Summary Basis of Decision for Spikevax (previously COVID-19 Vaccine Moderna)

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 Spikevax (previously COVID-19 Vaccine Moderna) is located below.

Recent Activity for Spikevax (previously COVID-19 Vaccine Moderna)

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.

Post-Authorization Activity Table (PAAT) for Spikevax (previously COVID-19 Vaccine Moderna)

Updated: 2024-03-22

The following table describes post-authorization activity for Spikevax (previously COVID-19 Vaccine Moderna), a product which contains the medicinal ingredient elasomeran or mRNA-1273 SARS-CoV-2. 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 02510014 - 100 mcg/0.5 mL elasomeran, dispersion, intramuscular administration
  • DIN 02527685 - 50 mcg/0.25 mL elasomeran, dispersion, intramuscular administration

Post-Authorization Activity Table (PAAT)

Activity/submission type, control number Date submitted Decision and date Summary of activities
DINs 02510014, 02527685 cancelled (post market) Not applicable Discontinuation date: 2024-01-19 The manufacturer notified Health Canada that sale of the drug has been discontinued post market. Health Canada cancelled the DINs pursuant to section C.01.014.6(1)(a) of the Food and Drug Regulations.
NDS # 278419 2023-08-21 Issued NOC 2023-10-04 Submission filed to transfer ownership of the drug product from ModernaTX, Inc. to Moderna Biopharma Canada Corporation. An NOC was issued.

Monthly safety report
Control # 276266

2023-06-15 Review completed 2023-09-26 Submission filed in response to commitments made as per the terms and conditions imposed on the authorization issued under the Food and Drug Regulations. Monthly safety report #23 for the period 2023-04-18 to 2023-05-17. The sponsor was asked to provide updated assessments for the ongoing monitoring of safety events.

Monthly safety report
Control # 275285

2023-05-15 Review completed 2023-09-20 Submission filed in response to commitments made as per the terms and conditions imposed on the authorization issued under the Food and Drug Regulations. Monthly safety report #22 for the period 2023-03-18 to 2023-04-17. The sponsor was asked to provide updated assessments for the ongoing monitoring of safety events.

Monthly safety report
Control # 274403

2023-04-17 Review completed 2023-06-29 Submission filed in response to commitments made as per the terms and conditions imposed on the authorization issued under the Food and Drug Regulations. Monthly safety report #21 for the period 2023-02-18 to 2023-03-17. The sponsor was asked to provide updated assessments for the ongoing monitoring of safety events.
Monthly safety report
Control # 273354
2023-03-16 Review completed 2023-06-29 Submission filed in response to commitments made as per the terms and conditions imposed on the authorization issued under the Food and Drug Regulations. Monthly safety report #20 for the period 2023-01-18 to 2023-02-17. The sponsor was asked to provide updated assessments for the ongoing monitoring of safety events.
Monthly safety report
Control # 272453
2023-02-16 Review completed 2023-06-15 Submission filed in response to commitments made as per the terms and conditions imposed on the authorization issued under the Food and Drug Regulations. Monthly safety report #19 for the period 2022-12-18 to 2023-01-17. The sponsor was asked to provide updated assessments for the ongoing monitoring of safety events.

Amended Terms and Conditions
Control # 252733, 263775

Not applicable

Terms and conditions amended post authorization
2023-06-09

Health Canada updated the Risk Management Plan Terms and Conditions for Spikevax to reflect the accumulation of safety data and information gained in the post-market setting for this vaccine.
PBRER # 272833 2023-03-01 Review completed 2023-06-02 Submission filed in response to commitments made as per the terms and conditions imposed on the authorization issued under the Food and Drug Regulations. PBRER #4 for the period 2022-06-19 to 2022-12-17. The sponsor was asked to provide updated assessments for the ongoing monitoring of safety events.
Post-Market Information Request Review Control # 271477 2023-01-17 Review completed 2023-04-27 Health Canada conducted an ad-hoc review of available data on heavy menstrual bleeding following vaccination. Health Canada requested that the sponsor submit an updated review on this issue in the next PSUR/PBRER. Health Canada will continue to monitor the safety and effectiveness of this vaccine.
Monthly safety report Control # 271450 2023-01-16 Review completed 2023-03-13 Submission filed in response to commitments made as per the terms and conditions imposed on the authorization issued under the Food and Drug Regulations. Monthly safety report #18 for the period 2022-11-19 to 2022-12-17. The sponsor was asked to provide updated assessments for the ongoing monitoring of safety events.
Monthly safety report Control # 270693 2022-12-15 Review completed
2023-02-27

Submission filed in response to commitments made as per the terms and conditions imposed on the authorization issued under the Food and Drug Regulations. Monthly safety report #17 for the period 2022-10-19 to 2022-11-18. The sponsor was asked to provide updated assessments for the ongoing monitoring of safety events.

PBRER # 267341 2022-08-29 Review completed
2023-01-31

Submission filed in response to commitments made as per the terms and conditions imposed on the authorization issued under the Food and Drug Regulations. PBRER #3 for the period 2022-01-01 to 2022-06-18. The sponsor was asked to provide updated assessments for the ongoing monitoring of safety events.

Monthly safety report Control # 269717 2022-11-15 Review completed
2023-01-24

Submission filed in response to commitments made as per the terms and conditions imposed on the authorization issued under the Food and Drug Regulations. Monthly safety report #16 for the period 2022-09-19 to 2022-10-18. The sponsor was asked to provide updated assessments for the ongoing monitoring of safety events.

Post-Market Information Request Review Control # 270676 2022-12-14 Review completed
2023-01-20

Information filed in response to commitments made as per the terms and conditions imposed on the authorization issued under the Food and Drug Regulations. Interim reports for ongoing study P901. The sponsor was asked to continue to provide updated assessments for the ongoing monitoring of safety studies.

Post-Market Information Request Review Control # 269195 2022-10-31 Review completed
2023-01-20

Information filed in response to commitments made as per the terms and conditions imposed on the authorization issued under the Food and Drug Regulations. Interim reports for ongoing study P911. The sponsor was asked to continue to provide updated assessments for the ongoing monitoring of safety studies.

Post-Market Information Request Review Control # 269193 2022-10-31 Review completed
2023-01-20

Information filed in response to commitments made as per the terms and conditions imposed on the authorization issued under the Food and Drug Regulations. Interim reports for ongoing study P903. The sponsor was asked to continue to provide updated assessments for the ongoing monitoring of safety studies.

SNDS # 262408 2022-03-16 Issued NOC (subject to terms and conditions)
2023-01-12

Submission filed as a Level I – Supplement to extend the use of a 50 µg dose booster of Spikevax currently approved for adults 18 years and older to adolescents (12 to <18 years) to prevent COVID-19 caused by SARS-CoV-2. The submission was reviewed and considered acceptable, and an NOC was issued. Terms and conditions were imposed on the authorization. A Regulatory Decision Summary was published.

Monthly safety report Control # 268787 2022-10-18 Review completed
2022-12-08

Submission filed in response to commitments made as per the terms and conditions imposed on the authorization issued under the Food and Drug Regulations. Monthly safety report #15 for the period 2022-08-19 to 2022-09-18. The sponsor was asked to provide updated assessments for the ongoing monitoring of safety events.

Post-Market Information Request Review Control # 268287 2022-09-29 Review completed
2022-11-25

Information filed in response to commitments made as per the terms and conditions imposed on the authorization issued under the Food and Drug Regulations. Interim reports for ongoing study P905. The sponsor was asked to continue to provide updated assessments for the ongoing monitoring of safety studies.

Post-Market Information Request Review Control # 268276 2022-09-29 Review completed
2022-11-25

Information filed in response to commitments made as per the terms and conditions imposed on the authorization issued under the Food and Drug Regulations. Interim reports for ongoing study P904. The sponsor was asked to continue to provide updated assessments for the ongoing monitoring of safety studies.

Monthly safety report Control # 267920 2022-09-15 Review completed
2022-11-25

Submission filed in response to commitments made as per the terms and conditions imposed on the authorization issued under the Food and Drug Regulations. Monthly safety report #14 for the period 2022-07-19 to 2022-08-18. The sponsor was asked to provide updated assessments for the ongoing monitoring of safety events.

Monthly safety report
Control # 267010
2022-08-16 Review completed
2022-10-04

Submission filed in response to commitments made as per the terms and conditions imposed on the authorization issued under the Food and Drug Regulations. Monthly safety report #13 for the period 2022-06-16 to 2022-07-18. The sponsor was asked to provide updated assessments for the ongoing monitoring of safety events.

Bi-monthly safety report
Control # 266110
2022-07-15 Review completed
2022-09-21

Information filed as per the terms and conditions imposed on the authorization issued under the Food and Drug Regulations. Bi-monthly safety report #3 for the period 2022-04-16 to 2022-06-15. The sponsor was asked to provide updated assessments for the ongoing monitoring of safety events.

SNDS # 262952 2022-04-01 Cancellation Letter Received
2022-09-16

Submission filed as a Level I – Supplement for a new indication: as subsequent booster doses in individuals 50 years of age and older who have received a primary series and a first booster dose of any Health Canada-approved COVID-19 vaccine at least 3 months after receipt of a first booster dose. A Summary of Cancellation was published.

Post-Market Information Request Review Control # 263842 2022-04-29 Review completed
2022-08-10

Information filed in response to commitments made as per the terms and conditions imposed on the authorization issued under the Food and Drug Regulations. Interim reports for ongoing studies P903 and P904. The sponsor was asked to continue to provide updated assessments for the ongoing monitoring of safety studies.

SNDS # 263775 2022-04-29 Issued NOC (subject to terms and conditions)
2022-07-14

Submission filed as a Level I – Supplement to seek authorization for use of Spikevax in children 6 months to 5 years of age. The submission was reviewed and considered acceptable, and an NOC was issued. Terms and conditions were imposed on the authorization. A Regulatory Decision Summary was published.

Drug product (DIN 02527685) market notification Not applicable Date of first sale:
2022-07-14

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

Bi-monthly safety report
Control # 264306
2022-05-16 Review completed
2022-07-13

Information filed as per the terms and conditions imposed on the authorization issued under the Food and Drug Regulations. Bi-monthly safety report #2 for the period 2022-02-16 to 2022-04-15. The sponsor was asked to provide updated assessments for the ongoing monitoring of safety events.

PSUR # 262232 2022-03-10 Review completed
2022-07-11

Submission filed as per the terms and conditions imposed on the authorization issued under the Food and Drug Regulations. PSUR #2 for the period 2021-07-01 to 2021-12-31. The sponsor was asked to provide updated assessments for the ongoing monitoring of safety events.

Post-Market Information Request Review Control # 262954 2022-04-01 Review completed
2022-07-05

Health Canada conducted an ad-hoc review of available data on pregnancy- and breastfeeding-related outcomes. Health Canada requested that the sponsor submit interim and final reports, and regular summaries of post-authorization safety studies, and to continue to submit any detailed analyses. The information was assessed and Health Canada will continue to monitor the safety and effectiveness of this vaccine.

Health Product Risk Communication Not applicable Posted
2022-06-06

Health Product Risk Communication posted (Distribution of a New Presentation of Spikevax [elasomeran] COVID-19 Vaccine [0.10 mg/mL in 2.5 mL multidose vial] with English-only Vial and Carton Labels), containing information on labelling, packaging, and product safety for healthcare professionals.

SNDS # 263161 2022-04-07 Issued NOC (subject to terms and conditions)
2022-06-01

Submission filed as a Level I – Supplement for a new presentation and updates to the Product Monograph. The submission was reviewed and considered acceptable, and an NOC was issued. Terms and conditions were imposed on the authorization. A new DIN (02527685) was issued for the new presentation.

Bi-monthly safety report
Control # 262189, 262409, 262953
2022-03-09 Review completed
2022-05-31

Information filed as per the terms and conditions imposed on the authorization issued under the Food and Drug Regulations. Bi-monthly safety report #1 for the period 2022-01-01 to 2022-02-15, and interim reports for ongoing studies P901 and P904. The sponsor was asked to provide updated assessments for the ongoing monitoring of safety events.

SNDS # 262273 2022-03-11 Issued NOC
2022-05-16

Submission filed as a Level I – Supplement to submit Canadian-specific bilingual labelling for Spikevax. The submission was reviewed and considered acceptable, and an NOC was issued.

NC # 262494 2022-03-18 Issued NOL
2022-05-06

Submission filed as a Level II (90 day) Notifiable Change for changes related to the manufacture of the drug substance. The submission was reviewed and considered acceptable, and an NOL was issued.

Amended Terms and Conditions Control # 252733 Not applicable Terms and conditions amended post authorization
2022-04-20

Health Canada imposed a new Term and Condition to the authorization of Spikevax. The Term and Condition of monthly safety reports is considered closed and has been replaced with the requirement to submit bi-monthly safety reports. In addition, the sponsor is required to submit Periodic Safety Update Reports / Periodic Benefit Risk Evaluation Reports every 6 months.

Risk Management Plan Control # 259827 2021-12-21 Review completed
2022-04-12
Submission filed in response to commitments made as per the terms and conditions imposed on the authorization issued under the Food and Drug Regulations, and included the pharmacovigilance plan for the booster indication approved with SNDS # 257293. The submission was reviewed and considered acceptable. The current post-market safety data are consistent with the labelled safety profile of Spikevax.
Monthly safety report
Control # 260469
2022-01-18 Review completed
2022-04-06
Submission filed in response to commitments made as per the terms and conditions imposed on the authorization issued under the Food and Drug Regulations. Monthly safety report #12 for the period 2021-12-01 to 2021-12-31, as well as interim reports for ongoing studies P901, P902 and P903. The sponsor was asked to provide updated assessments for the ongoing monitoring of safety events.
NC # 261785 2022-02-25 Issued NOL
2022-03-22
Submission filed as a Level II (90 day) Notifiable Change to update the release specifications for the drug substance and drug product. The submission was reviewed and considered acceptable, and an NOL was issued.
Post-Market Information Request Review Control # 257574 2021-10-13 Review completed
2022-03-18
Health Canada requested that the sponsor submit an updated cumulative review of events of myocarditis and/or pericarditis. The information was assessed and Health Canada will continue to monitor the safety and effectiveness of this vaccine. The current post-market safety data are consistent with the labelled safety profile of Spikevax.
NC # 261086 2022-02-03 Issued NOL
2022-03-17
Submission filed as a Level II (90 day) Notifiable Change to make changes to reference standards used in the release of the drug substance and drug product. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 258658 2021-11-16 Issued NOC (subject to terms and conditions)
2022-03-17

Submission filed as a Level I – Supplement to seek authorization for use of Spikevax in individuals 6 to 11 years of age. The submission was reviewed and considered acceptable, and an NOC was issued. Terms and conditions were imposed on the authorization. A Regulatory Decision Summary was published.

Post-Market Information Request Review Control # 259122, 259123 2021-12-06 Review completed
2022-03-11
Health Canada requested that the sponsor submit their plan to address the impact of the new variant of concern (Omicron) on the effectiveness and on any associated safety issues of their COVID-19 vaccine. In addition, the sponsor was requested to submit any detailed analyses of the effectiveness of the vaccine against the new variant. The information was assessed and Health Canada will continue to monitor the safety and effectiveness of this vaccine.
Monthly safety report
Control # 259638
2021-12-16 Review completed
2022-02-18
Submission filed in response to commitments made as per the terms and conditions imposed on the authorization issued under the Food and Drug Regulations. Monthly safety report #11 for the period 2021-11-01 to 2021-11-30. The sponsor was asked to provide updated assessments for the ongoing monitoring of safety events.
Monthly safety report
Control # 258708
2021-11-17 Review completed
2022-01-21
Submission filed in response to commitments made as per the terms and conditions imposed on the authorization issued under the Food and Drug Regulations. Monthly safety report #10 for the period 2021-10-01 to 2021-10-31. The sponsor was asked to provide updated assessments for the ongoing monitoring of safety events.
Health Product Risk Communication Not applicable Posted
2022-01-11
Health Product Risk Communication posted (Shelf Life Extension for the Spikevax [elasomeran] COVID-19 Vaccine with Printed Expiry Dates on Vial and Carton Labels), containing information on labelling, packaging, product safety and supply for healthcare professionals.
NC # 259289 2021-12-06 Issued NOL
2021-12-23
Submission filed as a Level II (90 day) Notifiable Change to extend the shelf life from 7 to 9 months. The submission was reviewed and considered acceptable, and an NOL was issued.
Risk Management Plan
Control # 257655
2021-10-15 Review completed
2021-12-20
An update to the European Union (EU) Risk Management Plan (RMP) version 2.3 filed to include information about ongoing safety data, and the adolescent indication. The review concluded that the update is acceptable at this time.
Monthly safety report
Control # 257655
2021-10-15 Review completed
2021-12-07
Submission filed in response to commitments made as per the terms and conditions imposed on the authorization issued under the Food and Drug Regulations. Monthly safety report #9 for the period 2021-09-01 to 2021-09-30. The sponsor was asked to provide updated assessments for the ongoing monitoring of safety events.
Monthly safety report
Control # 256687
2021-09-16 Review completed
2021-12-07
Submission filed in response to commitments made as per the terms and conditions imposed on the authorization issued under the Interim Order Respecting the Importation, Sale and Advertising of Drugs for Use in Relation to COVID-19 (Interim Order). Monthly safety report #8 for the period 2021-08-01 to 2021-08-31. The sponsor was asked to provide updated assessments for the ongoing monitoring of safety events.
SNDS # 257293 2021-10-06 Issued NOC (subject to terms and conditions)
2021-11-12

Submission filed as a Level I – Supplement to seek authorization for a booster dose of Spikevax. The submission was reviewed and considered acceptable, and an NOC was issued. Terms and conditions were imposed on the authorization. A Regulatory Decision Summary was published.

Health Product Risk Communication Not applicable Posted
2021-11-10
Health Product Risk Communication posted (Distribution of Spikevax [elasomeran] COVID-19 Vaccine with English-only Vial and Carton Labels), containing important information about supply for healthcare professionals.
PSUR # 256785 2021-09-20 Review completed
2021-11-04
Submission filed as per the terms and conditions imposed on the authorization issued under the Food and Drug Regulations. PSUR #1 for the period 2020-12-18 to 2021-06-30. The sponsor was asked to provide updated assessments for the ongoing monitoring of safety events.
Updated Health Product Risk Communication Not applicable Posted
2021-10-29
Health Product Risk Communication updated (Importation of COVID-19 Vaccine Moderna with up to 15 Doses per Vial and English-only Vial and Carton Labels [US-Labelled Supply]), containing important information about labelling, safety, packaging and supply for healthcare professionals.
NC # 257706 2021-10-19 Issued NOL
2021-10-29
Submission filed as a Level II (90 day) Notifiable Change to extend the shelf life of 13 lots from 7 to 9 months. The submission was reviewed and considered acceptable, and an NOL was issued.
Drug product (DIN 02510014) market notification Not applicable Date of first sale
2021-09-30
The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NDS # 252733 2021-05-15 Issued NOC (subject to terms and conditions)
2021-09-16

NOC issued for New Drug Submission. The submission was reviewed and considered acceptable, and an NOC was issued. Terms and conditions were imposed on the authorization. Product name changed from COVID-19 Vaccine Moderna to Spikevax. Regulatory Decision Summary published. DIN 02510014 was issued.

Monthly safety report
Control # 255696
2021-08-15 Review completed
2021-09-15
Information filed as per the terms and conditions imposed on the authorization issued under the Interim Order Respecting the Importation, Sale and Advertising of Drugs for Use in Relation to COVID-19 (Interim Order). Monthly safety report #7 for the period 2021-07-01 to 2021-07-31. The sponsor was asked to provide updated assessments for the ongoing monitoring of safety events.
Amendment # 255935 2021-08-25 Authorization amended
2021-09-03
An application submitted to amend the authorization in respect of this drug (relating to a Product Monograph update) has been reviewed and it has been determined that the changes are acceptable. The changes were in response to an Advisement Letter issued by Health Canada, requesting the sponsor update the Product Monograph to include information related to facial paralysis (Bell's palsy) in the Post-market Adverse Reactions and Patient Medication Information sections. The authorization under the Interim Order has been amended to permit these changes.

The authorization in respect of this drug (so amended) continues to be subject to terms and conditions that pertain to matters other than these changes. No additional terms and conditions were imposed when the authorization was amended to reflect these changes.
Amendment # 253430 2021-06-04 Authorization amended
2021-08-27
An application submitted to amend the authorization in respect of this drug (relating to relating to an expansion of the currently-approved indication to children 12 to 17 years of age) has been reviewed and it has been determined that the changes are acceptable. The authorization under the Interim Order has been amended to permit these changes. An updated Risk Management Plan was submitted and approved. The current post-market safety data are consistent with the labelled safety profile of the COVID-19 Vaccine Moderna.

A Summary of the rationale for authorization for use in relation to the COVID-19 pandemic was published.

Additional terms and conditions were imposed on this authorization when it was amended to permit this change, to ascertain the continued safe use of the product.
Monthly safety report
Control # 254480
2021-07-15 Review completed
2021-08-17

Information filed as per the terms and conditions imposed on the authorization issued under the Interim Order Respecting the Importation, Sale and Advertising of Drugs for Use in Relation to COVID-19 (Interim Order). Monthly safety report #6 for the period 2021-06-01 to 2021-06-30. The sponsor was asked to provide updated assessments for the ongoing monitoring of safety events.

Amendment # 253863 2021-06-17 Authorization amended
2021-08-16

An application submitted to amend the authorization in respect of this drug (relating to changes to the manufacturing process for the drug substance) has been reviewed and it has been determined that the changes are acceptable. The authorization under the Interim Order has been amended to permit these changes.

The authorization in respect of this drug (so amended) continues to be subject to terms and conditions that pertain to matters other than these changes. No additional terms and conditions were imposed when the authorization was amended to reflect these changes.

Amendment # 253474 2021-06-08 Authorization amended
2021-08-04

An application submitted to amend the authorization in respect of this drug (relating to a new manufacturing site for the drug product) has been reviewed and it has been determined that the changes are acceptable. The authorization under the Interim Order has been amended to permit these changes.

The authorization in respect of this drug (so amended) continues to be subject to terms and conditions that pertain to matters other than these changes. No additional terms and conditions were imposed when the authorization was amended to reflect these changes.

Amendment # 254062 2021-06-23 Authorization amended
2021-07-21

An application submitted to amend the authorization in respect of this drug (relating to an increase in manufacturing scale of the drug substance) has been reviewed and it has been determined that the changes are acceptable. The authorization under the Interim Order has been amended to permit these changes.

The authorization in respect of this drug (so amended) continues to be subject to terms and conditions that pertain to matters other than these changes. No additional terms and conditions were imposed when the authorization was amended to reflect these changes.

Monthly safety report
Control # 253365
2021-06-17 Review completed
2021-07-08

Information filed as per the terms and conditions imposed on the authorization issued under the Interim Order Respecting the Importation, Sale and Advertising of Drugs for Use in Relation to COVID-19 (Interim Order). Monthly safety report #5 for the period 2021-05-01 to 2021-05-31. The sponsor was asked to provide updated assessments for the ongoing monitoring of safety events.

Advisory Not applicable Posted
2021-06-30

Advisory posted (Health Canada updates Pfizer-BioNTech and Moderna COVID-19 vaccine labels to include information on myocarditis and pericarditis), containing safety information for the general public.

Amendment # 254172 2021-06-28 Authorization amended
2021-06-30

An application submitted to amend the authorization in respect of this drug (relating to a Product Monograph update) has been reviewed and it has been determined that the changes are acceptable. The changes were in response to an Advisement Letter issued by Health Canada to manufacturers of COVID-19 mRNA vaccines, requesting they update labelling with respect to new safety information concerning myocarditis and pericarditis. The authorization under the Interim Order has been amended to permit these changes.

The authorization in respect of this drug (so amended) continues to be subject to terms and conditions that pertain to matters other than these changes. No additional terms and conditions were imposed when the authorization was amended to reflect these changes.

Amendment # 253864 2021-06-18 Authorization amended
2021-06-23

An application submitted to amend the authorization in respect of this drug (authorizing a limited supply from the United States) has been reviewed and it has been determined that the changes are acceptable. The authorization under the Interim Order has been amended to permit these changes.

The authorization in respect of this drug (so amended) continues to be subject to terms and conditions that pertain to matters other than these changes. No additional terms and conditions were imposed when the authorization was amended to reflect these changes.

Dear Healthcare Professional Letter Not applicable Posted
2021-06-14
Dear Healthcare Professional Letter posted (Importation of COVID-19 Vaccine Moderna with up to 15 Doses per Vial and English-only Vial and Carton Labels [US-Labelled Supply]), containing information on supply, labelling and packaging for healthcare professionals.
Amendment # 253433 2021-06-07 Authorization amended
2021-06-11
An application submitted to amend the authorization in respect of this drug (authorizing a limited supply from the United States) has been reviewed and it has been determined that the changes are acceptable. The authorization under the Interim Order has been amended to permit these changes.

The authorization in respect of this drug (so amended) continues to be subject to terms and conditions that pertain to matters other than these changes. No additional terms and conditions were imposed when the authorization was amended to reflect these changes.
Risk Management Plan Control # 253384 2021-06-03 Review completed
2021-06-10
An administrative update to the European Union (EU) Risk Management Plan (RMP) version 1.2 was filed. The review concluded that the update is acceptable at this time.
Amendment # 251607 2021-04-13 Authorization amended
2021-06-09
An application submitted to amend the authorization in respect of this drug (relating to updates to the Product Monograph and storage conditions) has been reviewed and it has been determined that the changes are acceptable. The in-use time for filled syringes and punctured vials was extended from 6 to 24 hours, and room temperature storage of unpunctured vials was extended from 12 to 24 hours. The authorization under the Interim Order has been amended to permit these changes.

The authorization in respect of this drug (so amended) continues to be subject to terms and conditions that pertain to matters other than these changes. No additional terms and conditions were imposed when the authorization was amended to reflect these changes.
Monthly safety report
Control # 252740
2021-05-14 Review completed
2021-06-07
Information filed as per the terms and conditions imposed on the authorization issued under the Interim Order Respecting the Importation, Sale and Advertising of Drugs for Use in Relation to COVID-19 (Interim Order). Monthly safety report #4 for the period 2021-04-01 to 2021-04-30. The sponsor was asked to provide updated assessments for the ongoing monitoring of safety events.
Amendment # 252738 2021-05-17 Authorization amended
2021-05-31

An application submitted to amend the authorization in respect of this drug (relating to new manufacturing sites for the drug substance) has been reviewed and it has been determined that the changes are acceptable. The authorization under the Interim Order has been amended to permit these changes.

The authorization in respect of this drug (so amended) continues to be subject to terms and conditions that pertain to matters other than these changes. No additional terms and conditions were imposed when the authorization was amended to reflect these changes.

Amendment # 250291 2021-03-08 Authorization amended
2021-05-17
An application submitted to amend the authorization in respect of this drug (relating to alternative quality control testing sites for the drug substance and drug product) has been reviewed and it has been determined that the changes are acceptable. The authorization under the Interim Order has been amended to permit these changes.

The authorization in respect of this drug (so amended) continues to be subject to terms and conditions that pertain to matters other than these changes. No additional terms and conditions were imposed when the authorization was amended to reflect these changes.
Monthly safety report
Control # 251801
2021-04-15 Review completed
2021-05-07
Information filed as per the terms and conditions imposed on the authorization issued under the Interim Order Respecting the Importation, Sale and Advertising of Drugs for Use in Relation to COVID-19 (Interim Order). Monthly safety report #3 for the period 2021-02-18 to 2021-03-31. The current post-market safety data are consistent with the labelled safety profile of COVID-19 Vaccine Moderna.
Monthly safety report
Control # 250475
2021-03-16 Review completed
2021-04-27
Information filed as per the terms and conditions imposed on the authorization issued under the Interim Order Respecting the Importation, Sale and Advertising of Drugs for Use in Relation to COVID-19 (Interim Order). Monthly safety report #2 for the period 2021-01-18 to 2021-02-17. The current post-market safety data are consistent with the labelled safety profile of COVID-19 Vaccine Moderna.
Amendment # 251731 2021-04-16 Authorization amended
2021-04-23
An application submitted to amend the authorization in respect of this drug (relating to an alternative container closure system) has been reviewed and it has been determined that the changes are acceptable. The authorization under the Interim Order has been amended to permit these changes.

The authorization in respect of this drug (so amended) continues to be subject to terms and conditions that pertain to matters other than these changes. No additional terms and conditions were imposed when the authorization was amended to reflect these changes.
Amendment # 251635 2021-04-13 Authorization amended
2021-04-23
An application submitted to amend the authorization in respect of this drug (relating to a new source of a raw material) has been reviewed and it has been determined that the changes are acceptable. The authorization under the Interim Order has been amended to permit these changes.

The authorization in respect of this drug (so amended) continues to be subject to terms and conditions that pertain to matters other than these changes. No additional terms and conditions were imposed when the authorization was amended to reflect these changes.
Amendment # 250173 2021-03-05 Authorization amended
2021-03-19
An application submitted to amend the authorization in respect of this drug (relating to manufacturing process changes for the drug substance and drug product) has been reviewed and it has been determined that the changes are acceptable. The authorization under the Interim Order has been amended to permit these changes.

The authorization in respect of this drug (so amended) continues to be subject to terms and conditions that pertain to matters other than these changes. No additional terms and conditions were imposed when the authorization was amended to reflect these changes.
Amendment # 249696 2021-02-09 Authorization amended
2021-03-10
An application submitted to amend the authorization in respect of this drug (relating to a Canadian-specific label) has been reviewed and it has been determined that the changes are acceptable. The authorization under the Interim Order has been amended to permit these changes.

The authorization in respect of this drug (so amended) continues to be subject to terms and conditions that pertain to matters other than these changes. No additional terms and conditions were imposed when the authorization was amended to reflect these changes.
Monthly safety report
Control # 249434
2021-02-15 Review completed
2021-03-02
Information filed as per the terms and conditions imposed on the authorization issued under the Interim Order Respecting the Importation, Sale and Advertising of Drugs for Use in Relation to COVID-19 (Interim Order). Monthly safety report #1 for the period 2020-12-18 to 2021-01-17. The current post-market safety data are consistent with the labelled safety profile of COVID-19 Vaccine Moderna.
Amendment # 249865 2021-02-26 Authorization amended
2021-02-27
An application submitted to amend the authorization in respect of this drug (relating to a new source of a raw material) has been reviewed and it has been determined that the changes are acceptable. The authorization under the Interim Order has been amended to permit these changes.

The authorization in respect of this drug (so amended) continues to be subject to terms and conditions that pertain to matters other than these changes. No additional terms and conditions were imposed when the authorization was amended to reflect these changes.
Amendment # 249649 2021-01-25 Authorization amended
2021-02-27
An application submitted to amend the authorization in respect of this drug (relating to a new source of a raw material) has been reviewed and it has been determined that the changes are acceptable. The authorization under the Interim Order has been amended to permit these changes.

The authorization in respect of this drug (so amended) continues to be subject to terms and conditions that pertain to matters other than these changes. No additional terms and conditions were imposed when the authorization was amended to reflect these changes.
Dear Healthcare Professional Letter Not applicable Posted
2021-02-22
Dear Healthcare Professional Letter posted (Updated English-only Global Vial and Carton Labels and Post-Market Adverse Reaction Information), containing important information about supply, label update, and product safety for healthcare professionals.
Amendment # 248159 2021-01-11 Authorization amended
2021-02-19
An application submitted to amend the authorization in respect of this drug has been reviewed and it has been determined that the changes are acceptable. The Product Monograph was updated with new safety information identified during pharmacovigilance activities. Anaphylaxis has now been reported through vaccine surveillance programs during mass vaccination. In addition, the brand name has been revised from Moderna COVID-19 Vaccine to COVID-19 Vaccine Moderna. The authorization under the Interim Order has been amended to permit these changes.

The authorization in respect of this drug (so amended) continues to be subject to terms and conditions that pertain to matters other than these changes. No additional terms and conditions were imposed when the authorization was amended to reflect these changes.
Risk Management Plan Control # 248156 2021-01-25 Review completed
2021-02-17
The updated Core (European Union [EU]) Risk Management Plan (RMP) and Canadian Addendum were filed as per the terms and conditions imposed on the authorization issued under the Interim Order Respecting the Importation, Sale and Advertising of Drugs for Use in Relation to COVID-19. The review of the Core EU RMP in conjunction with the Canadian Addendum is acceptable at this time. The safety concerns and their corresponding pharmacovigilance and risk minimization activities may be updated in a timely manner as more data becomes available in the clinical trial programs and in the real world use setting.
Drug product (DIN 02510014) market notification Not applicable Date of first sale:
2020-12-23
The manufacturer notified Health Canada of the date of first sale in accordance with section 8 of the Interim Order Respecting the Importation, Sale and Advertising of Drugs for Use in Relation to COVID-19.
Dear Healthcare Professional Letter Not applicable Posted
2020-12-23
Dear Healthcare Professional Letter posted (Authorization of the Moderna COVID-19 Vaccine with English-only Vial and Carton Labels), containing important information about supply and product safety for healthcare professionals.
Application # 244946 2020-10-12 Authorized (with terms and conditions)
2020-12-23
Authorized with terms and conditions under the Interim Order Respecting the Importation, Sale and Advertising of Drugs for Use in Relation to COVID-19
Summary Basis of Decision (SBD) for Spikevax (previously COVID-19 Vaccine Moderna)

Date SBD issued: 2021-01-06

The following information relates to the interim authorization of Spikevax (previously COVID-19 Vaccine Moderna).

mRNA-1273 SARS-CoV-2

Drug Identification Number (DIN):

  • DIN 02510014 - 100 µg/0.5 mL, suspension, intramuscular administration

Moderna Therapeutics Inc.

Application Control Number: 244946

 

On December 23, 2020, Health Canada issued an authorization under the Interim Order Respecting the Importation, Sale and Advertising of Drugs for Use in Relation to COVID-19 (Interim Order) to Moderna Therapeutics Inc. for the Moderna COVID‑19 Vaccine. The Interim Order, signed by the Minister of Health on September 16, 2020, establishes new authorization pathways with the intent to expedite the authorization for the importation, sale and advertising of drugs used in relation to coronavirus disease 2019 (COVID-19), while taking into consideration urgent public health needs caused by COVID-19.

The interim authorization of the Moderna COVID‑19 Vaccine was based on quality (chemistry and manufacturing), non‑clinical (pharmacology and toxicology), and clinical (immunogenicity, safety, and efficacy) information. Following review of the available information, Health Canada considers that the evidence provided meets the Health Canada standards published in the Guidance for Market Authorization Requirements for COVID-19 Vaccines. The evidence supports the conclusion that the benefits associated with the Moderna COVID‑19 Vaccine outweigh the risks, having regard to the uncertainties relating to the benefits and risks and the necessity of addressing the urgent public health need related to COVID‑19. Based on these considerations, the benefit‑risk profile of the Moderna COVID‑19 Vaccine is considered favourable for active immunization to prevent against COVID-19 caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus in individuals 18 years of age and older.

The interim authorization of the Moderna COVID‑19 Vaccine is subject to terms and conditions that need to be met by the sponsor to ascertain the continued quality, safety, and efficacy of the product. The terms and conditions may be amended at any time. Furthermore, this authorization may be revoked if new information does not support the safe and effective use of the product.

For further information on authorization under this pathway, refer to Health Canada's Interim Order Respecting the Importation, Sale, and Advertising of Drugs for Use in Relation to COVID-19 and the Information and Application Requirements for Drugs Authorized under the Interim Order: Guidance Document.

1 What was approved?

The Moderna COVID-19 Vaccine (mRNA-1273 SARS-CoV-2) is indicated for active immunization against coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus in individuals 18 years of age and older.

The authorization of the Moderna COVID‑19 Vaccine under the Interim Order Respecting the Importation, Sale, and Advertising of Drugs for Use in Relation to COVID-19 (Interim Order) is supported by results from the efficacy analysis of the pivotal Phase III study (Study mRNA‑1273‑P301 or COVE Study) which included 30,351 participants.

Based on the data submitted to and reviewed by Health Canada, the safety and efficacy of the Moderna COVID‑19 Vaccine have been established in participants 18 years of age and older. The safety and efficacy of the Moderna COVID‑19 Vaccine in individuals under 18 years of age have not yet been established.

Clinical studies of the Moderna COVID‑19 Vaccine include participants 65 years of age and older and their data contribute to the overall assessment of safety and efficacy.

In the ongoing pivotal Phase III clinical study (COVE Study), the safety and efficacy of the Moderna COVID‑19 Vaccine were assessed in individuals 18 years of age and older, including 3,583 participants 65 years of age and older. The efficacy of the Moderna COVID‑19 Vaccine was consistent between older subjects (≥65 years) and younger subjects (18 to 64 years). Participants 65 years of age and older reported solicited local and systemic adverse reactions at a lower rate than younger subjects 18‑64 years of age.

The Moderna COVID‑19 Vaccine is contraindicated in individuals who are hypersensitive to the active ingredient or to any ingredients in the formulation, including any non-medicinal ingredient or component of the container, or to a previous dose of the Moderna COVID‑19 Vaccine.

The Moderna COVID‑19 Vaccine (mRNA-1273 SARS-CoV-2, 100 µg/0.5 mL) is presented as a suspension. In addition to the medicinal ingredient, the suspension contains the lipid excipients [1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC)], PEG2000 DMG (1,2-dimyristoyl-rac-glycerol,methoxy-polyethyleneglycol), and lipid SM‑102, as well as acetic acid, cholesterol, sodium acetate, sucrose, tromethamine, tromethamine hydrochloride, 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 Moderna COVID-19 Vaccine Product Monograph, approved by Health Canada and available through the Drug Product Database and on the Health Canada COVID‑19 vaccines and treatments portal.

2 Why was Spikevax (previously COVID-19 Vaccine Moderna) approved?

Health Canada considers that sufficient evidence has been provided to support the conclusion that the benefits associated with the Moderna COVID‑19 Vaccine outweigh the risks, having regard to the uncertainties relating to the benefits and risks and the necessity of addressing the urgent public health need related to coronavirus disease 2019 (COVID‑19). Based on these considerations, the benefit risk-profile of the Moderna COVID‑19 Vaccine is deemed favourable for active immunization against COVID‑19 caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus in individuals 18 years of age and older.

The use of the Moderna COVID‑19 Vaccine is permitted under an authorization issued in accordance with section 5 of the Interim Order Respecting the Importation, Sale, and Advertising of Drugs for Use in Relation to COVID-19 (Interim Order). The interim authorization is subject to terms and conditions that need to be met by the sponsor to ascertain the continued quality, safety, and efficacy of the product.

Coronavirus disease 2019 is the infectious disease caused by the recently discovered coronavirus, SARS‑CoV‑2, that emerged in late 2019. In Canada, there have been 528,354 confirmed cases of COVID‑19 and 14,597 deaths as of December 23, 2020, the date of authorization of the Moderna COVID‑19 Vaccine. In most cases, COVID‑19 presents as a mild to moderately severe acute respiratory illness with fever, cough, shortness of breath, and breathing difficulties. People with COVID‑19 have reported a wide range of symptoms, ranging from mild symptoms to severe illness. Symptoms may appear 1 to 14 days after exposure to the virus, and may include fever or chills, cough, shortness of breath, fatigue, muscle or body aches, headache, new loss of taste or smell, sore throat, congestion or runny nose, nausea or vomiting, or diarrhea. The majority of patients infected with SARS‑CoV‑2 recover without significant sequelae. However, 10‑15% of cases progress to severe disease, and 5% become critically ill. Significant risk factors such as age and underlying medical issues increase the likelihood of developing a severe disease. In around 30% of cases, symptoms may linger or recur over the weeks following the initial recovery, even in patients who had a mild disease.

Care for individuals who have COVID‑19 has improved with clinical experience, and clinical management of COVID‑19 with a variety of therapies has continued to improve. On December 9, 2020, the Pfizer‑BioNTech COVID‑19 Vaccine was authorized by Health Canada under the Interim Order Respecting the Importation, Sale, and Advertising of Drugs for Use in Relation to COVID‑19 (Interim Order). This vaccine is indicated for active immunization to prevent COVID‑19 caused by the SARS‑CoV‑2 virus in individuals 16 years of age and older. Nevertheless, there remains an urgent need for further prophylactic vaccine options in the context of the ongoing and worsening pandemic. The Moderna COVID‑19 Vaccine is the second vaccine to protect against COVID‑19 to be authorized in Canada.

The Moderna COVID‑19 Vaccine is comprised of a messenger ribonucleic acid (mRNA)-lipid complex (lipid nanoparticle) dispersion, containing an mRNA (CX-024414) that encodes for the prefusion stabilized spike glycoprotein of the novel coronavirus (SARS-CoV-2) and four lipids acting as protectants and carriers of the mRNA. The four lipids are: SM‑102 (a custom-manufactured, ionizable lipid); PEG2000-DMG (1,2-dimyristoyl-rac-glycerol,methoxy-polyethyleneglycol); 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC); and cholesterol.

Clinical evidence for the efficacy of the Moderna COVID‑19 Vaccine is based primarily on the available data from the ongoing COVE Study (Study mRNA‑1273‑P301), a Phase III, pivotal clinical study. The COVE Study is a randomized, stratified, observer-blinded, placebo-controlled study to evaluate the efficacy, safety, and immunogenicity of the Moderna COVID‑19 Vaccine (mRNA-1273 SARS-CoV-2) in adults aged 18 years and older who have no known history of SARS-CoV-2 infection.

The COVE Study has enrolled 30,351 participants 18 years of age and older who were randomized evenly between two groups and who received two doses of the Moderna COVID‑19 Vaccine (mRNA-1273 SARS-CoV-2, 100 µg/0.5 mL; n = 15,181) or a placebo injection (0.9% sodium chloride; n = 15,170), administered 28 days apart. Randomization was stratified further into three groups: participants ≥65 years; participants <65 years and categorized to be at increased risk ("at risk") for complications of COVID‑19; and participants <65 years and "not at risk" for complications of COVID-19. Participants were followed for a median of 63 days from Dose 2 at the time of analysis.

COVE Study, Phase III; Participants in final efficacy analysis
  Vaccine group Placebo group Total
Male 7,366 (52.1%) 7,462 (53.0%) 14,828 (52.6%)
Female 6,768 (47.9%) 6,611 (47.0%) 13,379 (47.4%)
Total number of participants
(18 years of age and older)
14,134 14,073 28,207
Participants in safety analysis
Total number of participants
(18 years of age and older)
15,181 15,170 30,351

The primary efficacy endpoint of the COVE Study was to demonstrate vaccine efficacy of the Moderna COVID‑19 Vaccine to prevent symptomatic COVID‑19 starting 14 days after the second dose of vaccine. To be considered a case of COVID‑19 for the evaluation of the primary efficacy endpoint, the following criteria had to be met. The participant must:

  • have experienced at least two of the following systemic symptoms: fever (≥38°C), chills, myalgia, headache, sore throat, new olfactory and taste disorder(s), or
  • have experienced at least one of the following respiratory signs/symptoms: cough, shortness of breath or difficulty breathing, or clinical or radiographic evidence of pneumonia, and
  • have at least one nasopharyngeal swab, nasal swab, or saliva sample (or respiratory sample, if hospitalized) positive for SARS-CoV-2 confirmed by reverse transcription‑polymerase chain reaction (RT‑PCR).

The vaccine efficacy success criteria for the primary endpoint, predefined by the sponsor, was a lower bound of the 95% confidence interval (CI) above 30%.

At the time of the final primary efficacy analysis, participants had been followed for symptomatic COVID‑19 for a median of two months after the second dose, corresponding to 3,304.9 person‑years in the vaccine group and 3,273.7 person‑years in the placebo group.

As demonstrated through the results of the final efficacy analysis, the Moderna COVID-19 Vaccine met the primary efficacy endpoint of the study and exceeded Health Canada's vaccine efficacy success criteria.

Vaccine efficacy success criteria
As defined in Health Canada's Guidance for Market Authorization Requirements for COVID-19 Vaccines
Target threshold of at least 50% efficacy, with a lower bound of the 95% confidence interval (CI) above 30%

*Predefined by sponsor for the COVE Study, Phase III
The one-sided p-value is from the stratified Cox proportional hazard model to test the null hypothesis of vaccine efficacy ≤30%.
Efficacy rates observed in final efficacy analysis (COVE Study, Phase III)
  Vaccine efficacy rate Two-sided 95% CI
Overall
Participants 18 years of age and older
94.1%
(p<0.0001)*
89.3% to 96.8%
Participants 18 to <65 years of age 95.6% 90.6% to 97.9%
Participants 65 years of age and older 86.4% 61.4% to 95.5%

The Moderna COVID‑19 Vaccine met the primary efficacy endpoint of the study, as demonstrated through the results of the final efficacy analysis. It demonstrated a vaccine efficacy rate of 94.1% compared to placebo (95% CI: 89.3%, 96.8% [p value <0.0001]) in the overall group of participants who were over the age of 18 without evidence of prior SARS-CoV-2 infection. This analysis was based on 196 adjudicated cases of COVID‑19 starting at least 14 days after Dose 2 (185 in the placebo group and 11 in the vaccine group). Participants who received the Moderna COVID‑19 Vaccine in the 18 to <65 years of age group demonstrated a vaccine efficacy rate of 95.6% (95% CI: 90.6%, 97.9%). In participants 65 years of age and older who received the Moderna COVID‑19 Vaccine, the vaccine efficacy rate was 86.4% (95% CI: 61.4%, 95.5%).

The observed vaccine efficacy following the first dose of the Moderna COVID‑19 Vaccine appears to show some protection; however, there is insufficient data regarding protection beyond 28 days without a second dose.

The vaccine efficacy results for the key secondary endpoints were consistent with the efficacy evaluated for the primary endpoint. At the time of the primary analysis, there had been 30 cases of severe COVID‑19 reported in the study, with all cases occurring in the placebo group and no cases in the Moderna COVID-19 Vaccine group. The confinement of all severe cases to the placebo groups suggests no evidence for vaccine‑associated enhanced respiratory disease (VAERD).

The immunogenicity of the Moderna COVID‑19 Vaccine was evaluated in Study mRNA-1273-P201 (Phase IIa) and Study DMID 20-0003-P101 (Phase I). The results indicated that the Moderna COVID‑19 Vaccine elicited robust SARS‑CoV‑2 immune responses one to two weeks after Dose 2.

Evidence of the clinical safety of the Moderna COVID‑19 Vaccine was based primarily on data from the 30,351 participants in the Phase III pivotal study (COVE Study). Of the participants, 15,181 in the vaccine group and 15,170 in the placebo group received Dose 1. A total of 14,134 participants in the vaccine group and 14,073 participants in the placebo group received Dose 2. Participants were followed for a median of 92 days after Dose 1 and 63 days after Dose 2.

The Moderna COVID‑19 Vaccine exhibits significant reactogenicity. The most frequently reported adverse reactions (ARs) after Dose 1 or Dose 2 of the Moderna COVID‑19 vaccine were: pain at the injection site (92.0%), fatigue (70.0%), headache (64.7%), myalgia (61.5%), and chills (45.4%). The majority of local and systemic ARs were mild to moderate in severity and resolved within 2 to 3 days. Adverse reactions were more common in younger participants (18 to <65 years) as compared to older adults (≥65 years) and were more frequent and severe after Dose 2 of the Moderna COVID‑19 Vaccine. The absolute number of serious adverse events (SAEs) was 0.5% in Moderna COVID‑19 Vaccine recipients and 0.6% in placebo recipients. There were no life-threatening adverse events or deaths related to the vaccine.

The safety and efficacy of the Moderna COVID-19 Vaccine in pregnant women have not yet been established and the available data are insufficient to predict vaccine-associated risks in pregnancy. A total of 13 pregnant participants (6 in the vaccine group and 7 in the placebo group) were recorded in the safety database at the time of the data cut-off. These participants continue to be followed for pregnancy outcomes. There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Moderna COVID‑19 Vaccine during pregnancy. Women who are vaccinated with Moderna COVID‑19 Vaccine during pregnancy are encouraged to enroll in the registry.

It is unknown if the Moderna COVID‑19 Vaccine is excreted in human breast milk. Data are not available to assess the effects of the Moderna COVID‑19 Vaccine on the breastfed infant or on milk production.

No adequate and well-controlled studies were conducted in immunocompromised individuals. Individuals who are immunocompromised or taking immunosuppressive therapy at the time of vaccine administration may have diminished response to immunization.

The adverse event profile did not suggest any serious safety concerns associated with the vaccine. The frequency of serious adverse events was low without meaningful imbalances between study arms. The adverse events observed showed that the Moderna COVID‑19 Vaccine at 100 µg was safe and well tolerated in participants and within demographic subgroups based on age, sex, and race/ethnicity. No serious allergic reactions were associated with the vaccine. During the Phase III clinical trial, there was 1 reported case of anaphylaxis in the vaccine arm and 1 case reported following placebo, that were both found to be unrelated to the vaccination. The vaccine is contraindicated in individuals who are allergic to the active substance or to any ingredients in the vaccine.

Collectively, the results of the clinical efficacy and safety evaluation demonstrated that the Moderna COVID‑19 Vaccine met the safety requirements as specified in Health Canada's Guidance for Market Authorization Requirements for COVID-19 Vaccines. The vaccine was determined to be safe and well tolerated in participants 18 years of age and older when administered according to the recommended dosage regimen. Two important limitations noted are, a current lack of data for the long-term safety and efficacy of the vaccine, and a lack of data in sub-populations (e.g., pregnant or breastfeeding women, immunosuppressed patients, and children). These identified limitations are managed through labelling and the Risk Management Plan. It is noteworthy that the Phase III study is ongoing and will collect additional information on the long-term safety and efficacy of the Moderna COVID‑19 vaccine over a period of 24 months.

A Core (European Union) Risk Management Plan (RMP) for the Moderna COVID‑19 Vaccine was submitted by Moderna Therapeutics Inc. to Health Canada. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and, when needed, to describe measures that will be put in place to minimize risks associated with the product. The RMP for the Moderna COVID‑19 Vaccine includes information about the important potential risks of VAERD and anaphylactic reactions, including anaphylaxis. The RMP also identified six areas of missing (limited/no clinical data) information: "use in pediatric", "use in pregnant and breastfeeding women", "long‑term safety", "long‑term effectiveness" including "real‑world use", "safety and immunogenicity in subjects with immune-suppression", and "concomitant administration with non-COVID vaccines". Upon review, Health Canada recommended that "younger than 18 years of age" be specified in the "use in pediatric" populations as missing information in the RMP. In addition, Health Canada recommended the addition of vaccine-associated enhanced disease (VAED) as an important potential risk.

Overall, the RMP was considered to be acceptable and identified appropriate monitoring (pharmacovigilance) activities and risk minimization measures based on the safety profile of the product. The identified limitations and areas of missing information are managed through labelling and will continue to be investigated through ongoing and planned studies. The Phase III COVE Study is ongoing and will continue to collect information on the long-term safety and efficacy of the vaccine. In addition, there are post‑authorization commitments for monitoring the long-term safety and efficacy of the Moderna COVID‑19 Vaccine. As outlined in the terms and conditions, the RMP will be updated to reflect additional safety information, including that which is relevant to the Canadian-specific context, as it becomes available. In addition to regulatory requirements for post-market monitoring and reporting, monthly safety summary reports will be provided to Health Canada and will include information related to special populations (e.g., pregnant women). Results related to safety and effectiveness from ongoing and planned studies will be submitted as they become available. For more information, refer to the complete list of terms and conditions available on the Health Canada COVID‑19 vaccines and treatments portal.

Terms and conditions relating to developing and implementing Canadian-specific labelling have also been put in place.

Given the high unmet medical need and the emergency context of the COVID‑19 pandemic, Health Canada considers that the Moderna COVID‑19 Vaccine has a favourable benefit‑risk balance and an acceptable safety profile.

Pursuant to Section 5 of the Interim Order, the Moderna COVID‑19 Vaccine has been authorized for sale in Canada, with associated terms and conditions set out to ascertain the continued quality, safety and efficacy of the product. At any time, the terms and conditions may be amended. In addition, the authorization may be revoked if new information does not support the safe and effective use of the product.

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 Spikevax (previously COVID-19 Vaccine Moderna)?

The application for authorization of the Moderna COVID‑19 Vaccine (mRNA-1273 SARS-CoV-2) was filed on October 12, 2020, in accordance with section 3 of the Interim Order Respecting the Importation, Sale and Advertising of Drugs for Use in Relation to COVID-19 (Interim Order).

The intent of the Interim Order (signed by the Minister of Health on September 16, 2020), is to expedite the authorization of coronavirus disease 2019 (COVID‑19) drugs, while still protecting the health and safety of Canadians who will use these drugs. Authorizations under this Interim Order will be granted only if Health Canada determines that the benefits and risks of the product are supported by evidence that the drug is safe, effective and of high quality, taking into consideration the uncertainties related to the drug in the context of the urgent public health needs related to COVID‑19. As outlined in the Guidance Document: Information and Application Requirements for Drugs Authorized under the Interim Order, the Interim Order recognizes that applications may not be complete at the time of initial filing and information may be submitted as it becomes available, until the application is deemed complete. This process can reduce time to authorization for these important drugs while maintaining appropriate standards of safety, efficacy, and quality.

The Interim Order sets out a modified set of application requirements with the potential for a rolling submission of information. This allows Health Canada to begin its assessment using the information submitted by the applicant and accept new evidence as it becomes available until the application is deemed complete.

Following an expedited review of the clinical, non-clinical, and quality data submitted, Health Canada determined that sufficient evidence was provided to support the conclusion that the benefits associated with the Moderna COVID‑19 Vaccine outweigh the risks, taking into consideration the uncertainties relating to the benefits and risks and the necessity of addressing the urgent public health need related to COVID‑19. An authorization for sale of the Moderna COVID‑19 Vaccine, with imposed terms and conditions, was issued by Health Canada on December 23, 2020.

 

Submission Milestones: Spikevax (previously COVID-19 Vaccine Moderna)

Submission Milestone Date
Initial application filed by sponsor 2020-10-12
Initial clinical data submitted by sponsor 2020-10-30
Initial quality data submitted by sponsor 2020-10-30
Initial non-clinical data submitted by sponsor 2020-11-16
Educational material submitted by sponsor 2020-12-09
Risk Management Plan submitted by sponsor 2020-12-11
Health Canada Biostatistics Evaluation complete 2020-12-18
Health Canada Review of Risk Management Plan complete 2020-12-21
Health Canada Quality Evaluation complete 2020-12-21
Terms and Conditions finalized by Health Canada 2020-12-21
Health Canada Clinical/Medical Evaluation complete 2020-12-22
Final Product Monograph (English and French) submitted by sponsor 2020-12-22
Health Canada Labelling Review complete 2020-12-22
Interim authorization issued by Director General, Biologic and Radiopharmaceutical Drugs Directorate, Health Canada 2020-12-23

The Canadian regulatory decision on the review of the Moderna COVID‑19 Vaccine was based on a critical assessment of the data package submitted to Health Canada. The information submitted to Health Canada also included the Emergency Use Authorization Request filed to the United States Food and Drug Administration, which was consulted in the review of the final efficacy analysis. A European Risk Management Plan was also submitted.

For further information on authorization under this pathway, refer to Health Canada's Interim Order Respecting the Importation, Sale, and Advertising of Drugs for Use in Relation to COVID-19 and the Information and Application Requirements for Drugs Authorized under the Interim Order: Guidance Document.

4 What follow-up measures will the company take?

In accordance with section 10 of the Interim Order Respecting the Importation, Sale, and Advertising of Drugs for Use in Relation to COVID-19 (Interim Order), terms and conditions were imposed on the authorization issued in respect of the Moderna COVID‑19 Vaccine.

These terms and conditions set out requirements relating to clinical information, quality (chemistry and manufacturing), risk management plan (RMP) elements, and labelling, and were put in place to ascertain the continued quality, safety, and efficacy of the product.

The terms and conditions include (but are not limited to) the following:

  • The next database lock will be determined following changes to the protocol to address the crossing over of placebo recipients to the vaccine group. The sponsor will provide the amendment, including how the sponsor will try to keep patients in the study and the new data lock points as soon as possible. Based on the new data lock points, the sponsor will provide the following:
    • An overall safety summary within two weeks after the database lock; and
    • Full study report including safety, efficacy, and immunogenicity when available.
  • The sponsor will provide a safety update for participants in the Phase III COVE Study (mRNA‑1273‑P301) at the 6‑month safety follow-up, when available, for at least 3,000 vaccinated participants as well as for available and relevant data from placebo participants.
  • Also, to fill data gaps, for various sub-populations for example, the sponsor will provide results, when available, of all ongoing studies, or studies to come, conducted with the vaccine.

Additionally, the sponsor will:

  • Submit prompt reporting of adverse reactions to the Canada Vigilance Program.
  • Submit monthly safety reports for the period of the interim authorization, unless otherwise determined by Health Canada.
  • Provide, prior to distribution, patient information cards to support traceability, where required, which will include elements such as manufacturer name, name of vaccinee, space for recording dates of first and second doses and associated batch/lot numbers, and information on how to report any adverse events.
  • Provide, when available, an updated Canadian Addendum to the Core (European Union [EU]) RMP that will include vaccine-associated enhanced disease (VAED) as an important potential risk. It will also specify "younger than 18 years of age" in the "use in pediatric" populations as missing information in the RMP.
  • Provide an updated Core (EU) RMP and a Canadian Addendum in a timely manner if a signal of safety issue is observed in post‑authorization surveillance.
  • Submit final snapshots of all components of the electronic platform, containing Canadian‑specific labelling information for the Moderna COVID-19 Vaccine in French and English for Health Canada's review and records, prior to launch of the electronic platform.
  • Develop and distribute a Health Product Risk Communication, in French and English, with Health Canada approval and endorsement, to inform healthcare professionals about the authorization of the Moderna COVID‑19 Vaccine under the Interim Order with the English‑only vial and carton labels for the initial supply, to expedite global access of the drug in the context of the pandemic.
    • The letter should direct healthcare professionals to the electronic platform where they can find information about Canadian‑specific labelling in both official languages and should be issued prior to and alongside the distribution of the vaccine.
  • Commit to developing Canadian‑specific bilingual labelling for the Moderna COVID‑19 Vaccine and implementing such labelling at a point when the global supply and pandemic situation will allow. Health Canada should be kept informed of estimated timelines and proposed strategies.
    • During the period prior to implementation of the Canadian-specific bilingual labelling, an authorized interim version of the proposed Canadian labels should be made available to healthcare professionals as reference.
  • Submit a certificate of analysis for each lot distributed in Canada, as outlined in the Guidance for market authorization requirements for COVID‑19 vaccines: Quality, manufacturing and lot release requirements. In addition, certificates of analysis for lots distributed to the United States should be submitted on a quarterly basis, and a summary of batch disposition should be submitted on a biannual basis.
  • Promptly provide information with regard to additional process and assay validation, stability studies and any new manufacturing facilities or manufacturing changes to ensure continued alignment with the authorization under the Interim Order.
  • Provide notification of changes in the Good Manufacturing Practices status, when available, for any of the facilities included in the authorization as well as any new facilities relevant to the Canadian supply chain.
  • Provide stability information in a timely manner to support extension of the expiry date. Once approved, relevant databases should be updated with the new expiry date.
6 What other information is available about drugs?

Health Canada is committed to providing up‑to‑date information related to vaccines and treatments for COVID‑19. Up‑to‑date information can be found at the following links:

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

The clinical data provided in the application for authorization of the Moderna COVID‑19 Vaccine (mRNA-1273 SARS-CoV-2) under the Interim Order Respecting the Importation, Sale, and Advertising of Drugs for Use in Relation to COVID-19 (Interim Order) included results of the final primary efficacy analysis from the ongoing pivotal Phase III efficacy, safety and immunogenicity study (COVE Study or Study mRNA‑1273‑P301), in which the primary efficacy endpoint has been met. Data from a first-in-human, dose-ranging Phase I safety and immunogenicity study (Study DMID 20‑0003-P101), and the dose-confirmation Phase IIa safety and immunogenicity study (Study mRNA-1273-P201), have also been submitted in support of the dosage regimen, and the safety and immunogenicity of the vaccine. Across the three studies, 15,419 participants have been dosed with the 100 µg dose of mRNA-1273 SARS-CoV-2.

The clinical data reviewed in this application were submitted on a rolling basis, as is permitted under the Interim Order. The sponsor additionally submitted information related to the request for Emergency Use Authorization as filed to the United States Food and Drug Administration, to help inform the review.

Following review, terms and conditions were imposed upon the authorization of the Moderna COVID‑19 Vaccine to ascertain the continued quality, safety, and efficacy of the product.

Clinical Pharmacology

The Moderna COVID‑19 Vaccine platform is based on the delivery of messenger ribonucleic acid (mRNA) via lipid nanoparticles. After intramuscular injection, cells in the body take up the lipid nanoparticle, effectively delivering the mRNA sequence into cells for expression of the prefusion stabilized spike protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. The protein undergoes post-translational modification and trafficking resulting in properly folded, fully functional spike protein that is inserted into the cellular membrane of the expressing cells. The spike protein is membrane bound, mimicking the presentation of natural infection. The delivered mRNA does not enter the cellular nucleus or interact with the genome, is non-replicating, and is expressed transiently.

The expressed spike protein of SARS-CoV-2 is recognized by immune cells as a foreign antigen which elicits both humoral immune responses (binding antibody and neutralizing antibody) and cellular immune responses to the spike antigen, which may contribute to protection against coronavirus 2019 (COVID‑19) disease.

The estimated half-life for mRNA after injection is approximately 8 to 10 hours. The mRNA is degraded by native ribonucleases (enzymes which promote the breakdown of RNA) in the body. The expressed spike protein is expected to persist in the body for several days.

Immunogenicity was assessed as part of the clinical studies of the Moderna COVID‑19 Vaccine.

For further details, please refer to the Moderna COVID‑19 Vaccine Product Monograph, approved by Health Canada and available through the Drug Product Database and on the Health Canada COVID‑19 vaccines and treatments portal.

Clinical Efficacy

Clinical evidence for the efficacy of the Moderna COVID‑19 Vaccine is based primarily on available data from the pivotal Study mRNA‑1273‑P301 (COVE Study). This study is ongoing and data used for the present analysis have a cut-off date of November 21, 2020, providing a 2‑month (63 days) median exposure following Dose 2 for efficacy analysis.

The COVE Study is a Phase III randomized, stratified, observer-blinded, placebo-controlled study to evaluate the efficacy, safety, and immunogenicity of the Moderna COVID‑19 Vaccine (mRNA-1273 SARS-CoV-2, 100 µg/0.5 mL) in adults aged 18 years and older who have no known history of SARS-CoV-2 infection, but whose locations or circumstances put them at appreciable risk of acquiring COVID‑19 and/or SARS-CoV-2 infection. The study is being conducted at 99 sites across the United States. It is planned that participants will be followed for up to 24 months for assessments of safety and efficacy against COVID‑19.

The COVE Study has enrolled 30,351 participants 18 years of age and older who were randomly assigned in a 1:1 ratio to receive a 0.5 mL, two-dose regimen of either the Moderna COVID‑19 Vaccine (mRNA-1273 SARS-CoV-2, 100 µg/0.5 mL; n = 15,181) or a placebo (0.9% sodium chloride; n = 15,170) injection. Doses were administered 28 days apart.

Randomization was stratified based on age and, for those <65 years of age, based on the presence or absence of risk factors for severe illness from COVID‑19. The three strata for randomization were:

  • ≥65 years,
  • <65 years and categorized to be at increased risk ("at risk") for complications of COVID-19 (participants had at least 1 of the following risk factors at the time of screening: chronic lung disease or moderate to severe asthma; significant cardiac disease; severe obesity; diabetes; liver disease; or Human Immunodeficiency Virus [HIV] infection), and
  • <65 years and "not at risk".

The enrolled study population included 52.7% male and 47.3% female participants. The median age of the study population was 52 years (range 18 to 95) and 7,520 (24.8%) participants were over the age of 65. Of the participants, 22.5% were at increased risk of severe COVID‑19 due to at least one pre-existing medical condition. Pregnant or breastfeeding women and individuals with known history of SARS-CoV-2 infection, immunosuppressive or immunodeficient state, asplenia or recurrent severe infections were excluded from the study.

The primary efficacy endpoint was to demonstrate vaccine efficacy of the Moderna COVID‑19 Vaccine to prevent symptomatic COVID‑19 starting 14 days after the second dose of investigational product. Coronavirus 2019 disease cases were confirmed by a clinical Adjudication Committee (AC) that was assembled to review potential cases to determine if the criteria for the primary and secondary endpoints had been met. In addition, the following criteria had to be met. The participant must:

  • have experienced at least two of the following systemic symptoms: fever (≥38°C), chills, myalgia, headache, sore throat, new olfactory and taste disorder(s), or
  • have experienced at least one of the following respiratory signs/symptoms: cough, shortness of breath or difficulty breathing, or clinical or radiographic evidence of pneumonia, and
  • have at least one nasopharyngeal swab, nasal swab, or saliva sample (or respiratory sample, if hospitalized) positive for SARS-CoV-2 by reverse transcription‑polymerase chain reaction (RT‑PCR).

The analysis of the primary efficacy endpoint included 28,207 participants 18 years of age and older who received a two-dose regimen of either the Moderna COVID‑19 Vaccine (n = 14,134) or placebo (n = 14,073). The primary analysis population for efficacy was the Per-Protocol set. This was defined as all participants who received planned doses of the vaccine per schedule and who had no major protocol deviations that impacted critical or key study data. Protocol deviations were determined and documented by the sponsor prior to the data base lock and unblinding. Participants were analyzed according to the treatment group to which they were randomized. In the primary analysis of efficacy, cases were counted starting 14 days after the second dose of the vaccine. Vaccine efficacy was estimated by comparing COVID‑19 incidence per 1,000 person-years of follow-up in this population between the vaccine and placebo. Vaccine efficacy was defined as the percent reduction in the hazard of the primary endpoint (Moderna COVID‑19 Vaccine vs. placebo). The vaccine efficacy was estimated using one minus the hazard ratio (Moderna COVID‑19 Vaccine vs. placebo). A stratified Cox proportional hazard model was used to assess the magnitude of the treatment group difference (i.e., hazard ratio) between the Moderna COVID‑19 Vaccine and placebo. Participants are planned to be followed for up to 24 months for assessments of safety and efficacy against COVID‑19. At the time of the final primary efficacy analysis, participants had been followed for symptomatic COVID‑19 for a median of 2 months corresponding to 3,304.9 person years for the Moderna COVID‑19 Vaccine and 3,273.7 person years in the placebo group.

The Moderna COVID‑19 Vaccine met the primary efficacy endpoint of the study, as demonstrated through the results of the final primary efficacy analysis. With respect to the primary efficacy endpoint, the vaccine efficacy of the Moderna COVID‑19 Vaccine based on hazard ratio was 94.1% compared to placebo (95% confidence interval [CI]: 89.3%, 96.8% [p value <0.0001]) in the overall group of participants. This analysis was based on 196 adjudicated cases of COVID‑19 starting at least 14 days after Dose 2 (185 in the placebo group and 11 in the vaccine group). Participants who received the Moderna COVID‑19 Vaccine in the 18 to <65 years of age group demonstrated vaccine efficacy based on hazard ratio of 95.6% (95% CI: 90.6%, 97.9%). In participants 65 years of age and older who received the Moderna COVID‑19 Vaccine the vaccine efficacy rate based on hazard ratio was 86.4% (95% CI: 61.4%, 95.5%).

The vaccine efficacy results for the key secondary endpoints were consistent with the efficacy evaluated for the primary endpoint. At the time of the primary analysis, there have been 30 cases of severe COVID‑19 reported in the study, with all cases occurring in the placebo group and no cases occurring in the Moderna COVID‑19 Vaccine group.

Vaccine efficacy was consistent across age, gender, race, and ethnicity demographics and no clinically meaningful differences were observed. The observed vaccine efficacy following the first dose of the Moderna COVID‑19 Vaccine appears to show some protection; however, there is insufficient data regarding protection beyond 28 days without a second dose.

Findings from an immunogenicity and efficacy study support a two‑dose vaccination regimen. Based on the number of severe COVID‑19 cases observed after Dose 1 in the placebo group relative to the vaccine group, administration of the vaccine is not expected to be related to cases of vaccine‑associated enhanced respiratory disease (VAERD). Given the theoretical risk of VAERD based on evidence from other respiratory vaccines, this risk has been captured as an important potential risk in the Risk Management Plan (RMP) and will be monitored through post-market pharmacovigilance activities.

Immunogenicity

The immunogenicity of the Moderna COVID‑19 Vaccine was evaluated in Study DMID 20-0003-P101 (Phase I) and Study mRNA-1273-P201 (Phase IIa).

The immunogenicity of the Moderna COVID‑19 Vaccine was assessed by measuring changes from baseline in SARS-CoV-2-specific binding antibody (bAb) levels and neutralizing antibody (nAb) titers. In addition, in Study DMID 20-0003-P101, convalescent sera obtained from 41 patients who had recovered from SARS-CoV-2 infection were used during assay development to generate a relative benchmark (based on levels elicited by natural infection). To address concerns regarding the theoretical risk of enhanced respiratory disease after injection with the Moderna COVID‑19 Vaccine, an additional series of in vitro studies on cell-mediated immune response (CMI) were performed using peripheral blood mononuclear cells isolated from participants in Study DMID 20-0003-P101.

The ongoing Phase I Study DMID 20-0003-P101 is a dose-ranging safety and immunogenicity study that was planned to enroll approximately 155 healthy participants aged 18 years and older. A total of 120 participants were included in at least one of the immunogenicity analyses and 120 participants were included in the safety analyses. Immunogenicity was assessed for four different doses of mRNA-1273 SARS-CoV-2 vaccine. Participants received two injections separated by a 28‑day interval, of mRNA-1273 SARS-CoV-2 (25 µg, 50 µg, 100 µg, or 250 µg). SARS-CoV-2-specific nAb titers, bAb levels, and CMI were assessed at Day 0 (before Dose 1), 7 days and 21 days after Dose 1 (before Dose 2) and at 7, 21, 28, and 90 days after Dose 2.

Generally, concentrations of anti-spike antibodies increased in a dose-dependent manner and were higher in the 100 µg group compared to the 25 µg group. The preliminary results with a small number of participants showed bAb concentrations against the spike protein reached a maximum at 14 days post-Dose 2 and then declined; however, at 90 days post-Dose 2, the bAb titers remained higher than those in the convalescent sera for all dose levels in adults aged 18‑55 years and for the 100 µg groups in all age strata (18‑55 years; 56‑70 years; and >71 years). The nAb titers reached a maximum at 7 or 14 days post-Dose 2 and then declined; however, at 90 days post-Dose 2, the nAb titers remained higher than those in the convalescent sera at a dose of 100 µg and 250 µg in adults aged 18‑55 years and for the 100 µg groups in all age strata.

The analyses of cytokines of CD4+ and CD8+ T cells from participants demonstrated that the secreted cytokines were biased to a T‑helper 1 (Th1) profile (interferon gamma [IFNγ], interleukin-2 [IL‑2] and tumour necrosis factor alpha [TNF‑α]). This suggests that the risk of enhanced respiratory disease is low after vaccination with mRNA-1273.

The 100‑µg dose of mRNA-1273 SARS-CoV-2 was selected for use in later-stage studies based on greater immunogenicity compared with the 25‑µg dose and lower incidence of reactogenicity as compared with the 250‑µg dose.

The Phase IIa Study mRNA-1273-P201 is an ongoing, randomized, observer-blind, placebo-controlled, dose confirmation study to evaluate the safety, reactogenicity, and immunogenicity of mRNA-1273 SARS-CoV-2 vaccine in adults aged 18 years and older. A total of 600 participants were enrolled and randomized in a 1:1:1 ratio to receive 50 µg mRNA-1273 SARS-CoV-2, 100 µg mRNA-1273 SARS-CoV-2, or a placebo. The participants received two injections separated by a 28‑day interval.

The results of the study demonstrated that both bAb and nAb against the SARS-CoV-2 virus were developed 2 weeks after two doses, administered 28 days apart, of either 50 µg or 100 µg of mRNA-1273 SARS-CoV-2, with geometric mean fold rises (GMFRs) >20‑fold (bAb) and >50‑fold (microneutralization assay), regardless of dose level. This study is ongoing and will provide more data on long-term safety and antibody persistency.

Collectively, the results of the final efficacy analysis demonstrated that the Moderna COVID‑19 Vaccine met the vaccine efficacy success criteria as specified in Health Canada's Guidance for Market Authorization Requirements for COVID-19 Vaccines. The Phase III study is ongoing and data from the 6‑month time point will be submitted to assess longer term safety. In addition, the study will continue to provide additional information on the safety and efficacy of the Moderna COVID‑19 vaccine over a period of 24 months.

Indication

The sponsor filed the application for authorization of the Moderna COVID‑19 Vaccine under the Interim Order with the following indication, which was subsequently approved by Health Canada:

  • The Moderna COVID‑19 Vaccine (mRNA-1273 SARS-CoV-2) is indicated for active immunization against coronavirus disease 2019 (COVID‑19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus in individuals 18 years of age and older.

For more information, refer to the Moderna COVID‑19 Vaccine Product Monograph, approved by Health Canada and available through the Drug Product Database and on the Health Canada COVID‑19 vaccines and treatments portal.

Clinical Safety

The evidence of safety for the Moderna COVID‑19 Vaccine is largely based on data from the ongoing pivotal Phase III Study (COVE Study). Supportive data was also provided from the Phase IIa Study mRNA-1273-P201.

In the Phase IIa Study mRNA-1273-P201, the incidence of unsolicited treatment‑emergent adverse events (TEAEs), related unsolicited TEAEs, and medically attended adverse events (MAAEs) were comparable between the mRNA-1273 SARS‑CoV‑2 and placebo groups. One serious adverse event (SAE) was reported in Study mRNA-1273-P201, and assessed as unrelated to the mRNA-1273 SARS-CoV-2 vaccine. No serious adverse events have been reported through Day 119 in Study DMID 20-0003-P101.

The safety results for the present analysis of the Phase III COVE Study are based on data with a cut-off date for safety of November 25, 2020. The safety analysis set included 30,351 study participants who received a two-dose regimen of either the Moderna COVID‑19 Vaccine (n = 15,181) or placebo (n = 15,170). The median study duration for all participants in the safety set was 92 days from Dose 1 and 63 days from Dose 2. Participants were monitored for solicited local and systemic reactions, unsolicited adverse events and serious adverse events. The safety evaluation is ongoing.

During the study, 365 (1.2%) participants discontinued investigational product with slightly more discontinuing from the placebo group vs. the Moderna COVID‑19 Vaccine group. The most common reasons for discontinuation were: withdrawal of consent by the participant (231 [0.8%] participants), confirmed SARS-CoV-2 infection (i.e., diagnosed COVID‑19 by detection of SARS-CoV-2 in Day 1 nasopharyngeal swab or symptomatic COVID‑19 prior to Day 29; 84 [0.3%] participants), and other reasons (70 [0.2%] participants).

Solicited local and systemic adverse reactions were more common in participants who received the Moderna COVID‑19 Vaccine compared with placebo (92.4% vs 29.3%). The majority of adverse reactions in the Moderna COVID‑19 Vaccine group were mild to moderate in severity, occurred within the first 1 to 2 days after administration, and persisted for a median of 1 to 3 days.

Solicited local and systemic adverse reactions were more common after Dose 2 in the vaccine group. They were also more commonly reported by younger adults (18 to <65 years) compared with older adults (≥65 years). When they occurred in older adults, they tended to last one day longer than in younger adults.

The most common solicited local adverse reactions in the vaccine group vs. placebo group, respectively, were: injection site pain (92.0% vs. 26.6%); axillary swelling and tenderness/lymphadenopathy (19.8% vs. 7.2%); induration (14.7% vs. 0.6%); and erythema (10.0% vs. 0.8%). Fatigue and headaches were the most commonly reported solicited systemic adverse reactions after Dose 1, affecting roughly a third of Moderna COVID‑19 Vaccine recipients. After Dose 2, fatigue, headache, and myalgia were most commonly reported, affecting approximately two-thirds of the participants, while arthralgia and chills were reported in around 40% of participants.

There was no difference in the incidence of solicited local and systemic adverse reactions based on baseline SARS-CoV-2 status. The solicited adverse reaction profile in the pivotal COVE Study was similar to the profile observed in the 100‑µg mRNA-1273 SARS-CoV-2 vaccine treatment group in the Phase IIa Study mRNA-1273-P201.

Up to 28 days after any injection, the reported overall incidence of unsolicited TEAEs and MAAEs were comparable in participants who received the Moderna COVID‑19 Vaccine or placebo (21.5% vs. 23.1%, respectively). There was no apparent effect of age on the relative incidence of these TEAEs by vaccine group. There was also no difference in the incidence of unsolicited TEAEs based on SARS-CoV-2 serology at baseline.

The incidence of related TEAEs was higher in participants who received the Moderna COVID‑19 Vaccine compared with placebo. These related TEAEs were predominantly solicited adverse reactions occurring outside of the conventional 7‑day monitoring period after the injection (injection site pain, fatigue, headaches, myalgia, etc.).

The incidence of unsolicited TEAEs leading to discontinuation from study was greater in participants who received the placebo compared with the Moderna COVID‑19 Vaccine (85 participants [0.6%] vs. 45 participants [0.3%], respectively). This was largely due to a diagnosis of COVID‑19 prior to Day 29, which rendered these participants ineligible to receive Dose 2.

The unsolicited adverse event of lymphadenopathy-related events occurred in 1.1% of participants receiving the Moderna COVID‑19 Vaccine vs. 0.6% in the placebo group. All of the lymphadenopathy events were similar to the axillary swelling/tenderness in the injected arm reported as solicited adverse reactions.

Hypersensitivity events were reported in 1.5% of participants in the Moderna COVID‑19 Vaccine group compared to 1.1% of the placebo group. This imbalance was mostly due to injection site rash and injection site erythema/swelling occurring more frequently in the Moderna COVID‑19 Vaccine group.

As of the scheduled final analysis, three cases of Bell's palsy were reported in vaccine recipients and one case in a placebo recipient. The number of overall cases was small and the frequency of cases was consistent with the rate in the general population, therefore a causal relationship with the vaccine could not be determined.

There were no other notable patterns or numerical imbalances between treatment groups for specific categories of non-serious adverse events (including neurologic, musculoskeletal or inflammatory events) that would suggest a causal relationship to the Moderna COVID‑19 Vaccine.

The incidence and absolute number of serious adverse events and treatment-related adverse events in the 28 days after vaccination was comparable between the Moderna COVID‑19 Vaccine (0.5%) and placebo (0.6%) groups. Three serious adverse events were deemed related to the Moderna COVID‑19 Vaccine:

  • two cases of facial swelling occurring within 7 days of receiving Dose 2 (two female participants aged 46 and 51 who had prior history of cosmetic dermal filler injection); and
  • one case of nausea and vomiting with headaches and fever requiring in-hospital treatment and occurring within 7 days of receiving Dose 2 (61‑year‑old female participant with a past medical history of headaches with nausea and vomiting requiring hospitalization).

One case of rheumatoid arthritis occurring 10 days after Dose 1 in a 57‑year‑old male with prior dysthyroidia and thigh pain was also reported. A causal relationship with the vaccine is unclear.

The number of serious adverse events with a fatal outcome was balanced between treatment groups with none considered related to study treatment. At the time of the data cutoff date, 13 deaths were reported (6 in the vaccine group and 7 in the placebo group). The causes of death were consistent to those expected in the population enrolled in the study. One death in the placebo group was related to COVID‑19 disease. None of the deaths were related to the vaccine product.

Thirteen pregnancies (6 in the vaccine group and 7 in the placebo group) were reported during the Phase III COVE Study, as of December 3, 2020. Among pregnant participants who received the Moderna COVID‑19 Vaccine, all pregnancies are continuing to term without any complications reported to date. The safety and efficacy of the Moderna COVID‑19 Vaccine have not been established in pregnant women. There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Moderna COVID‑19 Vaccine during pregnancy. Women who are vaccinated with Moderna COVID‑19 Vaccine during pregnancy are encouraged to enroll in the registry.

It is unknown if the Moderna COVID‑19 Vaccine is excreted in breast milk. A risk to the newborns/infants cannot be excluded.

There were fewer cases of severe COVID‑19 or COVID‑19 from the time of randomization amongst participants who received the Moderna COVID‑19 Vaccine compared with placebo. The confinement of the majority of severe cases to the placebo group suggests no evidence of vaccine‑associated enhanced respiratory disease (VAERD).

In conclusion, there were no important safety issues identified and no life-threatening adverse events or deaths related to the Moderna COVID‑19 Vaccine. The adverse events observed showed that the Moderna COVID‑19 Vaccine at 100 µg was safe and well tolerated in participants and within demographic sub‑groups based on age, sex, and race/ethnicity.

Risk Management Plan

A Core (European Union [EU]) Risk Management Plan (RMP) for the Moderna COVID‑19 Vaccine was submitted by Moderna Therapeutics Inc. to Health Canada as part of the application for interim authorization. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and to describe measures that will be put in place to minimize risks associated with the product, when needed.

The following information relates to the RMP submitted by Moderna Therapeutics Inc., as part of the initial application for interim authorization. It is the sponsor's responsibility to monitor the safety profile of the drug and to submit an update to the RMP if there is a significant change to the drug's benefits, harms or uncertainties. Updates to the RMP will be reflected in the Post-Authorization Activity Table for the Moderna COVID-19 Vaccine.

Based on results from non-clinical and clinical studies, the RMP included no important identified risks and two important potential risks: VAERD and anaphylactic reactions, including anaphylaxis. The RMP also identified six areas of missing (limited/no clinical data) information: "use in pediatric", "use in pregnant and breastfeeding women", "long‑term safety", "long‑term effectiveness" including "real‑world use", "safety and immunogenicity in subjects with immune-suppression", and "concomitant administration with non-COVID vaccines".

The proposed routine and additional pharmacovigilance activities, as described in the RMP, for the above safety concerns are considered to be acceptable and the sponsor confirmed that they would be applied in the Canadian context. Additional pharmacovigilance activities include three planned studies: an active follow-up safety study, a pregnancy exposure registry, and a non-interventional prospective cohort study to evaluate effectiveness and long-term effectiveness in "real-world" use. Routine risk minimization measures (i.e., product monograph and labelling) are also considered to be appropriate.

Based on Health Canada's review of the RMP, it was recommended to specify in the missing information that "use in pediatric" is referring to those younger than 18 years of age. In addition, it is recommended to include vaccine-associated enhanced disease (VAED) as an important potential risk. As outlined in the terms and conditions that were put in place at the time of authorization, these safety concerns were recommended to be added to the revised Core (EU) RMP and/or Canadian Addendum to the RMP, which is expected to be submitted to Health Canada in January 2021. Further, the sponsor is expected to provide an updated Core (EU) RMP and Canadian Addendum in a timely manner if a signal of safety issue is identified in ongoing post-authorization surveillance.

Specifically, the sponsor will provide the following information for the following sub‑populations in the post-market period:

  • Older adults: Older adults were included in the clinical development program. The sponsor will monitor the safety and submit monthly safety reports to Health Canada.
  • Children: Children were not included in the clinical development program. This sub‑population was identified as missing information in the RMP. The sponsor will submit monthly safety reports to Health Canada. A study of the Moderna COVID‑19 Vaccine in adolescents (participants aged 12‑17) is planned.
  • Pregnant women: More information is needed about the use of the vaccine for pregnant women. This sub‑population was identified as missing information in the RMP. The sponsor will monitor and submit monthly safety reports to Health Canada. The sponsor will assess outcomes in pregnancy and lactation as part of all ongoing and planned studies, including a pregnancy exposure registry.
  • Breastfeeding women: This sub‑population was identified as missing information in the RMP. The sponsor will submit monthly safety reports to Health Canada. The sponsor will assess outcomes in pregnancy and lactation as part of all ongoing and planned studies, including a pregnancy exposure registry.
  • Immunocompromised individuals and patients with chronic or debilitating conditions: These were not included in the clinical development program. This sub‑population was identified as missing information in the RMP. The sponsor will submit monthly safety reports to Health Canada.
  • Anaphylaxis: This was identified as an important potential risk in the RMP. This will be assessed via routine pharmacovigilance activities, and reported in monthly summary safety reports.
  • Indigenous populations in Canada: Adverse drug reactions (ADRs) from all sub‑populations, including indigenous, will be reported as expeditiously as applicable, and will be assessed in the monthly reports. Other government departments as well as the sponsor will continue to be engaged in the assessment of ADRs in the indigenous sub‑population.

The sponsor will also provide prompt reporting of adverse reactions and monthly safety summary reports. To help facilitate this, the sponsor is required to provide, prior to distribution, patient information cards to support traceability, where required, that will include elements such as manufacturer name, name of vaccinee, space for recording dates of first and second doses and associated batch/lot numbers, and information on how to report any adverse events.

Results related to safety and effectiveness from ongoing and planned studies will be submitted for review as they become available and will include information related to special populations, for example pregnant women. Together, the results from these studies and the monthly safety summary reports are expected to address data gaps related to specific sub-populations, such as pediatric populations younger than 18 years of age, pregnant and breastfeeding women, individuals from diverse ethnic backgrounds and indigenous populations, where available, and immunocompromised individuals.

For more information, refer to the complete list of terms and conditions available on the Health Canada COVID‑19 vaccines and treatments portal.

Collectively, the results of the clinical safety evaluation demonstrated that the Moderna COVID‑19 Vaccine met the vaccine safety requirements as specified in Health Canada's Guidance for Market Authorization Requirements for COVID-19 Vaccines. The vaccine was determined to be safe and well tolerated in participants 18 years of age and older when administered according to the recommended dosage regimen. This Phase III study is ongoing and will continue to collect information on the long-term safety of the vaccine.

For more information, refer to the Moderna COVID‑19 Vaccine Product Monograph, approved by Health Canada and available through the Drug Product Database and on the Health Canada COVID‑19 vaccines and treatments portal.

7.2 Non-Clinical Basis for Decision

The non-clinical data submitted in the application for authorization of the Moderna COVID‑19 Vaccine (mRNA‑1273 SARS‑CoV‑2) under the Interim Order Respecting the Importation, Sale, and Advertising of Drugs for Use in Relation to COVID-19 included pharmacodynamic, repeat-dose toxicity, genotoxicity, and reproductive and developmental toxicity studies.

The medicinal ingredient in the Moderna COVID‑19 Vaccine, known as mRNA‑1273 SARS‑CoV‑2, was found to be immunogenic in mice, hamsters, and non-human primates. The administration of mRNA‑1273 SARS‑CoV‑2 elicited robust severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2)‑specific antibody binding after a single dose. A significant increase in neutralizing antibody responses was observed after the second (booster) dose. A two-dose immunization schedule also elicited a substantial dose-dependent binding antibody response in rats. Additionally, T‑helper 1 (Th1)‑dominant immune responses were evident in both mice and non-human primates.

Further, mRNA‑1273 SARS‑CoV‑2 was fully protective following viral challenge in immunized mice and hamsters when administered as a single-dose or two-dose schedule at ≥1 µg/dose and in immunized non-human primates when administered as a two-dose schedule at ≥30 µg/dose. Studies using aged mice further characterized the immune response and the level of protection from SARS‑CoV‑2 challenge using the Moderna COVID‑19 Vaccine platform. Finally, mRNA‑1273 SARS‑CoV‑2 did not promote vaccine-associated enhanced respiratory disease (VAERD) in mice, hamsters, and non-human primates when administered at doses predicted to be fully (optimal dose) or partially (sub‑optimal dose) protective.

The biodistribution of mRNA‑1273 SARS‑CoV‑2, a single‑stranded messenger ribonucleic acid (mRNA), was examined using a comparable lipid nanoparticle-formulated modified mRNA. In this study, following intramuscular administration to male rats, mRNA distributed mainly at the site of injection, proximal lymph nodes, distal lymph nodes, and the spleen, with an average half-life (t1/2) of all mRNA constructs combined being 14.9, 34.8, 31.1 and 63.0 hours, respectively. Low levels were also detected in plasma and other tissues (eyes, liver, testes, heart, lungs, bone marrow, jejunum, brain, and stomach) with the exception of the kidneys.

In repeat-dose toxicity studies, intramuscular administration of mRNA vaccines formulated in lipid nanoparticles comparable to the Moderna COVID‑19 Vaccine were well-tolerated in rats at doses ranging from 8.9 to 150 µg/dose once every 2 weeks for up to 6 weeks. Vaccine administration was associated with edema and erythema at the injection site and transient increases in body temperature and cytokine levels. Clinical pathology changes included decreases in lymphocytes and increases in neutrophils, eosinophils, and acute phase proteins. Histopathological changes at the injection site, lymph nodes, bone marrow, and spleen were also observed. Together, these changes are consistent with an expected immunostimulatory response and known acute phase response following intramuscular administration of a vaccine. In addition, in some studies, periportal to midzonal hepatocellular vacuolation was observed, which would be consistent with hepatic distribution of lipids that are part of the lipid nanoparticle formulation. Full or partial recovery from all findings was observed following a 2‑week recovery period. In addition, intramuscular administration of mRNA‑1273 SARS‑CoV‑2 up to 100 µg/dose was well tolerated in rats with clinical observations and pathology changes that were consistent with the results from other studies.

The novel lipid, SM‑102, used in the lipid nanoparticle formulation of the Moderna COVID‑19 Vaccine, was shown to be non-genotoxic based on results from the in vitro bacterial mutagenicity and human peripheral blood lymphocytes chromosome aberration assays. Equivocal results were obtained from two in vivo micronucleus assays conducted with intravenous administration of SM‑102-containing mRNA-based vaccines. Micronuclei formation observed in one study was likely a secondary response induced by elevated body temperature and cytokine levels due to systemic inflammation triggered by lipid nanoparticle at high intravenous doses. Taking into account the totality of the findings, the overall genotoxic risk is considered to be low for clinical use due to minimal systemic exposure following intramuscular administration, limited duration of exposure, and the in vitro results.

In the reproductive and developmental toxicity study, female rats were administered 100 µg of mRNA‑1273 SARS‑CoV‑2 by intramuscular injection 28 days prior to mating, 14 days prior to mating, and on gestation days 1 and 13. No mRNA‑1273 SARS‑CoV‑2-related maternal toxicity or overt adverse effects on pre- and post-natal development were observed. This included no observations of fetal external, visceral, or skeletal malformations, and no increases in fetal external or visceral variations. While mRNA‑1273 SARS‑CoV‑2-related increases in the fetal and litter incidences of skeletal variations of 1 or more wavy ribs and 1 or more rib nodules were observed, skeletal variations of this nature are known transient background findings in rats and consist of variations that largely resolve post-natally. These skeletal variations are therefore considered non-adverse in nature. Furthermore, the skeletal variations were observed at a maternal dose that is approximately 138‑fold greater than the human dose on a per kg body weight basis. Immunogenicity assessment in this study also demonstrated that mRNA‑1273 SARS‑CoV‑2 elicited antibody responses to the SARS-CoV‑2 spike 2 protein in maternal animals. High antibody titers were also observed in fetuses and pups, indicating transfer of antibodies via placental transfer and via milk.

Overall, the non‑clinical pharmacology and toxicology profile of mRNA‑1273 SARS-CoV‑2 supports its proposed clinical use. The results of the non‑clinical studies as well as the potential risks to humans have been included in the Moderna COVID‑19 Vaccine Product Monograph. Considering the intended use of the Moderna COVID‑19 Vaccine, there are no pharmacological or toxicological issues within this application to preclude authorization of the product.

For more information, refer to the Moderna COVID‑19 Vaccine Product Monograph, approved by Health Canada and available through the Drug Product Database and on the Health Canada COVID‑19 vaccines and treatments portal.

7.3 Quality Basis for Decision

Quality (chemistry and manufacturing) data were provided in the application for authorization of the Moderna COVID‑19 Vaccine (mRNA-1273 SARS-CoV-2) under the Interim Order Respecting the Importation, Sale, and Advertising of Drugs for Use in Relation to COVID-19 (Interim Order). The standards Health Canada applied to the review of this vaccine are aligned with those of international regulatory authorities for vaccines in the context of a global pandemic. The interim authorization of the Moderna COVID‑19 Vaccine is associated with terms and conditions that need to be met by the sponsor to ascertain the continued quality, safety, and efficacy of the drug product.

The Moderna COVID‑19 Vaccine (mRNA-1273 SARS-CoV-2) is a prophylactic vaccine developed to prevent COVID‑19 caused by infection with the severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2). The nucleoside-modified messenger ribonucleic acid (mRNA) in the vaccine is formulated in lipid nanoparticles, which enable delivery of the mRNA into the host's cells for expression of the spike protein (antigen) of the SARS‑CoV‑2. The vaccine elicits both neutralizing antibody and cellular immune responses to the spike antigen, which may contribute to protection against COVID‑19.

Characterization of the Drug Substance

The mRNA-1273 SARS-CoV-2 drug substance is a single-stranded, 5'‑capped mRNA that encodes for the prefusion stabilized spike glycoprotein of the SARS‑CoV‑2. The resulting spike glycoprotein is a full-length protein with two point modifications, leading to an antigenically stable prefusion conformation. This conformation improves the stimulation of production of neutralizing antibodies against the SARS‑CoV‑2.

The mRNA has been designed to avoid intrinsic immunostimulatory activity, to enhance gene expression, and to improve stability. Various modifications to the mRNA sequence have been introduced to improve protein translation.

Detailed characterization studies were performed to provide assurance that the drug substance consistently exhibits the desired characteristic structure and biological activity.

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

The pharmaceutical development of the Moderna COVID‑19 Vaccine (mRNA-1273 SARS-CoV-2) utilizes principles described in the International Council for Harmonisation (ICH) Pharmaceutical Development guidelines (Q8), and is based on sound scientific knowledge and prior experience with similar platform products. The product development is further guided by risk assessment studies and development studies.

The drug substance is first synthesized using in vitro transcription reaction involving a linearized plasma template. This is followed by purification and concentration steps before being further processed or stored frozen at -25°C to -15°C.

The manufacture of the drug product involves the dilution and sterile filtration of the mRNA embedded in lipid nanoparticles. Finally, the drug product is aseptically filled into 10R glass vials. Following the filling operation, the vials are visually inspected, labelled, and frozen at -25°C to -15°C.

The in-process controls and lot release tests for the drug substance and drug product are based on scientifically relevant assays and appropriate specifications to monitor key quality attributes. The sponsor provided enough information to support the consistency of production. This information, together with additional characterization studies and the experience of the sponsor with similar platform products, is considered sufficient to support authorization under the Interim Order. In addition, risk mitigation measures are addressed through requirements outlined in the terms and conditions imposed on the interim authorization of the vaccine.

Control of the Drug Substance and Drug Product

The drug substance and drug product are tested against suitable reference standards to verify that they meet approved specifications. Analytical procedures are validated and in compliance with ICH guidelines. The results are within proposed specification limits.

All validation acceptance criteria were achieved using lots from manufacturing runs conducted as part of the process development or as part of the validation studies. This information together with additional characterization studies and the experience of the sponsor with other vaccines based on the same platform is sufficient to support authorization under the Interim Order.

Risk mitigation measures are addressed through requirements outlined in the terms and conditions imposed on the interim authorization of the vaccine and the required additional oversight through Health Canada's Guidance for Sponsors: Lot Release Program for Schedule D (Biologic) Drugs.

Stability of the Drug Substance and Drug Product

The stability data provided for the drug substance support the proposed shelf life of 12 months when stored at the recommended storage condition of -25°C to -15°C. This is primarily based on stability data for small-scale batches, since there is limited long-term stability data available for batches manufactured at commercial scale. Additional studies for the product manufactured at commercial scale are ongoing and will be submitted to Health Canada for review and approval post authorization (see terms and conditions).

The stability data provided for the drug product support the initial commercial shelf life of 7 months of storage at -25°C to -15°C that can include up to 1 month of storage at 2°C to 8°C, plus 12 hours at 8°C to 25°C when refrigerated at the point of care site. Clinical in-use stability was demonstrated for up to 6 hours after first puncture of the vial.

The stability profiles were based on the evaluation and monitoring of all the stability-indicating attributes. The analytical procedures used in the stability programs assess the composition, strength, purity, safety and general quality attributes of the drug product.

The proposed packaging and components are considered acceptable.

Facilities and Equipment

Travel restrictions due to the COVID‑19 pandemic prevented Health Canada from conducting on-site evaluations of the drug substance and drug product manufacturing facilities.

Based on the provided information, the design, operations, and controls of the facilities and equipment involved in production are considered suitable for the activities and products manufactured.

The facilities involved in production are compliant with Good Manufacturing Practices.

Adventitious Agents Safety Evaluation

Raw materials used in the manufacturing process are adequately tested to ensure freedom from adventitious agents. The excipients used in the drug product formulation are not of animal or human origin.