2018-01-02

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

Health product advertising complaint closed

Not applicable

Date received:

2017-11-01

A health product advertising complaint regarding the advertising of unauthorized claims was closed. No follow-up was required as a satisfactory response was received from the company.

NDS # 200244

2016-11-17

Issued NOC 2017-10-13

Notice of Compliance issued for New Drug Submission.
Summary Basis of Decision (SBD) for Shingrix

Date SBD issued: 2018-01-15

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

Varicella Zoster Virus (VZV) glycoprotein E (gE)
50 µg/0.5 mL, suspension for intramuscular injection

Drug Identification Number (DIN):

  • 02468425

GlaxoSmithKline Inc.

New Drug Submission Control Number: 200244

 

On October 13, 2017, Health Canada issued a Notice of Compliance to GlaxoSmithKline Inc. for the vaccine Shingrix.

The market authorization was based on quality (chemistry and manufacturing), non-clinical (pharmacology and toxicology), and clinical (immunology, safety, and effectiveness) information submitted. Based on Health Canada's review, the benefit-risk profile of Shingrix is favourable for the prevention of herpes zoster (HZ, or shingles) in adults 50 years of age or older.

 

1 What was approved?

 

Shingrix, an active immunizing agent, was authorized for the prevention of herpes zoster (HZ or shingles) in adults 50 years of age or older.

Shingrix is contraindicated for patients with a known hypersensitivity to the active substance or to any component of the vaccine.

Shingrix 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.

Shingrix (50 µg/0.5 mL non-live recombinant AS01B adjuvanted Varicella Zoster Virus glycoprotein E [VZV gE]) is presented as a suspension for intramuscular injection. The vaccine is supplied as a vial of lyophilized recombinant VZV gE which is reconstituted at the time of use with the accompanying vial of AS01B adjuvant suspension. The AS01B adjuvant suspension is composed of QS-21 (the plant extract Quillaja saponaria Molina fraction 21) and MPL (3-O-desacyl-4'-monophosphoryl lipid A) combined with DOPC (dioleoyl phophatidylcholine) and cholesterol.

After reconstitution, one dose (0.5 mL) contains:

  • Varicella Zoster Virus gE: 50 µg
  • Quillaja saponaria Molina fraction 21: 50 µg
  • 3-O-desacyl-4'-monophosphoryl lipid A: 50 µg

The additional excipients in the powder (gE) are dipotassium phosphate, polysorbate 80, sodium dihydrogen phosphate dihydrate, and sucrose.

The additional excipients in the suspension (AS01B) are cholesterol, dioleoyl phosphatidylcholine, disodium phosphate anhydrous, potassium dihydrogen phosphate, sodium chloride, and water for injection.

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 Shingrix Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

2 Why was Shingrix approved?

 

Health Canada considers that the benefit-risk profile of Shingrix is favourable for the prevention of herpes zoster (HZ or shingles) in adults 50 years of age or older.

Herpes zoster or shingles is a debilitating disease that is caused by the reactivation of the dormant varicella zoster virus (VZV) when VZV-specific immunity weakens due to advancing age or an immunocompromising condition. Shingrix is an HZ vaccine designed to induce antigen-specific cellular and humoral immune responses in individuals with pre-existing immunity against VZV.

Nearly all adult Canadians (≥90%) have had chickenpox (varicella) and are therefore at risk for HZ. This disease occurs most frequently among older adults and immunocompromised persons. In Canada, it has been estimated that 30% of the population will develop HZ at some point in their lives. This number increases to almost 50% for those who live to 85 years of age.

The efficacy of Shingrix was assessed in two pivotal, randomized, observer-blind, placebo-controlled and multicentre studies. The studies demonstrated that Shingrix was effective in the prevention of HZ and was immunogenic (cell-mediated immunity and humoral immunity) in adults 50 years of age or older following 2-dose vaccinations. Shingrix significantly reduced the risk of developing HZ in subjects ≥50 years of age as compared to placebo and was consistent regardless of age at immunization. The available data showed that the efficacy was maintained at a high level for up to 4 years. As some cases of HZ are followed by HZ-related complications such as postherpetic neuralgia (PHN), preventing HZ can avoid these debilitating complications.

Shingrix was generally well tolerated, and has an acceptable safety profile based on the non-clinical data and clinical studies. Appropriate warnings and precautions are in place in the Shingrix Product Monograph to address the potential safety concerns.

A Risk Management Plan (RMP) for Shingrix was submitted by GlaxoSmithKline Inc. 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.

A Look-alike Sound-alike brand name assessment was performed and the proposed name Shingrix was accepted.

Overall, the benefits of Shingrix for the prevention of HZ in adults 50 years of age or older outweigh the risks.

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 Shingrix?

 

Submission Milestones: Shingrix

Submission Milestone Date
Pre-submission meetings: 2015-10-15
Submission filed: 2016-11-17
Screening  
Screening Acceptance Letter issued: 2016-12-22
Review  
On-Site Evaluation: 2017-06-12 - 2017-06-16
Review of Risk Management Plan complete: 2017-06-19
Biostatistics Evaluation complete: 2017-09-22
Clinical Evaluation complete: 2017-09-27
Labelling Review complete: 2017-10-06
Quality Evaluation complete: 2017-10-13
Notice of Compliance issued by Director General, Biologics and Genetic Therapies Directorate: 2017-10-13

 

The Canadian regulatory decision on the quality, non-clinical and clinical review of Shingrix was based on a critical assessment of the data package submitted to Health Canada. The foreign review documentation from the European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) was used as an added reference.

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

 

4 What follow-up measures will the company take?

 

As part of the marketing authorization for Shingrix, 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):

  • Revising the validity criteria of some content release assays as stated in the Post-Notice of Compliance Letter.
  • Re-assessing several release specifications for the gE drug substance and drug product gE final container, as well as for adjuvant components, as stated in the Post-Notice of Compliance Letter.
  • Providing some additional characterisation data for the next 30 gE final container lots, including stability data (for lots included in a stability program) and providing the results to Health Canada as soon as the data become available.

 

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

 

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's life cycle.

The PAAT for Shingrix 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

The antigen component of Shingrix is one of the major glycoproteins from varicella zoster virus (VZV) and is unable to replicate. When the vaccine antigen is combined with the AS01B Adjuvant System, Shingrix induces antigen-specific cellular and humoral immune responses in individuals with pre-existing immunity against VZV. Although no immunological correlate for protection against herpes zoster (HZ) has been identified, current knowledge suggests that VZV-specific cell-mediated immunity (CMI) is of primary importance in preventing HZ. The VZV-specific antibodies may help control viral dissemination and may thereby help limit the severity of HZ.

The pharmacodynamics of Shingrix was assessed through the analysis of immunogenicity described in the Clinical Efficacy section.

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

Clinical Efficacy

The vaccine efficacy of Shingrix for the prevention of herpes zoster (HZ or shingles) was evaluated in two pivotal Phase III efficacy studies, Zoster-006 and Zoster-022, with the primary objective to demonstrate vaccine efficacy against HZ in adults ≥50 years of age and ≥70 years of age, respectively. The incidence of confirmed HZ cases was the primary endpoint. All suspected cases of HZ were confirmed by Polymerase Chain Reaction (PCR) testing and/or the HZ Adjudication Committee (HZAC), and the HZAC classification served as the final case definition only when the case could not be confirmed or excluded by PCR. The co-primary objectives of the Zoster-006/022 pooled analysis were to evaluate the vaccine efficacy against postherpetic neuralgia (PHN) and HZ in subjects ≥70 years of age, across both studies.

Study Zoster-006 was a placebo-controlled, observer-blind, clinical study conducted in 18 countries, from North America (United States and Canada), Latin America, Europe, Asia, and Australia. A total of 15,411 subjects ≥50 years were randomized 1:1 to receive two doses (0 and 2 months) of either Shingrix (number of subjects [n] = 7,698) or placebo (n = 7,713). The mean age of subjects was 62.3 years. Subjects were followed for the development of HZ for a median of 3.1 years (range: 0 to 3.7 years). The study excluded, among others, subjects who were immunocompromised, had a previous history of HZ, were previously vaccinated against varicella or HZ, and patients whose survival was not expected to be at least 4 years, or with conditions that might interfere with study evaluations. Randomization was stratified by age: 50 to 59 years, 60 to 69 years, 70 to 79 years, and ≥80 years in a 8:5:3:1 ratio. Shingrix significantly reduced the risk of developing HZ by 97.2% (95% confidence interval [CI]: 93.7, 99.0) in subjects ≥0 years of age as compared to placebo. The vaccine efficacy against HZ in adults ≥50 years of age remained high and was 93.1% (95% CI: 81.2, 98.2; p <0.0001) in the fourth year after vaccination.

Study Zoster-022 was a placebo-controlled, observer-blind, clinical study conducted in the same 18 countries as Study Zoster-006, in which 13,900 subjects aged 70 years and older were randomized 1:1 to receive two doses (at 0 and 2 months) of either Shingrix (n = 6,950) or placebo (n = 6,950). The mean age of subjects was 75.6 years. Subjects were followed for the development of HZ and PHN for a median of 3.9 years (range: 0 to 4.5 years). The study exclusion criteria were the same as for Study Zoster-006. Randomization was stratified by age: 70 to 79 years and ≥80 years in a 3:1 ratio. In Study Zoster-022, a total of 23 confirmed HZ episodes were reported in the Shingrix group and 223 in the placebo group. The overall Shingrix vaccine efficacy was 89.79% (95% CI: 84.29, 93.66; p<0.0001) in subjects ≥70 years of age as compared to placebo.

The efficacy of Shingrix to prevent HZ in subjects ≥70 years of age was also evaluated by combining the results from studies Zoster-006 and Zoster-022 through a pre-specified pooled analysis in the modified Total Vaccinated Cohort (mTVC), which included subjects randomized in the study who received a second dose of the vaccine and did not develop a confirmed case of HZ within one month after the second dose. A total of 8,250 and 8,346 subjects ≥50 years of age who received Shingrix and placebo, respectively, were included in the pre-specified pooled mTVC analysis. The overall HZ vaccine efficacy in subjects ≥70 years of age was 91.3% (95% CI: 86.8, 94.5; p<0.0001) after a median follow-up time of 3.9 (0-4.5) years.

The pooled mTVC analysis also analyzed the efficacy of Shingrix for the prevention of PHN and HZ-related complications (HZ vasculitis, disseminated disease, ophthalmic disease, neurologic disease, visceral disease, and stroke). In the analysis, PHN was defined as HZ-associated pain (rated as 3 or greater on a 0 to 10-point scale by the study subject) occurring or persisting at least 90 days following the onset of rash in evaluable cases of HZ using the Zoster Brief Pain Inventory questionnaire. The overall vaccine efficacy against PHN in subjects ≥70 years of age was 88.8% (95% CI: 68.7-97.1), with 4 PHN cases in the Shingrix group and 36 in the placebo group.

The observed overall vaccine efficacy against PHN may be directly a consequence of vaccine efficacy against HZ. In addition, the reduction of PHN incidence in subjects ≥50 years of age in Study Zoster-006 or in subjects ≥70 years of age in Study Zoster-022 with a confirmed HZ episode and reduction of HZ-related complication incidences (other than PHN) were also inconclusive. Therefore, the data presented in this drug submission cannot sufficiently support the indication for "prevention of HZ-related complications such as postherpetic neuralgia (PHN) in adults 50 years of age or older", but the important data are included in the Shingrix Product Monograph.

Immunogenicity

The gE-specific CD4+ T-cell activity for cell-mediated immunity (CMI) was measured by intracellular cytokine staining (ICS) assay in terms of frequency of gE-specific CD4[2+] T-cells. Anti-gE antibody levels were measured by anti-gE enzyme-linked immunosorbent assay (gE ELISA). The vaccine response rate (VRR) for anti-gE was defined as the percentage of subjects with at least a 4-fold increase in post-Dose 2 anti-gE antibody concentration compared with the pre-vaccination anti-gE antibody concentration (for subjects seropositive at baseline) or with the anti-gE antibody cut-off value of 97 mIU/mL (for subjects seronegative at baseline). An immunological correlate of protection against HZ has not been established; therefore a specific level of immunological response above which the individual is protected is unknown.

Subjects ≥50 years of age showed strong peak anti-gE antibody responses and gE-specific CMI (CD4 T-cells producing at least two cytokines) following two doses of Shingrix at 1 month post-Dose 2 (Month 3), and then the responses became lower one year post-Dose 2 (Month 14) but persisted well above pre-vaccination levels up to three years post-Dose 2 (Month 38). The Vaccine Response Rate (VRR) for anti-gE antibody was 98.5% (95% CI: 97.6, 99.1), 89.5% (95% CI: 87.4, 91.3), 83.4% (95% CI: 80.9, 85.6) and 80.9% (95% CI: 78.2, 83.3) at Months 3, 14, 26 and 38, respectively, in Zoster-006.

Two doses of Shingrix were required for optimal immune response to Shingrix, based on the observation that two doses of Shingrix provided higher gE-specific and varicella zoster virus (VZV) specific CMI and humoral immune responses than one dose of Shingrix. Consequently, the vaccine efficacy to HZ was demonstrated by the 0, 2-month schedule in two pivotal studies.

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

Indication

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

  • Shingrix is indicated for prevention of herpes zoster (HZ) and HZ-related complications, such as postherpetic neuralgia (PHN), in adults 50 years of age or older.

Based upon the review of the submitted data, Health Canada recommended the following indication:

  • Shingrix is indicated for prevention of herpes zoster (HZ) in adults 50 years of age or older.

Clinical Safety

The safety database included data from more than 17,000 adults ≥50 years of age who received at least one dose of Shingrix. Of these subjects, 14,645 were from the two pivotal Phase III placebo-controlled studies (Zoster-006 and Zoster-022, described in the Clinical Efficacy section). Overall (Dose 1 and Dose 2 considered), in subjects from the Total Vaccinated Cohort (TVC) diary card, a higher percentage of subjects reported solicited and unsolicited local and general adverse events (AEs, any grade, grade 3, related, and grade 3 related as per investigator assessment) in the Shingrix group compared to the placebo group. No imbalance was observed between the Shingrix and placebo groups in serious adverse events (SAEs), vaccine-related SAEs, fatal SAEs or potential immune-mediated diseases reported during the study. Compliance for receipt of the second dose was >95% in the Shingrix and placebo groups. Shingrix was generally well tolerated.

The most frequently reported AEs were pain at the injection site (68.1% overall/dose), myalgia (32.9% overall/dose), fatigue (32.2% overall/dose), headache (26.3% overall/dose), fever (12.5% overall/dose) and gastrointestinal symptoms (10.7% overall/dose). The majority of these reactions were of mild to moderate severity and were not long-lasting (median duration of 2 to 3 days). The incidence of unsolicited AEs reported from Day 7 through Day 29 after each dose was comparable between the groups. Within the 30-day post-vaccination period, at least one unsolicited AE of gout or gouty arthritis was experienced by 27 subjects (0.2%) in the Shingrix group and 8 subjects (0.1%) in the placebo group. In special populations, limited safety data are available for immunocompromised individuals. There are no data on the use of Shingrix in pregnant and nursing women. Appropriate warnings and precautions are in place in the approved Shingrix Product Monograph to address the potential safety concerns.

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

 

 

 

7.2 Non-Clinical Basis for Decision

 

Non-clinical pharmacology and toxicity studies were undertaken with various formulations containing the gE antigen and adjuvants. To evaluate the safety of Shingrix, a number of pivotal Good Laboratory Practices (GLP) studies were conducted, including repeat-dose toxicity studies, local tolerance and reproductive toxicity studies. A safety pharmacology study was also performed with gE antigen/AS01B adjuvant. The non-clinical package is acceptable. No safety concerns were identified in the non-clinical toxicity studies performed in rats and rabbits with Shingrix.

In view of the intended use of Shingrix, there are no pharmacological/toxicological issues within this submission which preclude authorization of the product. Appropriate warnings and precautionary measures are in place in the Shingrix Product Monograph to address the identified safety concerns.

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

 

 

7.3 Quality Basis for Decision

 

Shingrix is a sterile, non-live vaccine indicated for the prevention of HZ in adults 50 years of age or older. The vaccine is supplied as a vial of lyophilized recombinant varicella zoster virus surface glycoprotein E (VZV gE) which is reconstituted at the time of use with the accompanying vial of AS01B adjuvant suspension.

The AS01B adjuvant suspension contains 50 µg of each of the immuno-enhancers QS-21 (Quillaja saponaria Molina, fraction 21) and MPL (3-O-desacyl-4'-monophosphoryl lipid A) combined with liposomes.

The gE antigen is supplied as a lyophilized powder in single dose vials (50 µg/dose). The AS01B liquid adjuvant suspension is provided in separate single dose vials (0.5 mL/dose) and is used to reconstitute the gE vial content prior to intramuscular injection. After reconstitution the vaccine should be used promptly; if this is not possible, the vaccine should be stored in a refrigerator and discarded if not used within 6 hours.

Characterization of the Drug Substance

Detailed characterization studies were performed to provide assurance that the VZV gE antigen consistently exhibits the required characteristic structure and biological activity.

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

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

The gE antigen used in the vaccine is a purified recombinant protein produced in Chinese Hamster Ovary (CHO) cells. The recombinant protein is secreted into the cell culture supernatant during production and then purified in a multi-step process which includes passage through chromatography columns, low pH inactivation, and nanofiltration. This sterile purified bulk drug substance is stored in bags until formulation in phosphate buffer (with sucrose and polysorbate 80 stabilizers), followed by sterile filtration, aseptic filling into glass vials, and lyophilization.

The Adjuvant System AS01B is manufactured by mixing a concentrated solution of phosphate buffer and sodium chloride with water for injection, and subsequently adding the appropriate amount of the two intermediates: concentrated liposomes bulk (containing MPL, dioleoyl phophatidylcholine [DOPC] and cholesterol) and QS-21 liquid bulk. After mixing the two intermediates, a maturation time is applied before sterile filtration and filling into glass vials.

The overall manufacturing control strategy to ensure sterility, identity, purity, and potency of the Shingrix vaccine is considered acceptable.

In-process controls and lot release tests for the drug substance/drug product were established and validated.

The materials used in the manufacture 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, Drug Product, and Adjuvant

During the review of the drug submission, Health Canada had some concerns regarding the adequacy of the control parameters in place for the analytical method used to measure the vaccine potency (gE potency assay) as well as the potency release specifications for final containers. The sponsor agreed to modify their method control parameters as well as to tighten their gE antigen content release specification during the review time frame. They also re-assessed the gE antigen content results for all of the Phase III lots to ensure that results remained valid after applying the new control parameters. The potency results of the Phase III lots were not impacted by the method changes and are considered to be reliable. Modifications were also made to one impurity assay, which is based on similar principles. Based on the modifications made for both assays, as well as through the post-NOC commitments made, the sponsor has adequately addressed all of Health Canada's concerns with these methods.

In general, the established test specifications and validated analytical test methods for gE drug substance, drug product, and AS01B adjuvant are considered acceptable. They provide assurance that the final Shingrix vaccine product is adequate in terms of identity, purity, potency, and safety. In addition, the sponsor committed to reassessing the release specifications for a number of drug substance, drug product, and AS01B adjuvant test methods, thus, confirming their commitment to continuous quality improvements.

The gE drug product manufacturing process was validated using three consecutive commercial-scale lots. All process measurements and process monitoring test results as well as the quality control testing results for all three lots met the acceptance criteria. In addition, results were comparable to the Phase III clinical lots. Batch analysis data provided for approximately ten additional commercial-scale lots further confirmed the consistency of the manufacturing process.

The AS01B adjuvant manufacturing process was also validated using three consecutive commercial-scale lots. All process measurements and process monitoring test results as well as the quality control testing results for all three lots met the acceptance criteria. Additional supportive batch data were provided from earlier manufacturing processes and are acceptable and comparable to commercial batch data.

The process validation data, batch analysis data, and controls are considered acceptable and confirm the quality of the AS01B adjuvant for use with the gE antigen drug product.

The chemistry and manufacturing information submitted has demonstrated that the drug substance, drug product, and adjuvant can be consistently manufactured to meet the specifications proposed by the sponsor and agreed to by Health Canada. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes.

Shingrix vaccine 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, Drug Product, and Adjuvant

Based on the stability data submitted, the proposed shelf life and storage conditions for the drug substance, drug product, and adjuvant were adequately supported and are considered to be satisfactory. The proposed 36-month shelf life at +2 to +8°C for both the gE final container drug product and the AS01B adjuvant is considered acceptable. The reconstituted vaccine (Shingrix) in-use shelf life of 6 hours when stored at +2 to +8°C is also considered acceptable.

The proposed packaging and components are considered acceptable.

Facilities and Equipment

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

An On-Site Evaluation (OSE) of the manufacturing processes for the gE antigen drug substance, drug product, and AS01B adjuvant was performed at the manufacturing site by Health Canada experts. The OSE provided sufficient assurance that the manufacturing process is appropriate to produce a high quality final vaccine product.

Adventitious Agents Safety Evaluation

The gE drug substance purification process has the capacity to effectively clear or inactivate a broad spectrum of adventitious and endogenous virus types. Besides performing viral clearance studies, the extensive characterization testing of the master, working, and end-of-production cell banks for adventitious agents, such as bacteria, viruses, and mycoplasma, provided assurance that the cell banks are not a source of adventitious agents contamination. In addition, routine quality control testing is performed at relevant stages of manufacturing to ensure that no bacterial, fungal or viral adventitious agents are present in the cell bank system, drug substance lots, or final vaccine lots.

 

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