Summary Basis of Decision for Vaxzevria (previously the AstraZeneca COVID-19 Vaccine)

Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Vaxzevria (previously the AstraZeneca COVID-19 Vaccine) is located below.

Recent Activity for Vaxzevria (previously the AstraZeneca COVID-19 Vaccine)

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 Vaxzevria (previously the AstraZeneca COVID-19 Vaccine)

Updated:

2023-09-22

The following table describes post-authorization activity for Vaxzevria (previously the AstraZeneca COVID-19 Vaccine), a product which contains the medicinal ingredient ChAdOx1‑S (recombinant). For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the list of abbreviations that are found in PAATs.

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

Drug Identification Number (DIN):

  • DIN 02510847 - 5 x 1010 virus particles/0.5 mL ChAdOx1‑S (recombinant), 10‑dose vial, solution, intramuscular administration
  • DIN 02511444 - 5 x 1010 virus particles/0.5 mL ChAdOx1‑S (recombinant), 8‑dose vial, solution, intramuscular administration

Post-Authorization Activity Table (PAAT)

Activity/submission type, control number Date submitted Decision and date Summary of activities
Risk Management Plan update
Control # 272970
2023-02-28 Review completed 2023-08-11 The updated Core (European Union [EU]) Risk Management Plan (RMP) version 8 and Canadian Addendum version 6.1 were filed as per the terms and conditions imposed on the authorization issued under the Food and Drug Regulations. The review concluded that the RMP and Canadian Addendum are acceptable at this time. The current post-market safety data are consistent with the labelled safety profile of Vaxzevria.
DIN 02510847 reported as dormant Not applicable 2023-07-27 The manufacturer reported the DIN as dormant as per section C.01.014.71 and subsection C.01.014.5(1)(a)(ii) of the Food and Drug Regulations.
PBRER Control # 272971 2023-02-28 Review completed 2023-06-27 Information filed as per as per the terms and conditions imposed on the authorization issued under the Food and Drug Regulations. PBRER #4 for the period 2022-06-29 to 2022-12-28. The sponsor was asked to provide updated assessments for the ongoing monitoring of safety events.
Amended Terms and Conditions Control # 253700 Not applicable Review completed 2023-05-29 Health Canada updated the Risk Management Plan Terms and Conditions for Vaxzevria to reflect the accumulation of safety data and information gained in the post-market setting for this vaccine.
Post-Market Information Request Review Control # 265358 2022-09-08 Review completed
2023-03-10

Health Canada conducted a third ad-hoc review of available data on the risk of thrombosis with thrombocytopenia syndrome (TTS) with viral vector vaccines Jcvoden and Vaxzevria. The sponsors were requested to submit all available data to Health Canada for review. The information was assessed, and Health Canada will continue to monitor the safety of these vaccines.

PBRER Control # 267684 2022-09-06 Review completed
2023-01-24

Information filed as per as per the terms and conditions imposed on the authorization issued under the Food and Drug Regulations. PBRER #3 for the period 2021-12-29 to 2022-06-28. The sponsor was asked to provide updated assessments for the ongoing monitoring of safety events.

SNDS # 267545 2022-09-02 Issued NOC
2022-12-14

Submission filed as a Level II – Supplement (Safety) to update the PM with new safety information related to tinnitus and cutaneous vasculitis, and migrate it to the 2020 format. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Adverse Reactions section of the PM, and corresponding changes were made to Part III: Patient Medication Information. An NOC was issued.

PBRER Control # 262073 2022-03-04 Review completed
2022-06-29

Information filed as per the terms and conditions imposed on the authorization issued under the Food and Drug Regulations. Six-month PBRER #2 for the period 2021-06-29 to 2021-12-28. The sponsor was asked to provide updated assessments for the ongoing monitoring of safety events.

NC # 261920 2022-03-01 Issued NOL
2022-05-09
Submission filed as a Level II (90 day) Notifiable Change to add a new assay for the release of the drug substance and drug product. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 261469 2022-02-11 Issued NOC
2022-05-05
Submission filed as a Level II – Supplement (Safety) to update the Product Monograph (PM). The PM was updated to reflect new information on thrombosis and thrombocytopenia, and thrombosis without thrombocytopenia. Changes were made to the Warnings and Precautions and Patient Medication Information sections of the PM. The submission was reviewed and considered acceptable, and an NOC was issued.
Risk Management Plan update
Control # 261469
2022-02-11 Review completed
2022-05-05
The updated Core (European Union [EU]) Risk Management Plan (RMP) version 7.0 and Canadian Addendum version 5.2 were filed as per the terms and conditions imposed on the authorization issued under the Food and Drug Regulations. The review concluded that the RMP and Canadian Addendum are acceptable at this time. The current post-market safety data are consistent with the labelled safety profile of Vaxzevria.
SNDS # 259446 2021-12-10 Cancellation Letter Received
2022-03-31
Submission filed as a Level I – Supplement to seek authorization for a booster dose of Vaxzevria. A Summary of Cancellation was published.
Bi-monthly safety report Control # 261476 2022-02-14 Review completed
2022-04-08
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 2021-12-01 to 2022-01-31. The sponsor was asked to provide updated assessments for the ongoing monitoring of safety events.
NC # 262361 2022-03-14 Issued NOL
2022-03-21
Submission filed as a Level II (90 day) Notifiable Change to add new working host cell banks. The submission was reviewed and considered acceptable, and an NOL was issued.
Post-Market Information Request Review Control # 259117, 259118 2021-12-07 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.
Amended Terms and Conditions Control # 253700 Not applicable Terms and conditions amended post authorization
2022-02-28
Health Canada imposed a new Term and Condition to the authorization of Vaxzevria. The sponsor is required to submit Periodic Safety Update Reports / Periodic Benefit Risk Evaluation Reports every 6 months. Health Canada considered the Term and Condition of bi-monthly safety reports closed.
Bi-monthly safety report Control # 259636 2021-12-15 Review completed
2022-02-18
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 2021-10-01 to 2021-11-30. The sponsor was asked to provide updated assessments for the ongoing monitoring of safety events.
Bi-monthly safety report Control # 257622 2021-10-15 Review completed
2021-12-10
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). Bi-monthly safety report #1 for the period 2021-08-01 to 2021-09-30. The sponsor was asked to commit to conducting cumulative reviews of ongoing monitoring of safety events and to provide an update to the Risk Management Plan.
NDS # 253700 2021-06-14 Issued NOC (subject to terms and conditions)
2021-11-19
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. A Regulatory Decision Summary was published. DIN 02510847 was issued. DIN 02511444 was not transitioned to the Food and Drug Regulations when the Interim Order Respecting the Importation, Sale and Advertising of Drugs for Use in Relation to COVID-19 expired.
Public advisory Not applicable Posted
2021-11-09
Public Advisory posted (Health Canada is updating the labels of the Janssen and Vaxzevria [AstraZeneca] COVID-19 vaccines), containing important information about product safety for the general public.
Amendment # 255966 2021-08-20 Authorization amended
2021-09-15
An application submitted to amend the authorization in respect of this drug (relating to a change in product name from the AstraZeneca COVID-19 Vaccine to Vaxzevria) 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 update
Control # 256225
2021-08-31 Review completed
2021-09-15
The updated Core (European Union) Risk Management Plan (RMP) version 4 and Canadian Addendum version 4 succession 4 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 concluded that the RMP is acceptable at this time. The current post-market safety data are consistent with the labelled safety profile of the AstraZeneca COVID-19 Vaccine.
Monthly safety report
Control # 255663
2021-08-15 Review completed
2021-09-14
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 2021-06-29 to 2021-07-31. The sponsor was asked to commit to conducting cumulative reviews of ongoing monitoring of safety events.
Periodic Benefit-Risk Evaluation Report
Control # 256224
2021-08-31 Review completed
2021-09-14
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). Six-month Periodic Benefit-Risk Evaluation Report (PBRER) #1 for the period 2020-12-29 to 2021-06-28. The sponsor was asked to provide updated assessments for the ongoing monitoring of safety events.
Monthly safety report
Control # 254485
2021-07-15 Review completed
2021-08-14

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 2021-06-28. The sponsor was asked to commit to conducting cumulative reviews of ongoing monitoring of safety events.

Risk Management Plan update
Control # 254799
2021-07-15 Review completed
2021-08-13

Updated Core (European Union) Risk Management Plan (RMP) and Canadian Addendum 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). The review concluded that the RMP is acceptable at this time. The safety concerns identified 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. The sponsor was requested to update the RMP to expand on the important potential risk of nervous system disorders including Guillain-Barré syndrome.

Amendment # 254869 2021-07-19 Authorization amended
2021-08-13

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 Product Monograph was updated to include information related to Guillain-Barré syndrome; changes were made to the Warnings and Precautions, 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 # 254400 2021-07-05 Authorization amended
2021-07-22

An application submitted to amend the authorization in respect of this drug (relating to an update to the manufacturing process and a new testing site 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 # 253385
2021-06-15 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 update the Product Monograph to reflect the risk of Guillain-Barré syndrome and to submit an updated Risk Management Plan to include thrombocytopenia as an important potential risk.

Risk Management Plan update
Control # 252882
2021-06-11 Review completed
2021-07-07

Canadian Addendum to European Union Risk Management Plan Version 4 succession 2 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). The review concluded that the RMP is acceptable at this time. The safety concerns identified 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. The sponsor was requested to update the RMP to align with the revised Product Monograph and risk minimization measures for the important identified risk of thrombosis in combination with thrombocytopenia and the important potential risk of thrombosis.

Dear Healthcare Professional Letter Not applicable Posted
2021-06-29

Dear Healthcare Professional Letter posted (AstraZeneca COVID-19 Vaccine and Covishield: Risk of Capillary Leak Syndrome), containing important information for healthcare professionals.

Amendment # 252495 2021-05-07 Authorization amended
2021-06-29

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 Product Monograph was updated to include information related to capillary leak syndrome, thrombosis and thrombotic events; changes were made to the Warnings and Precautions, Post-Market Adverse Reactions and Non-Clinical Toxicology 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 # 254063 2021-06-23 Authorization amended
2021-06-25

An application submitted to amend the authorization in respect of this drug (relating to an alternative test 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 # 253383 2021-06-03 Authorization amended
2021-06-22

An application submitted to amend the authorization in respect of this drug (relating to a new manufacturing and testing 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 # 252545 2021-05-10 Authorization amended
2021-06-09
An application submitted to amend the authorization in respect of this drug (relating to a new reference standard and alternative 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 # 252386
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 as well as other post-market safety data. The sponsor was asked to provide updated assessments for the ongoing monitoring of safety events.
Amendment # 253087 2021-05-26 Authorization amended
2021-06-02
An application submitted to amend the authorization in respect of this drug (relating to an alternative testing 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 # 253134 2021-05-27 Authorization amended
2021-05-28
An application submitted to amend the authorization in respect of this drug (relating to the extension of the shelf life of two lots from 6 to 7 months) 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 update
Control # 251571
2021-04-28 Review completed
2021-05-19
Updated Core (European Union) Risk Management Plan (RMP) and Canadian Addendum 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). The review concluded that the RMP is acceptable at this time. The safety concerns identified 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. The sponsor was requested to submit an updated RMP to add one important potential risk and additional risk minimization measures to adequately reflect the information on thrombosis with thrombocytopenia syndrome.
Amendment # 251908 2021-04-22 Authorization amended
2021-05-09
An application submitted to amend the authorization in respect of this drug (relating to a new manufacturing site 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.
Monthly safety report
Control # 251336
2021-04-15 Review completed
2021-05-06
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 2021-03-01 to 2021-03-31. The current post-market safety data are consistent with the labelled safety profile of the AstraZeneca COVID-19 Vaccine.
Amendment # 251802 2021-04-20 Authorization amended
2021-04-23
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 Product Monograph was updated to include information related to thrombocytopenia and coagulation disorders in the Contraindications, Warnings and Precautions, 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.
Risk Management Plan update
Control # 251008
2021-04-08 Review completed
2021-04-21
Updated Core (European Union) Risk Management Plan (RMP) and Canadian Addendum 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). The review concluded that the RMP is acceptable at this time. The safety concerns identified 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.
Risk Management Plan update
Control # 250447
2021-03-17 Review completed
2021-04-21
Updated Core (European Union) Risk Management Plan (RMP) and Canadian Addendum 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). The review concluded that the RMP is acceptable at this time. The safety concerns identified 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.
Summary Safety Review posted Not applicable Posted
2021-04-19
Summary Safety Review posted for the AstraZeneca COVID-19 Vaccine (Assessing the Potential Risk of Thrombosis in combination with Thrombocytopenia).
New safety review started by Health Canada Not applicable Started between
2021-03-01
Health Canada started a safety review for the AstraZeneca COVID-19 Vaccine, in response to case reports of thrombosis (blood clots) in combination with thrombocytopenia (low blood platelets).
Advisory Not applicable Published
2021-04-14
Advisory posted (Health Canada provides update on the AstraZeneca and Covishield COVID-19 vaccines), containing important information for the general public, healthcare professionals and hospitals.
Amendment # 251532 2021-04-09 Authorization amended
2021-04-14
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. A literature review and additional safety data were submitted. The Product Monograph and Healthcare Professional and Public Guides were updated to include information related to thrombosis with thrombocytopenia. 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 # 250447
2021-03-15 Review completed
2021-04-07
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 #2 for the period 2021-02-01 to 2021-02-28. The current post-market safety data are consistent with the labelled safety profile of the AstraZeneca COVID-19 Vaccine.
Amendment # 250727
Amended terms and conditions
Not applicable Terms and conditions amended post authorization
2021-04-06
One of the terms and conditions imposed on the authorization of the AstraZeneca COVID-19 Vaccine was amended. An extension was granted to provide a complete response to Term #1 issued 2021-03-29.
Dear Healthcare Professional Letter Not applicable Published
2021-04-01
Dear Healthcare Professional Letter posted (Important Safety Information on the Importation of AstraZeneca COVID-19 Vaccine with English-only Vial and Carton Labels [US-Labelled Supply]), containing important information for healthcare professionals.
Drug product (DIN 02510847) market notification Not applicable Date of first sale
2021-04-01
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.
Amendment # 250891 2021-03-23 Authorization amended
2021-03-31
An application submitted to amend the authorization in respect of this drug (relating to new manufacturing 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.

Additional terms and conditions were imposed on this authorization when it was amended to permit this change, to ascertain the continued quality of the drug substance and drug product manufactured at the new sites.
Amendment # 250727
Additional terms and conditions
Not applicable Terms and conditions imposed post authorization
2021-03-29
Additional terms and conditions were imposed on the authorization of the AstraZeneca COVID-19 Vaccine. The information requested by Health Canada will support the ongoing evaluation of recent reports of rare thrombotic events with thrombocytopenia, and allow Health Canada to determine whether additional risk mitigation measures are needed.
Dear Healthcare Professional Letter Not applicable Published
2021-03-24
Dear Healthcare Professional Letter posted (Important Safety Information on AstraZeneca COVID-19 Vaccine and Covishield: Risk of Thrombosis and Thrombocytopenia), containing important safety information for healthcare professionals.
Amendment # 250727 2021-03-22 Authorization amended
2021-03-24
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 changes were in response to an Advisement Letter issued by Health Canada, dated 2021-03-20, requesting a labelling update as per new evidence and information reviewed to address the signs and symptoms of thromboembolism and/or thrombocytopenia. The Product Monograph was updated to include information related to thrombocytopenia and coagulation disorders in the Warnings and Precautions, Adverse Reactions, 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 # 250447 2021-03-15 Authorization amended
2021-03-24
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 to include information related to hypersensitivity including anaphylaxis as well as information related to administration, a pregnancy exposure registry, and adverse reactions. 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.
Advisement Letter Not applicable Issued
2021-03-20
Health Canada issued an Advisement Letter, requesting a labelling update as per new evidence and information reviewed to address the signs and symptoms of thromboembolism and/or thrombocytopenia.
Amendment # 250081 2021-03-04 Authorization amended
2021-03-12
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 and other documents were updated to include reference to Covishield. 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.
Advisory Not applicable Published
2021-03-11
Advisory posted (Adverse events in Europe following immunization with the AstraZeneca COVID-19 Vaccine), containing important information for the general public.
Dear Healthcare Professional Letter Not applicable Published
2021-03-01
Dear Healthcare Professional Letter posted (Authorization of the AstraZeneca COVID-19 Vaccine with English-only Vial and Carton Labels), containing important information about supply and product safety for healthcare professionals.
Application # 244627 2020-10-01 Authorized (with terms and conditions)
2021-02-26
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 Vaxzevria (previously the AstraZeneca COVID-19 Vaccine)

Date SBD issued: 2021-03-05

The following information relates to the new drug submission for Vaxzevria (previously the AstraZeneca COVID-19 Vaccine).

ChAdOx1-S (recombinant)

Drug Identification Number (DIN):

  • DIN 02510847 - 5 x 1010 virus particles/0.5 mL ChAdOx1‑S (recombinant), 10‑dose vial, solution, intramuscular administration
  • DIN 02511444 - 5 x 1010 virus particles/0.5 mL ChAdOx1‑S (recombinant), 8‑dose vial, solution, intramuscular administration

AstraZeneca Canada Inc.

Application Control Number: 244627

 

On February 26, 2021, 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 AstraZeneca Canada Inc. for the AstraZeneca 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 AstraZeneca 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 AstraZeneca 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 AstraZeneca COVID‑19 Vaccine is considered favourable for active immunization of individuals 18 years of age and older for the prevention of COVID‑19.

The interim authorization of the AstraZeneca 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 AstraZeneca COVID‑19 Vaccine (ChAdOx1‑S [recombinant]) is indicated for active immunization of individuals 18 years of age and older for the prevention of coronavirus disease 2019 (COVID‑19).

The authorization of the AstraZeneca 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 an interim analysis of pooled data from four ongoing clinical studies: COV001, COV002, COV003, and COV005.

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

Of the available clinical trial data, the results were too limited to allow a reliable estimate of vaccine efficacy in individuals ≥65 years of age. Efficacy in individuals ≥65 years of age is supported by immunogenicity data, emerging real world information, and post-market experience in regions where the vaccine has been deployed, which suggest at this point in time a potential benefit and no safety concerns. Efficacy in this age group will be updated as additional data become available from currently ongoing trials.

The AstraZeneca COVID‑19 Vaccine is contraindicated in individuals who are hypersensitive to the active substance or to any ingredient in the formulation.

The AstraZeneca COVID‑19 Vaccine (ChAdOx1‑S [recombinant], 5 x 1010 virus particles/0.5 mL dose) is presented as a solution and is available in 8‑ and 10‑dose vials. In addition to the medicinal ingredient, the solution contains disodium edetate dihydrate, ethanol, L‑Histidine, L‑Histidine hydrochloride monohydrate, magnesium chloride hexahydrate, polysorbate 80, sodium chloride, sucrose, 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 AstraZeneca 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 Vaxzevria (previously the AstraZeneca COVID-19 Vaccine) approved?

Health Canada considers that sufficient evidence has been provided to support the conclusion that the benefits associated with the AstraZeneca 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 AstraZeneca COVID‑19 Vaccine is deemed favourable for active immunization of individuals 18 years of age and older for the prevention of coronavirus disease 2019 (COVID‑19).

The use of the AstraZeneca 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 severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) virus that emerged in late 2019. In Canada, there have been 861,472 confirmed cases of COVID‑19 and 21,915 deaths as of February 26, 2021, the date of authorization of the AstraZeneca COVID‑19 Vaccine, and these numbers are still increasing. It is predominantly a respiratory illness that can affect other organs. People with COVID‑19 can be asymptomatic, or can experience a range of symptoms from mild 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, loss of taste or smell, sore throat, congestion or runny nose, nausea or vomiting, and diarrhea. The majority of patients infected with the SARS‑CoV‑2 virus recover without significant sequelae. However, 10% to 15% of cases progress to severe disease, and 5% of patients 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. To date, Health Canada has authorized two other vaccines under the Interim Order. On December 9, 2020, the Pfizer-BioNTech COVID‑19 Vaccine was authorized for active immunization to prevent COVID‑19 caused by the SARS‑CoV‑2 virus in individuals 16 years of age and older. On December 23, 2020, the Moderna COVID‑19 Vaccine was authorized for active immunization against COVID‑19 caused by the SARS‑CoV‑2 virus in individuals 18 years of age and older. Maintaining a stable supply of these vaccines for Canada has been challenging and there remains an urgent need for further prophylactic vaccine options in the context of the ongoing and worsening pandemic. The AstraZeneca COVID‑19 Vaccine is the third vaccine to be authorized in Canada for protection against COVID‑19.

The medicinal ingredient in the AstraZeneca COVID‑19 Vaccine, ChAdOx1‑S (recombinant), is a single recombinant, replication-deficient chimpanzee adenovirus (ChAdOx1) vector encoding the unmodified SARS‑CoV‑2 spike (S) glycoprotein. Following administration, the S glycoprotein of SARS‑CoV‑2 is expressed locally, stimulating neutralizing antibody and cellular immune responses.

The safety and efficacy of the AstraZeneca COVID‑19 Vaccine have been evaluated based on an interim analysis of pooled data from four ongoing randomized, blinded, controlled studies:

  • COV001 (NCT04324606), a Phase I/II study in healthy adults 18 to 55 years of age conducted in the United Kingdom (UK);
  • COV002 (NCT04400838), a Phase II/III study in adults 18 years of age or older conducted in the UK;
  • COV003 (ISRCTN89951424), a Phase III study in adults 18 years of age or older conducted in Brazil; and
  • COV005 (NCT04444674), a Phase I/II study in adults aged 18 to 65 years of age conducted in South Africa.

Vaccine efficacy was based on the interim analysis (November 4, 2020 data cut-off date) of pooled data from the COV002 and COV003 studies. The pre-defined criteria for the interim efficacy analysis of COV002 and COV003 exceeded the threshold of ≥5 severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) virologically confirmed COVID‑19 cases per study and therefore were included in the efficacy analysis; COV001 and COV005 did not exceed such a threshold and were therefore excluded from this interim analysis.

The primary endpoint to demonstrate vaccine efficacy of the AstraZeneca COVID‑19 Vaccine against COVID‑19 following a two-dose regimen, based on pooled data from the COV002 and COV003 studies, was defined as first case of SARS‑CoV‑2 virologically confirmed symptomatic COVID‑19 occurring ≥15 days post Dose 2. The majority of participants received two doses (Dose 1 and Dose 2) of the AstraZeneca COVID‑19 Vaccine intramuscularly 4 to 12 weeks apart. The interim analysis of the primary efficacy endpoint (data cut-off November 4, 2020) included 11,636 participants 18 years of age or older (5,807 in the AstraZeneca COVID‑19 Vaccine group and 5,829 in the control group). At the time of the interim analysis, participants had been followed for symptomatic COVID‑19 for a median of 63 days (range: 16 to 94 days) after Dose 2, corresponding to exposure of 921 person years in the AstraZeneca COVID‑19 Vaccine group and 925 person years in the control group. Participants randomized to the AstraZeneca COVID‑19 Vaccine received either two standard doses (SD) of 5 x 1010 virus particles per dose (SD/SD cohort) or, due to a difference in concentration determination between two analytical methods, one low dose (LD) of 2.2 x 1010 virus particles followed by one standard dose of 5 x 1010 virus particles (LD/SD cohort). Due to late implementation of a 2‑dose regimen, the interval between Dose 1 and Dose 2 was variable: 86 participants (0.7%) had a dose interval of less than 4 weeks, 8,786 (75.5%) had a dose interval of 4 to 12 weeks, and 2,764 (23.8%) had dose interval of more than 12 weeks.

Baseline demographics were balanced across the AstraZeneca COVID‑19 Vaccine and control treatment groups. Overall, among the participants who received the AstraZeneca COVID‑19 Vaccine, 94.3% of participants were 18 to 64 years old and 5.7% were ≥65 years of age.

Immunogenicity was based on an interim analysis of pooled data from the COV001, COV002, COV003, and COV005 studies.

The evidence of safety for the AstraZeneca COVID‑19 Vaccine was based on an interim analysis of pooled data from the COV001, COV002, COV003, and COV005 studies consisting of 23,745 participants who had received at least one dose of study intervention up to the data cut-off date of November 4, 2020. Of these 23,745 participants, 12,021 received at least one dose of the AstraZeneca COVID‑19 Vaccine and 11,724 received control (meningococcal vaccine or saline placebo). In the AstraZeneca COVID‑19 Vaccine group, 8,266 participants received two doses of which 6,568 received standard doses (SD/SD cohort); 10,852 (90.3%) were 18 to 64 years of age and 1,169 (9.7%) were ≥65 years of age. At the time of the data cut-off on November 4, 2020, the median duration of follow-up post Dose 2 was 63 days for participants 18 to 64 years of age and 30 days for participants ≥65 years of age. Overall, 3% of participants were seropositive at baseline. Just over one third of participants had at least one comorbidity at baseline, the most common of which were obesity (body mass index ≥30 kg/m2), hypertension, and asthma.

A different population (called the Solicited Adverse Reaction [AR] Set) was used by Health Canada for evaluation of solicited ARs, due to differences in collection of solicited events between the COV005 study and the other three studies. This set included those participants in the COV001, COV002, and COV003 studies who had received at least one standard dose of the AstraZeneca COVID‑19 Vaccine, and who were given diary cards to record solicited ARs. The Solicited AR Set consisted of 3,332 participants, 1,736 of whom received the AstraZeneca COVID‑19 Vaccine and 1,596 of whom received the control. Of the 1,736 participants who received the AstraZeneca COVID‑19 vaccine, 1,334 (76.8%) were 18 to 64 years of age and 402 (23.2%) were ≥65 years of age. With the exception of 98 participants who were enrolled in the COV003 study, all participants in the control group received meningococcal vaccine for both vaccinations; the 98 participants in the COV003 study received meningococcal vaccine for Dose 1 followed by saline placebo for Dose 2.

COV002 and COV003; Participants in interim pooled efficacy analysis
  Vaccine group Control group Total
Male 2,282 (39.3%) 2,307 (39.6%) 4,589 (39.4%)
Female 3,525 (60.7%) 3,521 (60.4%) 7,046 (60.6%)
Transgender 0 1 (<0.1%) 1 (<0.1%)
Total number of participants
(18 years of age and older)
5,807 5,829 11,636
COV001, COV002, COV003, and COV005; Participants in interim pooled safety analysis
  Vaccine group Control group Total
Total number of participants
(18 years of age and older)
12,021 11,724 23,745

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 received a two-dose regimen of either the AstraZeneca COVID‑19 Vaccine or control,
  • have been seronegative at baseline,
  • have had follow-up data ≥15 days post Dose 2,
  • have had a positive polymerase chain reaction (PCR) test (or other nucleic acid amplification test) with the sampling date ≥15 days post Dose 2, and
  • have experienced at least one of the following COVID‑19 symptom(s) with an onset date ≥15 days post Dose 2: objective fever (defined as ≥37.8 °C), cough, shortness of breath, or new loss of taste or smell.

The vaccine efficacy success criteria for the primary endpoint, predefined by the sponsor, was a lower bound of the 95% confidence interval (CI) above 20%.

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 interim pooled efficacy analysis
A vaccine efficacy success criteria for the primary endpoint with a lower bound of the 95% CI above 20%.
Efficacy rates observed in interim pooled efficacy analysis in SD/SD cohort (COV002 and COV003)
  Vaccine efficacy rate Two-sided 95% CI
Overall
Participants 18 years of age and older
62.1% 41.0% to 75.7%

The studies met the pre-defined primary efficacy endpoint and exceeded Health Canada's vaccine efficacy success criterion of the lower bound of the 95% CI >30% set out by Health Canada's Guidance for Market Authorization Requirements for COVID‑19 Vaccines. At the time of interim analysis, a total of 131 participants had SARS‑CoV‑2 virologically confirmed COVID‑19 occurring ≥15 days post Dose 2; 30 (0.5%) in the AstraZeneca COVID‑19 Vaccine group and 101 (1.7%) in the control group. Compared to control, efficacy of the AstraZeneca COVID‑19 Vaccine in participants with first COVID‑19 occurrence from 15 days post Dose 2 was 70.42% (two-sided 95.84% CI: 58.84%, 80.63%; p<0.001). At the time of interim analysis, there were 0 (n = 5,807) severe COVID‑19 cases (World Health Organization [WHO] severity score ≥6) starting 15 days post Dose 2 in the AstraZeneca COVID‑19 Vaccine group and 1 (n = 5,829) severe case in the control group. The above vaccine efficacy was based on the pre-specified analysis; however, the results should be interpreted with caution given that it excludes 51% of randomized and vaccinated participants, the majority of which had only received a single dose. In addition, a significant difference was observed in vaccine efficacy between the LD/SD cohort and the SD/SD cohort. The findings may also be confounded by the variability in dosing interval.

In seronegative participants who received two standard doses (SD/SD cohort) (4,440 in the AstraZeneca COVID‑19 Vaccine group and 4,455 in the control group), a total of 98 participants had virologically confirmed COVID‑19 occurring ≥15 days post Dose 2 (27 cases in the AstraZeneca COVID‑19 Vaccine group and 71 cases in the control group). In this population, vaccine efficacy from 15 days post Dose 2 was 62.1% (two-sided 95% CI: 41.0%, 75.7%).

Based on an updated analysis in an expanded population (data cut-off December 7, 2020) with data that are subject to change as additional cases become available, vaccine efficacy was 59.5% (two-sided 95% CI: 45.8%, 69.7%) in participants who received two standard doses (SD/SD cohort) with Dose 2 administered 4 to 12 weeks after Dose 1. Regarding COVID‑19 hospitalization (WHO severity score ≥4) in these data, there were 0 (n = 5,258) cases of COVID‑19 hospitalization in participants who received two doses of the AstraZeneca COVID‑19 Vaccine (≥15 days post Dose 2) as compared to 8 (n = 5,210) for the control group, including one severe case (WHO severity score ≥6), reported for the control group.

Of the available clinical trial data, the results were too limited to allow a reliable estimate of vaccine efficacy in individuals ≥65 years of age. Efficacy in individuals ≥65 years of age is supported by immunogenicity data, emerging real world information, and post-market experience in regions where the vaccine has been deployed, which suggest at this point in time a potential benefit and no safety concerns. Efficacy in this age group will be updated as additional data become available from currently ongoing trials.

Solicited ARs were more common in participants who received the AstraZeneca COVID‑19 Vaccine compared to the control group (meningococcal vaccine or saline placebo), occurring in 97.0% and 87.4%, respectively, of participants 18 to 64 years of age, and 83.8% and 67.0%, respectively, of participants ≥65 years of age. The majority of these events were mild to moderate in severity.

In adults 18 to 64 years of age who received the AstraZeneca COVID‑19 Vaccine, the most frequently reported ARs after any dose were tenderness (81.1% vs. 57.9% in the control group) and pain (63.0% vs. 42.0%) at the injection site, fatigue (67.7% and 50.2%), headache (64.4% vs. 46.2%), and myalgia (55.1% vs. 26.8%). When compared with Dose 1, ARs reported after Dose 2 were milder and reported less frequently. Local ARs were less common in participants ≥65 years of age, occurring in 56.0% of participants in the AstraZeneca COVID‑19 Vaccine group and 33.3% in the control group. Systemic ARs were also less common in participants ≥65 years of age, with fatigue occurring in 44.5% of participants in the AstraZeneca COVID‑19 Vaccine group (vs. 33.6% in the control group) and headache occurring in 34.8% of participants (vs. 28.7% in the control group).The most common events of Grade ≥3 severity were malaise, feverishness and chills (all approximately 4%) in participants 18 to 64 years of age, and malaise (<1%) in participants ≥65 years of age.

The incidence of unsolicited adverse events (AEs) in the first 28 days was higher in the AstraZeneca COVID‑19 Vaccine group than in the control group (37.8% and 27.9% respectively). Study intervention-related AEs, including related neurological AEs, were also more common in the AstraZeneca COVID‑19 Vaccine group than the control group (27.9% and 18.5%, respectively). Most of the non-serious AEs were reported within the first 7 days of vaccination, were self-limited, and were consistent with AEs commonly observed following vaccination. The following were more common in the AstraZeneca COVID‑19 Vaccine group than in the control group: diarrhea (1.3% vs. 1.0%), hyperhydrosis (0.3% vs. 0.1%), and decreased appetite (0.2% vs. 0.1%). Some relevant reactions occurred at similar rates between the AstraZeneca COVID‑19 Vaccine and control groups, such as lymphadenopathy (0.3%), pruritis (0.2%), and rash (0.2%). Specific vaccine-related neurological events that occurred at higher rates in the AstraZeneca COVID‑19 Vaccine group than the control group included headache/migraine (9.3% vs. 6.1%), dizziness (0.6 % vs. 0.5 %) and somnolence (0.3% vs. 0.2%). Rates of unsolicited AEs were generally slightly lower in participants ≥65 years of age than in adults 18 to 64 years of age (24.6% vs. 33.3%, respectively). There appeared to be no differences in the incidence of unsolicited AEs based on comorbidity or serostatus at baseline.

The incidence of serious adverse events (SAEs) was 0.7% in AstraZeneca COVID‑19 Vaccine recipients and 0.8% in control recipients. No difference was noted in rates of SAEs based on age. Two immune-mediated neurological events were noted in the studies for which a causal relationship to the AstraZeneca COVID‑19 Vaccine could not be excluded: a case of transverse myelitis and a case of Grade 3 Bell's palsy. There were no life-threatening adverse events and no deaths related to the AstraZeneca COVID‑19 Vaccine. Based on the available data, the AstraZeneca COVID‑19 Vaccine at the indicated dose was considered safe and well tolerated.

The safety and efficacy of the AstraZeneca COVID‑19 Vaccine in pregnant women have not been established. Women who were pregnant or breastfeeding were excluded from the clinical studies. Pregnancy was reported in 21 participants (12 in the AstraZeneca COVID‑19 Vaccine group and 9 in the control group) 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 the AstraZeneca COVID‑19 Vaccine during pregnancy. Women who are vaccinated with the AstraZeneca COVID‑19 Vaccine during pregnancy are encouraged to enroll in the registry.

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

No data are currently available in immunocompromised individuals or in individuals taking immunosuppressants.

Collectively, the results of the clinical efficacy and safety evaluation demonstrated that the AstraZeneca COVID‑19 Vaccine met the safety requirements as specified in Health Canada's Guidance for Market Authorization Requirements for COVID‑19 Vaccines. The AstraZeneca COVID‑19 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 standard doses of 5 x 1010 virus particle given 4 to 12 weeks apart).

A Core (European Union [EU]) Risk Management Plan (RMP) in conjunction with the Canadian Specific Addendum for the AstraZeneca COVID‑19 Vaccine was submitted by AstraZeneca Canada 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. Following Health Canada review, the RMP for the AstraZeneca COVID‑19 Vaccine includes the following as important potential risks: "anaphylaxis", "nervous system disorders including immune mediated neurological conditions", and "vaccine-associated enhanced disease including vaccine-associated enhanced respiratory disease". In addition, the following areas of missing information are included: "use in pregnant and breastfeeding women", "use in the pediatric population <18 years of age", "use in immunocompromised patients and patients with chronic or debilitating conditions", "use in subjects with severe and/or uncontrolled underlying disease", "interaction with other vaccines", "long-term effectiveness", and "long-term safety". It was noted that there was limited recruitment of persons ≥65 years of age and a lack of information regarding special populations (including Canadian indigenous populations, patients with chronic illness, immunocompromised individuals, and frail elderly) in the clinical data submitted by AstraZeneca Canada Inc.

Overall, the RMP was considered to be acceptable and identified appropriate monitoring (pharmacovigilance) activities and risk minimization measures (i.e., product monograph and labelling) based on the safety profile of the product. The identified limitations and areas of missing information are managed through labelling and the RMP, and will continue to be investigated through ongoing and planned studies. The COV001, COV002, COV003, and COV005 studies are ongoing and will continue to collect information on the long-term safety, efficacy, and immunogenicity of the AstraZeneca COVID‑19 Vaccine. An additional Phase III study is underway in the United States, Peru, and Chile with interim analysis expected to be available in spring 2021. AstraZeneca Canada Inc. is also planning four post-authorization studies: a Phase IV Enhanced Active Surveillance Study of People Vaccinated with the vaccine; a Pregnancy Registry; a Post-marketing Safety Study; and a Post-marketing Effectiveness Study.

Terms and conditions were put in place at the time of authorization to require monitoring of the long-term safety and efficacy of AstraZeneca COVID‑19 Vaccine. Further, as outlined in the terms and conditions, in addition to regulatory requirements for post-market monitoring and prioritized reporting of AEs following immunization, monthly safety summary reports will be provided to Health Canada and will include information related to special populations (e.g., pregnant women). In addition, 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. For more information, refer to the complete list of terms and conditions available on the Health Canada COVID‑19 vaccines and treatments portal.

Definitive data regarding protection against emerging SARS‑CoV‑2 variants (e.g., those originating in the United Kingdom, Brazil and South Africa) are not yet available. The potential impact on vaccine efficacy and safety will be monitored. As outlined in the terms and conditions, data regarding protection against emerging variants will be provided, when available.

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 AstraZeneca COVID‑19 Vaccine has a favourable benefit‑risk balance and an acceptable safety profile.

Pursuant to Section 5 of the Interim Order, the AstraZeneca 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 Vaxzevria (previously the AstraZeneca COVID-19 Vaccine)?

The application for authorization of the AstraZeneca COVID‑19 Vaccine (ChAdOx1‑S [recombinant]) was filed on October 1, 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 AstraZeneca 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 AstraZeneca COVID‑19 Vaccine, with imposed terms and conditions, was issued by Health Canada on February 26, 2021.

 

Submission Milestones: Vaxzevria (previously the AstraZeneca COVID-19 Vaccine)

Submission Milestone Date
Pre-application meeting 2020-09-28
Initial application filed by sponsor 2020-10-01
Initial non-clinical data submitted by sponsor 2020-10-01
Initial quality data submitted by sponsor 2020-11-05
Initial clinical data submitted by sponsor 2020-12-04
Risk Management Plan submitted by sponsor 2020-12-21
Educational material submitted by sponsor 2020-12-30
Health Canada Review of Risk Management Plan complete 2021-02-01
Health Canada Quality Evaluation complete 2021-02-24
Health Canada Clinical/Medical Evaluation complete 2021-02-24
Terms and Conditions finalized by Health Canada 2021-02-24
Final Product Monograph (English and French) submitted by sponsor 2021-02-24
Health Canada Labelling Review complete 2021-02-25
Health Canada Biostatistics Evaluation complete 2021-02-26
Interim authorization issued by Director General, Biologic and Radiopharmaceutical Drugs Directorate, Health Canada 2021-02-26

The Canadian regulatory decision on the review of the AstraZeneca COVID‑19 Vaccine was based on a critical assessment of the data package submitted to Health Canada. Foreign reviews by the European Medicines Agency, the United Kingdom's Medicines and Healthcare Products Regulatory Agency, Australia's Therapeutic Goods Administration, and Switzerland's SwissMedic were used as added references. 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 AstraZeneca 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 sponsor will:

  • Provide available data as soon as possible, from the pooled analyses of COV001/2/3/5. Health Canada expects related updates in Clinical Overview and Clinical Summaries.
  • Provide available analyzed data as soon as possible of the Phase III study D8110C00001 (United States, Chile and Peru). Health Canada considers that this study is important to confirm the benefit and risk of AstraZeneca COVID‑19 Vaccine. Health Canada expects the following documents:
    • Study Synopsis.
    • Updated Clinical Overview and Clinical Summaries.
  • Provide all data and narratives for serious adverse events of nervous system disorders from the Phase III trial D8110C00001 as soon as possible following unblinding of these subjects.
  • Provide clinical study reports for COV001, COV002, COV003, and COV005, when available.
  • Provide data regarding protection against emerging variants, when available (e.g., United Kingdom, Brazil, South Africa).
  • Provide serious adverse events and adverse events of special interest data from the other trials that are currently underway: COV004‑Kenya, D8111C00001‑Russia, D8111C00002‑Japan, and ICMR/SIICOVISHIELD‑India.

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 Order authorization, unless otherwise determined by Health Canada.
  • Provide an updated Canadian Addendum to the Core (European Union [EU]) Risk Management Plan (RMP) that will include a description of the planned pharmacovigilance activities for monitoring of use in pregnant and breastfeeding women in Canada.
  • Provide an updated Core (EU) RMP and 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 AstraZeneca 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 AstraZeneca COVID‑19 Vaccine under the Interim Order with foreign labelling for the initial supply, to expedite 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 distribution of the AstraZeneca COVID‑19 Vaccine until such a time that Canadian‑specific labelling is implemented.
  • Implement Canadian‑specific bilingual labelling and keep Health Canada informed of the estimated timelines and proposed strategies. During the period prior to implementation, approved mock‑ups of the proposed Canadian labels should be made available to healthcare professionals as reference.
  • Submit a lot release protocol for each lot to be distributed in Canada. The sponsor will require a lot release letter from Health Canada prior to distribution in the Canadian market. A summary of batch disposition should be submitted on a biannual basis from the facilities approved to supply Canada.
  • 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 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.
  • 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.
  • Health Canada requests that supporting stability information (real time and/or accelerated) is provided for batches manufactured with Process 4 at the sites relevant to this submission prior to the release of any lots in the Canadian market.
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 basis of decision for the AstraZeneca COVID‑19 Vaccine (ChAdOx1‑S [recombinant]) under the Interim Order Respecting the Importation, Sale, and Advertising of Drugs for Use in Relation to COVID‑19 (Interim Order) was based on four ongoing randomized, blinded, controlled studies:

  • COV001 (NCT04324606), a Phase I/II study in healthy adults 18 to 55 years of age conducted in the United Kingdom (UK);
  • COV002 (NCT04400838), a Phase II/III study in adults 18 years of age or older conducted in the UK;
  • COV003 (ISRCTN89951424), a Phase III study in adults 18 years of age or older conducted in Brazil; and
  • COV005 (NCT04444674), a Phase I/II study in adults aged 18 to 65 years of age conducted in South Africa.

The studies excluded participants with a history of anaphylaxis or angioedema; participants with severe and/or uncontrolled cardiovascular, gastrointestinal, liver, renal, endocrine/metabolic disease, and neurological illnesses; pregnant or breastfeeding women; and participants with known history of severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) virus infection as well as those with severe immunosuppression.

Three of the four studies (COV001, COV002 and COV003) were originally planned to investigate a single-dose regimen but were amended while ongoing to investigate a two‑dose regimen in view of early immunogenicity results. Following amendments to the study protocols to introduce a second dose (Dose 2), the booster (Dose 2) was planned to be given at the earliest possible time (in principle, 28 days after the first dose [Dose 1]), but due to logistical constraints, this interval was variable. Participants are planned to be followed for up to 12 months for assessments of safety and efficacy against coronavirus disease 2019 (COVID‑19).

Vaccine efficacy was calculated as 1‑relative risk derived from a robust Poisson regression model adjusted for age. The global pooled analysis plan allowed for an interim and a final efficacy analysis with alpha (α) adjusted between the two analyses using a flexible gamma α‑spending function, with significance being declared if the lower bound of the (1 ‑ α)% confidence interval is greater than 20%. Evidence of efficacy at the time of the interim analysis was not considered a reason to stop the studies and all studies are continuing to accrue further data that will be included in future analyses. The first interim analysis was planned to be triggered when at least 53 cases in participants who had received two standard doses (SD) of 5 x 1010 viral particles per dose (SD/SD cohort) had met the primary outcome definition more than at least 15 days post Dose 2. Due to the rapid increase in incidence of COVID‑19 in the UK in October, more than 53 cases had accrued by the time of data cut-off of November 4, 2020. There were 98 cases available for inclusion in the SD/SD cohort. The primary efficacy endpoint analysis met the statistical criterion of success with the lower bound of the confidence interval being >20%. It also exceeded the more stringent criterion of >30% set out by Health Canada's Guidance for Market Authorization Requirements for COVID‑19 Vaccines.

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 foreign review by the European Medicines Agency, the United Kingdom's Medicines and Healthcare Products Regulatory Agency, Australia's Therapeutic Goods Administration, and Switzerland's SwissMedic.

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

Clinical Pharmacology

The AstraZeneca COVID‑19 Vaccine is a monovalent vaccine composed of a single recombinant, replication-deficient chimpanzee adenovirus (ChAdOx1) vector encoding the unmodified spike (S) glycoprotein of the severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) virus. Following administration, the S glycoprotein of the SARS‑CoV‑2 virus is expressed locally, stimulating humoral (neutralizing antibody) and cellular immune responses towards the SARS‑CoV‑2 virus, which may contribute to protection against coronavirus 2019 disease (COVID‑19).

The immunogenicity of the AstraZeneca COVID‑19 Vaccine was based on an interim analysis of pooled data from the COV001, COV002, COV003, and COV005 studies.

Following vaccination with the AstraZeneca COVID‑19 Vaccine in participants who were seronegative at baseline, seroconversion (as measured by a ≥4‑fold increase from baseline in S‑binding antibodies) was demonstrated in ≥98% of participants at 28 days post Dose 1 and >99% at 28 days post Dose 2.

In adults ≥65 years of age, seroconversion rates were 97.8% (number of participants [n] = 136) after the first standard dose and 100.0% (n = 111) after the second standard dose. The increase in S‑binding antibodies was lower for participants ≥65 years of age (28 days after the second standard dose: geometric mean titre [GMT] = 20,727.02 [n = 116]) when compared to participants 18 to 64 years of age (28 days after the second standard dose: GMT = 30,695.30 [n = 703]).

In participants with serological evidence of prior SARS‑CoV‑2 infection at baseline (GMT = 13,137.97 [n = 29]), S‑binding antibody titres peaked 28 days after Dose 1 (GMT = 175,120.84 [n = 28]).

However, these findings need to be interpreted with caution because there is no immune correlate of protection. Further, the analysis of immunogenicity is exploratory and was based on subsets of participants.

For further details, please refer to the AstraZeneca 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 vaccine efficacy of the AstraZeneca COVID‑19 Vaccine was based on an interim analysis of pooled data from the COV002 and COV003 studies. The pre-defined criteria for the interim efficacy analysis of these studies exceeded the threshold of ≥5 severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) virologically confirmed coronavirus 2019 disease (COVID‑19) cases per study and therefore were included in the efficacy analysis. The COV001 and COV005 studies did not exceed such a threshold and were therefore excluded from this interim analysis. Despite some differences across the COV002 and COV003 studies, there was sufficient consistency to justify the pooled analysis of data. Further, pooling of the data provided greater precision for both efficacy and safety outcomes than can be achieved in individual studies, and provided a broader understanding of the use of the vaccine in different populations.

The interim analysis of the primary efficacy endpoint (data cut-off November 4, 2020) included 11,636 participants 18 years of age and older, randomized to receive two doses of the AstraZeneca COVID‑19 Vaccine (number of participants [n] = 5,807) or control (n = 5,829), administered by intramuscular injection. At the time of the interim analysis, participants had been followed for symptomatic COVID‑19 for a median of 63 days (range: 16 to 94 days) post Dose 2, corresponding to exposure of 921 person‑years in the AstraZeneca COVID‑19 Vaccine group and 925 person‑years in the control group. Participants randomized to the AstraZeneca COVID‑19 Vaccine received either two standard doses (SD) of 5.0 x 1010 virus particles per dose (SD/SD cohort) or, due to a difference in concentration determination between two analytical methods leading to some participants receiving a lower dose, one low dose (LD) of 2.2 x 1010 virus particles followed by one standard dose of 5 x 1010 virus particles (LD/SD cohort). Participants randomized to the control received either two doses of meningococcal vaccine or a dose of meningococcal vaccine followed by a dose of saline. Due to late implementation of a two‑dose regimen, the interval between Dose 1 and Dose 2 was variable: 86 participants (0.7%) had a dose interval of less than 4 weeks, 8,786 (75.5%) had a dose interval of 4 to 12 weeks, and 2,764 (23.8%) had a dose interval of more than 12 weeks.

Baseline demographics were balanced across the AstraZeneca COVID‑19 Vaccine group and the control treatment group. Overall, among the participants who received the AstraZeneca COVID‑19 Vaccine, 94.3% of participants were 18 to 64 years of age (with 5.7% being ≥65 years of age); 60.7% of participants were female; 82.8% were White, 4.6% were Asian, and 4.4% were Black. A total of 2,070 (35.6%) participants had at least one pre-existing comorbidity, defined as a body mass index ≥30 kg/m2, cardiovascular disorder, respiratory disease, or diabetes. The median follow-up time post Dose 1 and post Dose 2 was 132 days and 63 days, respectively.

The primary endpoint to demonstrate vaccine efficacy of the AstraZeneca COVID‑19 Vaccine against COVID‑19 following a two-dose regimen was defined as first case of SARS‑CoV‑2 virologically confirmed symptomatic COVID‑19 occurring ≥15 days post Dose 2 of study intervention, with at least one of the following symptoms: objective fever (defined as ≥37.8 °C), cough, shortness of breath, or loss of taste or smell. Final determination of COVID‑19 was made by an adjudication committee, who also assigned disease severity according to the World Health Organization (WHO) clinical progression scale.

At the time of the interim analysis, the study met the pre-specified primary endpoint. A total of 131 participants had SARS‑CoV‑2 virologically confirmed COVID‑19 occurring ≥15 days post Dose 2; 30 (0.5%) cases in the AstraZeneca COVID‑19 Vaccine group and 101 (1.7%) in the control group. Compared to control, the efficacy of the AstraZeneca COVID‑19 Vaccine in participants with first COVID‑19 occurrence from 15 days post Dose 2 was 70.42% (two-sided 95.84% confidence interval [CI]: 58.84%, 80.63%; p<0.001).

There were 0 (n = 5,807) cases of COVID‑19 hospitalization starting 15 days post Dose 2 (WHO severity score ≥4) in participants who received two doses of the AstraZeneca COVID‑19 Vaccine compared to 5 (n = 5,829) for the control group. There were 0 and 1 cases of severe COVID‑19 cases (WHO severity score ≥6) starting 15 days post Dose 2 in the AstraZeneca COVID‑19 Vaccine group and the control group, respectively.

The above vaccine efficacy was based on the pre-specified analysis; however, the results should be interpreted with caution given that it excludes 51% of randomized and vaccinated participants, the majority of which had only received a single dose. In addition, a significant difference was observed in vaccine efficacy between the LD/SD cohort and the SD/SD cohort. The findings may also be confounded by the variability in dosing interval.

In seronegative participants who received two standard doses (SD/SD cohort: 4,440 in the AstraZeneca COVID‑19 Vaccine group and 4,455 in the control group), a total of 98 participants had SARS‑CoV‑2 virologically confirmed COVID‑19 occurring ≥15 days post Dose 2; 27 cases in the AstraZeneca COVID‑19 Vaccine group and 71 cases in the control group. In this population, vaccine efficacy from 15 days post Dose 2 was 62.1% (two-sided 95% CI: 41.0%, 75.7%).

Based on an updated analysis in an expanded population (data cut-off of December 7, 2020) with data that are subject to change as additional cases become available, vaccine efficacy was 59.5% (two-sided 95% CI: 45.8%, 69.7%) in participants who received two standard doses (SD/SD cohort) with Dose 2 administered 4 to 12 weeks after Dose 1. Regarding COVID‑19 hospitalization (WHO severity score ≥4) in these data, there were 0 (n = 5,258) cases of COVID-19 hospitalization in participants who received two doses of AstraZeneca COVID-19 Vaccine (≥15 days post Dose 2) as compared to 8 (n = 5,210) for the control group, including one severe case (WHO severity score ≥6), reported for the control group.

At the time of the interim analysis, there was a limited number of COVID‑19 cases in participants ≥65 years of age, as well as participants 56 to 64 years of age. Of the available clinical trial data, the results were too limited to allow a reliable estimate of vaccine efficacy in individuals ≥65 years of age. Efficacy in individuals ≥65 years of age is supported by immunogenicity data, emerging real world information, and post-market experience in regions where the vaccine has been deployed, which suggest at this point in time a potential benefit and no safety concerns. Efficacy in this age group will be updated as additional data become available from currently ongoing trials.

Definitive data regarding the efficacy of the AstraZeneca COVID‑19 Vaccine against emergent SARS‑CoV‑2 variant strains (e.g., those originating in the United Kingdom, Brazil, and South Africa) are not yet available. The potential impact on vaccine efficacy and safety will be monitored. This information will be provided as it becomes available (see terms and conditions).

Collectively, the efficacy data demonstrate that the AstraZeneca COVID‑19 Vaccine regimen met the vaccine efficacy success criteria as specified in Health Canada's Guidance for Market Authorization Requirements for COVID‑19 Vaccines. The COV001, COV002, COV003, and COV005 studies are ongoing and will continue to provide additional information on the efficacy of the AstraZeneca COVID‑19 Vaccine over a period of 12 months.

Indication

The sponsor filed the application for authorization of the AstraZeneca COVID‑19 Vaccine under the Interim Order with the following indication:

  • AstraZeneca COVID‑19 Vaccine (ChAdOx1‑S [recombinant]) is indicated for active immunization against coronavirus disease 2019 (COVID‑19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) in persons 18 years of age and older.

Health Canada approved the following indication:

  • AstraZeneca COVID‑19 Vaccine (ChAdOx1‑S [recombinant]) is indicated for active immunization of individuals 18 years of age and over for the prevention of coronavirus disease 2019 (COVID‑19).

For more information, refer to the AstraZeneca 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 AstraZeneca COVID‑19 Vaccine was based on an interim analysis of pooled data from four clinical studies described in the Clinical Efficacy section (COV001, COV002, COV003, and COV005) with a data cut-off date of November 4, 2020. There was heterogeneity between the studies in terms of the collection of safety information, control intervention (meningococcal vaccine or saline placebo), and advice regarding prophylactic use of acetaminophen.

The primary population for evaluation of unsolicited adverse events (AEs) and serious adverse events (SAEs) was the Any Dose for Safety Analysis Set. This population comprised 23,745 participants who had received at least one dose of study intervention up to the data cut-off date. Of these 23,745 participants, 12,021 received at least one dose of AstraZeneca COVID‑19 Vaccine and 11,724 received the control (control refers to meningococcal vaccine or saline placebo hereafter). Among the participants who received the AstraZeneca COVID‑19 Vaccine, 8,266 (68.8%) received two doses of which 6,568 received two standard doses (SD/SD cohort); 10,852 (90.3%) were between the ages of 18 to 64 and 1,169 (9.7%) were ≥65 years of age. At the time of data cut-off, the median duration of follow-up post Dose 2 was 63 days for participants 18 to 64 years of age and 30 days for participants ≥65 years of age. Overall, 3% of participants were seropositive at baseline and just over one third of participants had at least one comorbidity at baseline with the most common being obesity (body mass index ≥30 kg/m2), hypertension, and asthma.

A different population (called the Solicited Adverse Reactions [AR] Set) was used by Health Canada for evaluation of solicited ARs due to differences in collection of solicited events between the COV005 study and the other three studies. This set included participants in the COV001, COV002, and COV003 studies who had received at least one standard dose of the AstraZeneca COVID‑19 Vaccine and who were given diary cards to record solicited ARs. The Solicited AR Set consisted of 3,332 participants, 1,736 of whom received the AstraZeneca COVID‑19 Vaccine and 1,596 of whom received the control. Of the 1,736 participants who received the AstraZeneca COVID‑19 Vaccine, 1,334 (76.8%) were 18 to 64 years of age and 402 (23.2%) were ≥65 years of age. Participants in the control group received meningococcal vaccine for both vaccinations, with the exception of 98 participants in the COV003 study who received meningococcal vaccine for Dose 1 followed by saline placebo for Dose 2.

Solicited Adverse Reactions

Solicited ARs were more common in participants who received the AstraZeneca COVID‑19 Vaccine compared to the control group, occurring in 97.0% and 87.4%, respectively, of participants 18 to 64 years of age, and 83.8% and 67.0%, respectively, of participants ≥65 years of age. The majority of these events were mild to moderate in severity. Solicited ARs of Grade ≥3 were less common in adults ≥65 years of age after any dose, with local ARs (Grade ≥3) occurring in 1.0% of participants 18 to 64 years of age (none in participants ≥65 years of age), and systemic ARs (Grade ≥3) occurring in 11.9% of participants 18 to 64 years of age and 0.7% of participants ≥65 years of age. Solicited ARs were generally milder and reported less frequently after Dose 2 than after Dose 1. The incidence of participants with at least one solicited local or systemic event after vaccination was highest the first day after vaccination and gradually decreased through to Day 7.

In adults 18 to 64 years of age who received the AstraZeneca COVID‑19 Vaccine, the most frequently reported adverse reactions after any dose were tenderness (81.1% vs. 57.9% in the control group) and pain (63.0% vs. 42.0%) at the injection site, fatigue (67.7% vs. 50.2%), headache (64.4% vs. 46.2%), and myalgia (55.1% vs. 26.8%). The majority of these local and systemic ARs were mild to moderate in severity and were self-limited. Local ARs were less common in participants ≥65 years of age, occurring in 56.0% of participants in the AstraZeneca COVID‑19 Vaccine group and 33.3% of participants in the control group. Systemic ARs were also less common in participants ≥65 years of age, with fatigue occurring in 44.5% of participants in the AstraZeneca COVID‑19 Vaccine group (vs. 33.6% in the control group) and headache occurring in 34.8% of participants (vs. 28.7% in the control group). The most common events of Grade ≥3 severity were malaise, feverishness and chills (all approximately 4%) in participants 18 to 64 years of age, and malaise (<1%) in participants ≥65 years of age.

Unsolicited Adverse Events

The overall incidence of unsolicited adverse events within 28 days after vaccination with any dose was higher in the AstraZeneca COVID‑19 Vaccine group (37.8%) compared to the control (27.9%). Study intervention-related unsolicited AEs were also higher in the AstraZeneca COVID‑19 Vaccine group (29.7%) than in the control group (18.5%). The most frequently reported AEs that occurred in ≥2% of the AstraZeneca COVID‑19 Vaccine group were reported within 7 days of vaccination and were consistent with AEs commonly observed following vaccination (injection site AEs, headache, pyrexia, myalgia, fatigue, chills, malaise, asthenia, nausea).

The incidence of unsolicited AEs reported >7 days after any dose was similar between the AstraZeneca COVID‑19 Vaccine group and the control group (9.4% vs. 9.0%). Most of these unsolicited AEs occurring between 8 to 28 days were mild-to-moderate in severity, and the incidence of unsolicited AEs with severity Grade ≥3 was low and similar between the two groups (5.8% in the AstraZeneca COVID‑19 Vaccine group and 5.4% in the control group).

Rates of unsolicited AEs were generally slightly lower in participants ≥65 years of age (24.6%) than in adults 18 to 64 years of age (33.3%). There appeared to be no differences in the incidence of unsolicited AEs based on comorbidity or serostatus at baseline.

Other unsolicited events where there was an imbalance of AEs between the AstraZeneca COVID‑19 Vaccine group and the control group and that occurred at rates >0.1% in the AstraZeneca COVID‑19 Vaccine group included diarrhea (1.3% in the vaccine group vs. 1.0% in the control group), hyperhydrosis (0.3% vs. 0.1%), and decreased appetite (0.2% vs. 0.1%).

Lymphadenopathy, pruritis and rash are recognized uncommon AEs for the meningococcal comparator vaccine. Lymphadenopathy occurred at a rate of 0.3 % in both groups. Pruritis and rash occurred at rates of 0.2% each in both the AstraZeneca COVID‑19 Vaccine and control groups.

A numerical imbalance of neurological disorders was noted between the AstraZeneca COVID‑19 Vaccine and the control groups (11.7% and 7.8%, respectively) for non-serious events. Most of these AEs were considered related to the vaccine, with 1,117 (9.3%) of participants in the AstraZeneca COVID‑19 Vaccine group and 644 (5.5%) of participants in the control group experiencing a study intervention-related AE in the nervous system disorder category. Specific vaccine-related neurological events that occurred at higher rates in the AstraZeneca COVID‑19 Vaccine group than the control group included headache/migraine (9.3% vs. 6.1%), dizziness (0.6 % vs. 0.5 %) and somnolence (0.3% vs. 0.2%). Most of the neurological events were of mild-to-moderate severity, self-limited, and occurred within the first 7 days post vaccination.

Six cases of Bell's palsy occurred in the Any Dose for Safety Analysis Set: three in the AstraZeneca COVID‑19 Vaccine group, and three in the control group, all of whom had received meningococcal vaccine. One case (Grade 3) in the AstraZeneca COVID‑19 Vaccine group was considered vaccine-related.

Study intervention-related non-serious hypersensitivity reactions occurred at <0.1% in both groups, with an episode of vaccine-related Grade 1 injection-site erythema, warmth, and swelling occurring 12 days post Dose 1 in the AstraZeneca COVID‑19 Vaccine group. No vaccine-related anaphylaxis was noted in either group.

Serious Adverse Events

Following first vaccination and prior to data cut-off, SAEs were reported by 0.7% of participants in the AstraZeneca COVID‑19 Vaccine group and 0.8% of participants in the control group. A total of four SAEs were considered possibly related to the study intervention by the investigator: two in the AstraZeneca COVID‑19 Vaccine group, and two in the control group.

The two vaccine-related SAEs in the AstraZeneca COVID‑19 Vaccine group included a case of pyrexia (40.5 °C) associated with other symptoms of reactogenicity occurring in a 30‑year‑old male two days after Dose 2 and a case of transverse myelitis occurring in a 37‑year‑old female 14 days after Dose 2. The two vaccine-related SAEs in the control group included a case of myelitis and a case of autoimmune hemolytic anemia. Both participants in the control group had received the meningococcal vaccine.

Seven cases of neurological SAEs occurred in the AstraZeneca COVID‑19 Vaccine group and four occurred in the control group. Given the timing of the events, a causal relationship to the vaccine could not be ruled out for the cases of transverse myelitis in the AstraZeneca COVID‑19 vaccine group and of myelitis in the control group. The SAE of multiple sclerosis occurred 10 days after the AstraZeneca COVID‑19 Vaccine was administered to a 37‑year‑old female. Magnetic resonance imaging studies showed an acute spinal lesion and older cerebral lesions suggesting pre-existing, but previously unrecognized, multiple sclerosis. The AstraZeneca COVID‑19 Vaccine is unlikely to have caused the multiple sclerosis, however, given the timing, a relationship between the AstraZeneca COVID‑19 Vaccine and the flare leading to the diagnosis cannot be excluded. The risk of nervous system disorders, including immune-mediated neurological conditions, will continue to be monitored following authorization through the Risk Management Plan (RMP).

No participants withdrew from the AstraZeneca COVID‑19 Vaccine group due to an AE. There were two fatal SAEs in the vaccine group and four fatal SAEs in the control group, none of which were related to the vaccine. In addition, there was no evidence of vaccine-associated enhanced disease (VAED) at the time of data cut-off. Incidents of VAED will continue to be assessed as additional data become available.

Overall, there were no important safety issues identified and no life-threatening AEs or deaths related to the AstraZeneca COVID‑19 Vaccine.

While results suggested lower rates of solicited ARs and unsolicited AEs up to 28 days post dose for individuals ≥65 years of age, the sample size was small. No difference was noted in rates of SAEs based on age. The safety and efficacy of the AstraZeneca COVID‑19 Vaccine in individuals under 18 years of age have not been established and no data are available.

The safety and efficacy of the AstraZeneca COVID‑19 Vaccine in pregnant and breastfeeding women have not been established. Women who were pregnant or breastfeeding were excluded from the clinical studies. Pregnancy was reported for 21 participants; 12 in the AstraZeneca COVID‑19 Vaccine group and 9 in the control group. Of these pregnancies, 5 ended in spontaneous abortion; 2 in the AstraZeneca COVID‑19 Vaccine group and 3 in the control group. Due to limited duration of follow-up at the time of interim analysis, the outcome of the remaining pregnancies will continue to be followed. A definitive reproductive and developmental toxicity study in animals has not yet been completed but is ongoing, and therefore, the potential toxicity of the AstraZeneca COVID‑19 Vaccine to maternal animals during gestation, potential effects on pregnancy, and potential toxicity to the developing embryo/fetus are unknown. It is unknown if the AstraZeneca COVID‑19 Vaccine is excreted in human milk and data are not available to assess the effects of the vaccine on the breastfed infant or on milk production/excretion. Use in pregnant and breastfeeding women is included in the Risk Management Plan (RMP) as missing information.

No data are currently available in immunocompromised individuals. This will be followed up in the RMP.

In conclusion, there were no important safety issues identified and no life-threatening AEs or deaths related to the AstraZeneca COVID‑19 Vaccine. The AEs observed showed that two doses (5 x 1010 virus particles/dose) of the AstraZeneca COVID‑19 Vaccine, administered 4 to 12 weeks apart, was safe and well tolerated in participants.

Risk Management Plan

A Core (European Union [EU]) Risk Management Plan (RMP) in conjunction with the Canadian Specific Addendum for the AstraZeneca COVID‑19 Vaccine was submitted by AstraZeneca Canada 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 AstraZeneca Canada 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 benefits, harms or uncertainties of the drug. Updates to the RMP will be reflected in the Post-Authorization Activity Table for the AstraZeneca COVID‑19 Vaccine.

Based on results from non-clinical and clinical studies, the RMP included no important identified risks, two potential risks ("immune-mediated neurological conditions", "vaccine-associated enhanced disease"), and four areas of missing information ("use in pregnant and breastfeeding women", "use in subjects with severe immunodeficiency", "use in subjects with severe and/or uncontrolled underlying disease", and "use with other vaccines").

Based on Health Canada's review of the RMP, it was determined that "anaphylaxis", "nervous system disorders including immune mediated neurological conditions" (instead of "immune-mediated neurological conditions"), and "vaccine-associated enhanced disease including vaccine-associated enhanced respiratory disease" (instead of "vaccine-associated enhanced disease") should be included as important potential risks. For missing information, AstraZeneca Canada Inc. was also requested to add "use in the pediatric population <18 years of age", "use in immunocompromised patients and patients with chronic or debilitating conditions" (instead of "use in subjects with severe immunodeficiency"), "interaction with other vaccines" (instead of "use with other vaccines"), "long-term effectiveness", and "long-term safety". These safety concerns were added in the Canadian Addendum to the EU RMP.

In addition, Health Canada noted that there was limited recruitment of persons ≥65 years of age and a lack of information regarding special populations (including Canadian indigenous populations, patients with chronic illness, immunocompromised individuals, and frail elderly) in the clinical data submitted by AstraZeneca Canada Inc. Further, the optimal dosing interval is not well established at this time and data regarding protection against emerging variants (e.g., United Kingdom, Brazil and South Africa) and interaction with other vaccines and drugs is limited or not available.

The identified limitations and areas of missing information are managed through labelling and the RMP, and will continue to be investigated through ongoing and planned studies. The COV001, COV002, COV003, and COV005 studies are ongoing and will continue to collect information on the long-term safety, efficacy, and immunogenicity of the vaccine. An additional Phase III study is underway in the United States, Peru, and Chile with interim analysis expected to be available in spring 2021. Further, four post-authorization studies are planned: a Phase IV Enhanced Active Surveillance Study of People Vaccinated with the AstraZeneca COVID‑19 Vaccine; a Pregnancy Registry; a Post-marketing Safety Study; and a Post-marketing Effectiveness Study. Results related to safety and efficacy from ongoing and planned studies will be submitted as they become available. The proposed routine and additional pharmacovigilance activities, as described in the RMP, for the above safety concerns are considered to be acceptable and will be applied in the Canadian context. Routine risk minimization measures (i.e., product monograph and labelling) are also considered to be appropriate.

As outlined in the terms and conditions that were put in place at the time of authorization, a revised Canadian addendum to the RMP is expected to be submitted to Health Canada within 2 weeks following authorization. In addition, 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. Further to regulatory requirements for post-market monitoring and prioritized reporting of adverse events following immunization, monthly safety summary reports will be provided to Health Canada and will include information related to special populations (e.g., pregnant women).

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

  • Older adults: The sponsor will submit monthly safety reports to Health Canada, which will include analyses of sub-populations by age and gender.
  • 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. Studies of the AstraZeneca COVID-19 Vaccine in the pediatric population are 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 through a pregnancy 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 through a pregnancy 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 will provide 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 AstraZeneca 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 over when administered according to the recommended dosage regimen. The clinical studies are ongoing and will continue to collect information on the long-term safety of the vaccine.

For more information, refer to the AstraZeneca 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 AstraZeneca COVID‑19 Vaccine (ChAdOx1-S [recombinant]) under the Interim Order Respecting the Importation, Sale, and Advertising of Drugs for Use in Relation to COVID-19 included pharmacology, biodistribution, and repeat-dose toxicity studies.

Studies showed that ChAdOx1-S (recombinant) was immunogenic in mice, ferrets, non‑human primates, and pigs. In the porcine model, booster immunization enhanced antibody responses, with significant increases in severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) neutralizing antibody titres. A single administration of ChAdOx1‑S (recombinant) reduced viral load in bronchoalveolar lavage fluid and respiratory tract tissue of vaccinated animals, relative to vector controls. In a study in rhesus macaques, aimed at determining the efficacy of ChAdOx1‑S (recombinant), post‑vaccination SARS‑CoV‑2 challenge was conducted to evaluate protection and the potential for vaccine-associated enhanced respiratory disease (VAERD). No evidence of vaccine‑enhanced disease was observed in the vaccinated animals.

The effect of the D614G mutation on the efficacy of virus neutralization following vaccination was evaluated in ferrets. Variants of SARS‑CoV‑2 carrying the D614G mutation in the spike (S) protein are increasing in prevalence among sequenced viruses worldwide. Three isolates were used for virus neutralisation assays: SA01, which has identical amino acid sequence in S to Wuhan‑Hu‑1; VIC01, in which S differs from SA01 by a Ser247Arg mutation; and VIC31, in which S differs from SA01 by the Asp614Gly mutation. Overall, there were no significant effects of the D614G mutation on the relative neutralization of D614 and G614 variants in serum samples collected from ferrets that had received prime‑boost vaccinations. As such, challenge studies in animals may be relevant to determine the immunogenicity of the vaccine against new circulating strains of SARS-CoV-2.

Non‑clinical safety pharmacology, biodistribution, and toxicology studies were submitted and considered adequate for the purposes of this submission. The safety pharmacology study was conducted in male mice and demonstrated no adverse effects on select cardiovascular (arterial blood pressure and heart rate) and respiratory parameters following a single intramuscular dose of 2.59 × 1010 viral particles of ChAdOx1‑S (recombinant). Additionally, a neurobehavioural assessment performed as part of the pivotal repeat‑dose toxicity study indicated no adverse effects on central nervous system function in both male and female mice.

One biodistribution study evaluated the potential biodistribution of ChAdOx1-S (recombinant) in mice using a surrogate ChAdOx1-based vaccine. Two doses of the surrogate vaccine (2.4 × 1010 viral particles each) were administered to animals four weeks apart. The presence of vector deoxyribonucleic acid (DNA) was observed mainly at the site of injection, but also in systemic tissues (brain, heart, draining inguinal lymph nodes, kidneys, liver, lungs, testes, ovaries, and spleen) following the first dose. Four weeks after the second dose, viral vector DNA remained present at the site of injection, lymph nodes, brain, heart, liver, testes, and ovaries in a few animals. The presence of viral vector DNA was not observed in the spleen, kidneys, or lungs of any animal, suggesting elimination from these tissues by this time point. Overall, the biodistribution data demonstrated a general trend towards clearance from systemic tissues over time.

In the pivotal toxicology study, three once-weekly doses of 3.7 × 1010 viral particles each (equivalent to a dose approximately 1,000‑fold greater than the human dose on a per kilogram body weight basis) were administered to mice by intramuscular injection. Vaccine administration was associated with transiently increased body temperature, increased spleen weights, and decreased monocyte counts. Clinical chemistry changes (i.e., increased globulin levels coupled with decreased albumin levels and albumin/globulin ratios) indicated an acute phase response. An increased incidence of histopathological inflammation was observed at the site of injection, which extended into the fascia and connective tissue below the skeletal muscle. Collectively, these changes are consistent with an expected immunostimulatory response and known acute phase response following intramuscular administration of a vaccine. Full recovery from all findings was observed following a 28‑day recovery period.

Genotoxicity and carcinogenicity studies were not conducted for ChAdOx1‑S (recombinant), as such studies are not considered relevant to vaccines of this nature.

A definitive reproductive and developmental toxicity study has not been submitted to date, but is ongoing. Therefore, the potential toxicity of ChAdOx1‑S (recombinant) to maternal animals during gestation, potential effects on pregnancy, and potential toxicity to the developing embryo/fetus are unknown.

Based on mechanism of action and on the available background evidence within the scientific literature, the potential for integration into the host genome and the potential for germline integration are considered to be low.

The non‑clinical pharmacology and toxicology profile of ChAdOx1‑S (recombinant) 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 AstraZeneca COVID‑19 Vaccine Product Monograph. Considering the intended use of the AstraZeneca 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 AstraZeneca 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 AstraZeneca COVID‑19 Vaccine (ChAdOx1‑S [recombinant]) 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 regulatory authorities in other countries for vaccines in the context of a global pandemic. The interim authorization of the AstraZeneca 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 AstraZeneca COVID‑19 Vaccine (ChAdOx1‑S [recombinant]) is a prophylactic vaccine developed to prevent coronavirus disease 2019 (COVID‑19) caused by infection with the severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2). Replication‑deficient adenoviral particles serve as vectors for the delivery of recombinant double‑stranded deoxyribonucleic acid (DNA) into the host's cells, which enables the 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 drug substance, ChAdOx1‑S (recombinant), consists of a double‑stranded DNA genome enclosed within a replication‑deficient chimpanzee adenoviral vector. The genome encodes the unmodified SARS‑CoV‑2 spike protein, which is fused to a tissue plasminogen activator (tPA) leader sequence. The expression cassette also includes a modified human cytomegalovirus promoter and a bovine growth hormone polyadenylation sequence. The adenoviral vector is replication‑incompetent in human cells due to deletion of the E1 domains. Production of the drug substance therefore requires propagation in E1‑complementing human cell lines such as T‑Rex‑293 cells.

Detailed characterization studies were performed to provide assurance that the drug substance consistently exhibits the desired characteristic structure and biological activity. The structural properties of the drug substance have been analyzed using multiple orthogonal methods. Physicochemical and biological properties including biological activity, identity, morphology, size heterogeneity, particulate matter, and impurities were also characterized using techniques and methodologies suitable for their intended purposes.

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

The pharmaceutical development of the AstraZeneca COVID‑19 Vaccine (ChAdOx1‑S [recombinant]) 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 adenovirus vectors. The product development is further guided by risk assessment studies and development studies.

The drug substance, ChAdOx1‑S (recombinant), is manufactured using recombinant DNA technology in T‑Rex‑293 cells that have been genetically modified to allow for the amplification of the drug substance. A cell culture is initiated from a single vial from a working cell bank, transferred to progressively larger vessels as it expands, and ultimately pooled into a commercial scale bioreactor. Following cell expansion, the cell culture is supplemented with nutrients and the adenovirus working virus seed is added. The drug substance is then allowed to amplify and assemble in the production cells.

At defined times, the contents of the bioreactor are harvested and the cells are lysed, which releases the drug substance. The lysate is treated with nuclease to reduce host cell nucleic acid, and is purified through filtration and chromatography steps. The purified virus is concentrated, filtered, and formulated, and is stored frozen.

Manufacturing of the drug product, the AstraZeneca COVID‑19 Vaccine, involves thawing, mixing, and pooling the frozen drug substance, followed by dilution with formulation buffer and filtration to achieve the target concentration. The drug product is filled into sterile glass vials, which are then closed with sterile stoppers and sealed with aluminium caps. The vials are visually inspected, packaged, and labelled.

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 sponsor has submitted a generalized control strategy, as well as process validation data for the drug substance and drug product manufacturing sites relevant to the Canadian supply chain. The available data met the relevant acceptance criteria and reflected consistency in the manufacturing processes. Differences in the manufacturing process at certain sites are supported by additional oversight as well as process validation and comparability studies. As part of the terms and conditions, the sponsor is expected to specify the site‑specific steps for any additional manufacturing sites.

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 6 months when stored at the recommended long‑term storage condition of ‑90 °C to ‑55 °C. This is primarily based on stability data for small-scale batches used to support clinical studies, 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).

Based on the stability data provided for the drug product, an unopened multidose vial should be stored at 2 °C to 8 °C, must not be frozen, and must be stored in its outer carton to protect from light. From the time of vial puncture (first opening), chemical and physical in‑use stability has been demonstrated for no more than 6 hours at room temperature up to 30 °C, or 48 hours at 2 °C to 8 °C. An opened vial can be re‑refrigerated, but the cumulative storage time at room temperature must not exceed 6 hours, and the total cumulative storage time must not exceed 48 hours.

The stability profiles were based on the evaluation and monitoring of all the stability‑indicating attributes under real‑time and accelerated conditions. The analytical procedures used in the stability studies 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. Besides the production cell line, no materials of human origin were used for the production of this vaccine. Residual host cell protein is measured and controlled at levels deemed to be safe. Some animal‑derived materials were used to prepare cell banks. Benzonase (derived from milk) is used in routine manufacture and originates from sources with no or minimal risk of transmissible spongiform encephalopathy (TSE) or other human pathogens.