Summary Basis of Decision for Covifenz

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

Recent Activity for Covifenz

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 Covifenz

Updated:

2023-05-26

The following table describes post-authorization activity for Covifenz, a product which contains the medicinal ingredient virus-like particles (VLPs) of SARS-CoV-2 spike protein. 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 02521326 - 3.75 mcg/0.5 mL virus-like particles (VLPs) of SARS-COV-2 spike protein, emulsion, intramuscular administration

Post-Authorization Activity Table (PAAT)

Activity/submission type, control number Date submitted Decision and date Summary of activities
DIN 02521326 cancelled (pre market) Not applicable Discontinuation date: 2023-03-31 The manufacturer notified Health Canada that sale of the drug has been discontinued pre market. Health Canada cancelled the DIN(s) pursuant to section C.01.014.6(1)(a) of the Food and Drug Regulations.
SNDS # 267448 2022-08-30 Issued NOC 2023-03-30 Submission filed as a Level I – Supplement to expand the indication to include use in the elderly ≥65 years of age. The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published.
NC # 270218 2022-11-30 Issued NOL
2023-02-06

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

Monthly safety report
Control # 264095
2022-05-09 Review completed
2022-05-31

Submission filed in response to commitments made as per the terms and conditions imposed on the authorization issued under the Food and Drug Regulations. Monthly safety report #2 for the period 2022-03-27 to 2022-04-26. No post-market data is available as the vaccine has not yet been marketed or distributed. The sponsor was asked to pause the submission of the monthly safety report until the vaccine is marketed or distributed.

Monthly safety report
Control # 263180
2022-04-07 Review completed
2022-05-04

Submission filed in response to commitments made as per the terms and conditions imposed on the authorization issued under the Food and Drug Regulations. Monthly safety report #1 for the period 2022-02-24 to 2022-03-26. No safety information was presented in the report as the vaccine has not yet been marketed or distributed. The current safety data are consistent with the labelled safety profile of Covifenz.

NDS # 254598 2021-08-09 Issued NOC (subject to terms and conditions)
2022-02-24

NOC issued for New Drug Submission. Terms and conditions were imposed on the authorization.

Application # 251784 2021-04-19 Closed
2021-09-16

Application closed with expiry of Interim Order Respecting the Importation, Sale and Advertising of Drugs for Use in Relation to COVID-19.

Summary Basis of Decision (SBD) for Covifenz

Date SBD issued: 2022-04-11

The following information relates to the new drug submission for Covifenz.

Virus-like particles (VLPs) of SARS-CoV-2 spike protein

Drug Identification Number (DIN):

  • DIN 02521326 - 3.75 mcg/0.5 mL virus-like particles (VLPs) of SARS-COV-2 spike protein, emulsion, intramuscular administration

Medicago Inc.

New Drug Submission Control Number: 254598

 

On February 24, 2022, Health Canada issued a Notice of Compliance (NOC), subject to terms and conditions, to Medicago Inc. for the vaccine Covifenz.

The Food and Drug Regulations were amended on March 18, 2021 to incorporate flexibilities into the existing new drug submission (NDS) regulatory pathway, thereby facilitating the regulatory process for authorization of new drugs that treat or prevent coronavirus disease 2019 (COVID‑19). The modified requirements allow an NDS for a designated COVID‑19 drug to be filed through a rolling submission process, i.e., as the information becomes available. Sponsors are responsible for completing the required documentation and providing the necessary evidence to Health Canada. Health Canada will issue an NOC for a COVID‑19 drug if it is determined that the benefits and risks of the product are supported by evidence of the safety, efficacy, and consistent quality of the drug.

The market authorization was based on quality (chemistry and manufacturing), non‑clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada’s review, the benefit-risk profile of Covifenz is favourable for active immunization to prevent COVID‑19 caused by the severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) in individuals 18 to 64 years of age.

Covifenz is authorized in accordance with the Food and Drug Regulations, subject to terms and conditions that need to be met by the sponsor. Terms and conditions may be imposed or amended at any time. Additionally, failure to comply with the terms and conditions may result in compliance and enforcement actions being taken by Health Canada.

For further information on the amended regulatory pathway, refer to the Guidance on Amendments to the Food and Drug Regulations for Drugs for Use in Relation to COVID‑19.

1 What was approved?

Covifenz, an active immunizing agent, was authorized for active immunization to prevent coronavirus disease 2019 (COVID‑19) caused by severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) in individuals 18 to 64 years of age.

Covifenz is not authorized for use in pediatric patients (younger than 18 years of age), as its safety and efficacy have not been established in this population.

The safety and efficacy of Covifenz in individuals 65 years of age and older have not been established.

The antigen component of Covifenz (3.75 mcg/0.5 mL virus‑like particles [VLPs] of SARS‑CoV‑2 spike protein) is presented as a suspension. In addition to the medicinal ingredient, the suspension contains polysorbate 80, potassium phosphate monobasic anhydrous, sodium chloride, sodium phosphate dibasic anhydrous, and water for injection. Covifenz may contain trace amounts of polyethylene glycol, kanamycin, and carbenicillin. The adjuvant system 03 (AS03) emulsion component contains the naturally occurring molecules (DL‑alpha‑tocopherol and squalene), an emulsifier (polysorbate 80), and phosphate buffered saline. Prior to administration, the antigen component of Covifenz must be mixed with the AS03 emulsion component. The purpose of the addition of the AS03 adjuvant is to increase the immune response.

The use of Covifenz is contraindicated in individuals who are hypersensitive to the active substance or to any ingredient in the formulation, including any non‑medicinal ingredient, or component of the container.

Covifenz was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with its administration. The Covifenz Product Monograph is available through the Drug Product Database and on the Health Canada COVID‑19 vaccines and treatments portal.

For more information about the rationale for Health Canada's decision, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

2 Why was Covifenz approved?

Health Canada considers that the benefit‑risk profile of Covifenz is favourable for active immunization to prevent coronavirus disease 2019 (COVID‑19) caused by severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) in individuals 18 to 64 years of age. Covifenz is authorized in accordance with the Food and Drug Regulations, subject to terms and conditions that need to be met by the sponsor.

Coronavirus disease 2019 is the infectious disease caused by the novel coronavirus, SARS‑CoV‑2, which has spread rapidly and globally since its emergence in late 2019. On March 11, 2020, the World Health Organization declared COVID 19 a pandemic. In Canada, there have been 3,270,245 confirmed cases of COVID‑19 and approximately 36,377 deaths as of February 24, 2022, the date of authorization of Covifenz.

Severe acute respiratory syndrome coronavirus 2 is a highly transmissible and pathogenic coronavirus. The majority of SARS‑CoV‑2‑infected patients experience mild respiratory disease. However, following infection, some patients develop severe disease that requires oxygen support or critical disease with complications such as respiratory failure, sepsis and septic shock, thromboembolism, and/or multiorgan failure, including acute kidney injury and cardiac injury. Medical conditions or other factors that place patients at high risk for progression to severe COVID‑19 include older age, obesity, current smoker, chronic kidney disease, diabetes, immunosuppressive disease or immunosuppressive treatment, cardiovascular disease, chronic lung disease, sickle cell disease, neurodevelopmental disorders, active cancer, and medically related technological dependence. Other medical conditions or factors (e.g., race or ethnicity) may also place individual patients at high risk for progression to severe COVID‑19.

Health Canada has previously authorized the following vaccines for protection against COVID-19: Comirnaty (previously Pfizer‑BioNTech COVID‑19 Vaccine), Spikevax (previously COVID‑19 Vaccine Moderna), Vaxzevria (previously AstraZeneca COVID‑19 Vaccine), Covishield, Janssen COVID‑19 Vaccine, and Nuvaxovid for protection against COVID‑19.

Two of the currently authorized vaccine types are messenger ribonucleic acid (mRNA) vaccines (Comirnaty and Spikevax), two are viral vector‑based vaccines (Vaxzevria and Janssen COVID‑19 Vaccine), and one is a protein subunit vaccine (Nuvaxovid). Covishield was authorized under the Interim Order Respecting the Importation, Sale and Advertising of Drugs for Use in Relation to COVID‑19 which has since expired. While care for individuals who have COVID‑19 has improved with clinical experience, having multiple vaccine options is desirable as some patients may have contraindications to the currently approved vaccines.

Covifenz is a vaccine developed for active immunization against COVID‑19, which contains purified spike proteins of SARS‑CoV‑2 expressed in virus‑like particles (VLPs) produced by plant‑based technology. The enveloped VLPs present spike protein trimers on their surface, which have been stabilized in the prefusion conformation.

Evidence of the clinical efficacy of Covifenz is based primarily on the available data from Study 021, a Phase II/III study in participants 18 years of age and older. The immunogenicity of Covifenz was evaluated in Phase II of Study 021. The results from Phase II indicate that Covifenz induced a type 1 cell‑mediated immune response after the first vaccination, which increased three weeks after the second vaccination. A similar type 2 cell‑mediated immune response was observed after the second vaccination, demonstrating that Covifenz induced a balanced cell‑mediated immune response.

Phase III of Study 021 was ongoing at the time of authorization, and was designed to evaluate the efficacy, immunogenicity, and safety of Covifenz relative to placebo in participants 18 years of age and older. Participants with pre‑existing stable chronic disease (defined as no new onset or exacerbation of pre‑existing chronic disease three months prior to vaccination) were included in the study. Individuals who had a previous laboratory‑confirmed diagnosis of COVID‑19 were excluded from the study. Participants were randomized in a 1:1 ratio to receive either Covifenz or placebo as two doses 21 days apart. Demographic and baseline characteristics were balanced between the two treatment groups. The date of the first participant visit and data collection was March 15, 2021.

As of the efficacy data cut‑off date of August 20, 2021, 24,141 participants had been randomized to receive either Covifenz (12,074 participants) or placebo (12,067 participants). The per‑protocol population consisted of 20,090 participants, of whom 50.1% were females and 49.9% were males aged 18 to 64 years old. The median follow‑up time after the second dose was 3.1 months (range: 0 to 6.8 months) for participants who received Covifenz and 2.5 months (range: 0 to 6.8 months) for participants who received the placebo. Participants will continue follow up for 12 months after the second dose to evaluate the safety and durability of the immune response.

Study 021, Phase III

Participants in the final efficacy analysis

 

Vaccine group

Placebo group

Total

Total number of participants (18 years of age and older)

12,074

12,067

24,141

Male

6,107

6,186

12,293

Female

5,966

5,880

11,846

Missing information

1

1

2

Total number of participants 18 years of age and older in the per‑protocol set

10,554

9,536

20,090

Male

5,268

4,792

10,060

Female

5,286

4,744

10,030

Participants 18 to 64 years of age in the per‑protocol set

10,467

9,435

19,902

Participants 65 years of age and older in the per‑protocol set

87

101

188

Participants in the safety analysis

 

Vaccine group

Placebo group

Total

Total number of participants (18 years of age and older)

12,036

12,040

24,076

Male

6,085

6,169

12,254

Female

5,951

5,871

11,822

Participants 18 to 64 years of age

11,933

11,924

23,857

Participants 65 years of age and older

103

116

219

The primary efficacy endpoint was the first occurrence of laboratory‑confirmed symptomatic SARS‑CoV‑2 infection (with onset 7 days or longer after the second vaccination). In the per‑protocol population, 157 participants had a laboratory‑confirmed SARS‑CoV‑2 infection detected 7 days or longer after the second dose. Thirty‑nine cases were confirmed in participants who received Covifenz, and 118 cases were confirmed in participants who received the placebo. Based on these data, the success criteria for vaccine efficacy have been met, as the estimate for vaccine efficacy was 71.0% (95% confidence interval [CI]: 58.7, 80.0).

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%

Vaccine efficacy rates observed in Study 021 (per‑protocol set, data cut‑off date of August 20, 2021)

 

Vaccine efficacy rate

Two‑sided 95% CI

Participants 18 years of age and older

71.0%

58.7% to 80.0%

In the per‑protocol population, a first occurrence of severe COVID‑19 with onset 7 days or later after the second vaccination was detected in two participants, both in the placebo group.

As of December 3, 2021, SARS‑CoV‑2 genome sequencing was completed for 114 of the 157 cases (72.6 %). The cases in the vaccine group were caused by the Delta (number of participants [n] = 11) and Gamma (n = 6) strains. The cases in the placebo group were caused by the Alpha (n = 5), Delta (n = 39), Gamma (n = 46), Lambda (n = 3), and Mu (n = 4) strains. None of the cases were caused by the original strain. The two severe COVID‑19 cases observed in the placebo group were caused by the Gamma or Mu strain.

The clinical safety of Covifenz was mainly evaluated using data from the Phase III portion of Study 021. As of the safety data cut‑off date of October 25, 2021, the safety analysis set included 24,076 participants who had received at least one dose of either Covifenz (12,036 participants) or the placebo (12,040 participants). A second dose had been administered to 22,087 (91.7%) participants.

Solicited local and systemic adverse reactions were reported more frequently in participants who received Covifenz than in those who received the placebo. In adults 18 to 64 years of age, the most frequently reported solicited local and systemic adverse reactions after receiving the first and/or second dose of Covifenz were pain at the injection site (92.5%), headache (68.5%), muscle aches (67.8%), fatigue (64.7%), feeling of general discomfort (63.8%), chills (46.7%), joint aches (40.0%), swelling at the injection site (38.0%), swelling in the neck (22.2%), erythema at the injection site (20.1%), swelling in the axilla (15.1%) and fever (9.7%). The adverse reactions were usually mild or moderate in intensity and resolved within 1 to 3 days. Solicited local and systemic adverse reactions of Grade 2 or higher intensity were more frequently reported after the second dose than after the first dose. Less than 1.6% of solicited adverse reactions were of Grade 3 or higher intensity.

In the safety analysis set of participants 18 to 64 years of age, 11,933 participants received Covifenz and 11,924 participants received the placebo. There were no notable patterns or significant numerical imbalances between treatment groups with respect to unsolicited adverse events, medically attended adverse events, or adverse events leading to study withdrawal that would suggest a causal relationship to Covifenz. No deaths or serious adverse events related to Covifenz were reported.

Potential immune‑mediated diseases (pIMDs) were reported in 21 participants (<0.1%) who received Covifenz and 10 participants who received the placebo (<0.1%). The pIMDs reported only in participants who received Covifenz included pharyngeal swelling (5 cases), psoriasis (3 cases), arrhythmia (1 case), and deep vein thrombosis (1 case). Bell’s palsy/facial paralysis was reported in three participants who received Covifenz and one participant who received the placebo. One case of myocarditis was reported in each treatment group. The case of myocarditis in the Covifenz treatment group was in a participant who tested positive for COVID‑19. No cases of anaphylaxis were reported. The information available at the time of authorization was not sufficient to determine whether a causal relationship exists between pIMDs and the Covifenz vaccine.

The efficacy and safety data available in participants 65 years of age and older are limited, and are not sufficient to support an indication for individuals in this age group.

A Core Risk Management Plan (RMP) and a Canadian Addendum for Covifenz were submitted by Medicago Inc. to Health Canada. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product. The RMP for Covifenz includes information about the important potential risks of anaphylaxis and severe allergic reactions, vaccine‑associated enhanced disease (VAED), including vaccine‑associated enhanced respiratory disease (VAERD) and pIMDs. The RMP also identified seven areas of missing (limited/no clinical data) information: “use in pregnant and breastfeeding women”, “use in pediatric population”, “use in immunocompromised subjects”, “use in subjects with autoimmune or inflammatory disorders”, “use in frail subjects with unstable health conditions and comorbidities”, “interaction with other vaccines”, and “long‑term safety”. Upon review, Health Canada recommended the inclusion of “long‑term effectiveness” as missing (limited/no clinical data) information.

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 known 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 Phase III study is ongoing and will continue to collect information on the long-term safety and efficacy of Covifenz. In addition, there are post‑authorization commitments for monitoring the long‑term safety and effectiveness of Covifenz. As outlined in the terms and conditions, the RMP will be updated to reflect additional safety information, including that which is relevant to the Canadian‑specific context, as it becomes available. In addition to meeting the 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). Results related to safety and effectiveness from ongoing and planned studies will be submitted as they become available. For more information, refer to the terms and conditions available on the Health Canada COVID‑19 vaccines and treatments portal.

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

The sponsor submitted a brand name assessment that included testing for look‑alike sound‑alike attributes. Upon review, the proposed name Covifenz was accepted.

Covifenz has been shown to have a favourable benefit‑risk profile and an acceptable safety profile based on non‑clinical and clinical studies. Collectively, the results of the clinical efficacy and safety evaluation demonstrated that Covifenz met the 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 to 64 years of age when administered according to the recommended dosage regimen. Notably, the Phase III portion of Study 021 is ongoing and will collect additional information on the long‑term safety and efficacy of the vaccine over a period of 12 months. These data will be submitted to Health Canada when available.

At the time of authorization, important limitations of the data included the lack of information on the long‑term safety and efficacy of the vaccine, the duration of protection, protection against current and emerging variants, and the lack of or limited data for special populations. These limitations are considered adequately managed through labelling, terms and conditions associated with the authorization of Covifenz, the RMP, and adequate monitoring. Appropriate warnings and precautions are in place in the Covifenz Product Monograph to address the identified risks.

This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has issued a Notice of Compliance (NOC) pursuant to section C.08.004 of the Food and Drug Regulations. The NOC in respect of Covifenz is accompanied by terms and conditions imposed in accordance with section C.01.014.21 of the Food and Drug Regulations. Of note, terms and conditions may be imposed or amended at any time. All terms and conditions are enforceable under section 21.7 of the Food and Drugs Act. Failure to comply with the terms and conditions may result in compliance and enforcement actions being taken by Health Canada.

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 Covifenz?

The application for authorization of Covifenz was filed on April 19, 2021, 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 was to expedite the authorization of COVID‑19 drugs; it was signed by the Minister of Health on September 16, 2020 and was in place for one year. The Interim Order allowed the Minister to account for the urgent public health needs relating to COVID‑19 in deciding whether to authorize a COVID‑19 drug based on the provided evidence of safety, efficacy, and quality. Before the Interim Order expired, Medicago Inc. filed a New Drug Submission (NDS) for Covifenz on August 9, 2021.

The Food and Drug Regulations were amended on March 18, 2021 to incorporate flexibilities into the existing new drug submission (NDS) regulatory pathway, thereby facilitating the regulatory process for authorization of new drugs that treat or prevent coronavirus disease 2019 (COVID‑19). For example, to expedite the review process, the modified requirements allow an NDS for a designated COVID‑19 drug to be filed through a rolling submission process, i.e., as the information becomes available. This in turn allows Health Canada to commence a rolling review process of the information submitted. As outlined in the Guidance on amendments to the Food and Drug Regulations for drugs for use in relation to COVID‑19, Health Canada will begin its review using the information submitted by the sponsor and accept new evidence as it becomes available until the submission is deemed complete. The rolling process can reduce the time it takes to authorize these critical new drugs while maintaining appropriate standards of safety, efficacy, and quality. Sponsors are responsible for completing the required documentation and providing the necessary evidence to Health Canada. Health Canada will issue a Notice of Compliance (NOC) for a COVID‑19 drug if it is determined that the benefits and risks of the product are supported by evidence of the safety, efficacy, and consistent quality of the drug. Importantly, the amended regulations also allow the use of terms and conditions in order to ensure appropriate oversight, manage uncertainties or mitigate risks related to the drug in the context of the public health need due to COVID‑19.

The information for this NDS was provided on a rolling basis. Following an expedited review of the data submitted, Health Canada determined that sufficient evidence was provided to support the conclusion that the benefits of Covifenz outweigh the risks under the conditions of use recommended, with consideration given to the uncertainties relating to those benefits and risks as well as the public health need related to COVID‑19. Health Canada issued an NOC for Covifenz, with imposed terms and conditions, on February 24, 2022.

For further information on the amended NDS regulatory pathway, refer to the Guidance on Amendments to the Food and Drug Regulations for Drugs for Use in Relation to COVID‑19.

 

Submission Milestones: Covifenz

Submission Milestone Date
Application Milestone: Control # 251784  
Pre-application meeting 2021-04-08
Initial application filed by sponsor under the Interim Order 2021-04-19
Initial quality data submitted by sponsor 2021-04-19
Initial non-clinical data submitted by sponsor 2021-04-19
Initial clinical data submitted by sponsor 2021-04-19
Application closed with expiry of Interim Order 2021-09-16
Submission Milestone: Control # 254598  
Initial New Drug Submission filed by sponsor 2021-08-09
Screening Acceptance Letter issued 2021-09-23
Health Canada non-clinical evaluation completed 2021-11-21
Risk Management Plan submitted by sponsor 2021-12-15
Health Canada Risk Management Plan evaluation completed 2022-01-31
Health Canada quality evaluation completed 2022-02-17
Final Product Monograph (English) submitted by sponsor 2022-02-22
Final Product Monograph (French) submitted by sponsor 2022-02-22
Health Canada clinical/medical evaluation completed 2022-02-23
Health Canada labelling evaluation completed 2022-02-23
Terms and conditions finalized by Health Canada 2022-02-23
Notice of Compliance issued by Director General, Biologic and Radiopharmaceutical Drugs Directorate 2022-02-24
4 What follow-up measures will the company take?

The Notice of Compliance issued in respect of Covifenz is accompanied by terms and conditions imposed on the drug identification number assigned to Covifenz in accordance with section C.01.014.21 of the Food and Drug Regulations. Of note, terms and conditions may be imposed or amended at any time. Failure to comply with the terms and conditions may result in compliance and enforcement actions being taken by Health Canada.

These terms and conditions set out requirements relating to clinical, non‑clinical, quality (chemistry and manufacturing), labelling, and pharmacovigilance information. They were put in place to ensure appropriate oversight, manage uncertainties or mitigate risks, and ascertain the continued quality, safety, and efficacy of the product.

The terms and conditions include (but are not limited to) the requirements listed below.

With respect to information on clinical studies, the sponsor is required to submit the following when the data become available:

  • Safety and immunogenicity results for the period of 6 and 12 months after the second dose from Study 021.
  • Data regarding immunogenicity/efficacy against current and emerging variants of concern.
  • Results from the three planned post‑authorization safety studies (PASS), including two PASS studies that aim to assess the effectiveness and safety of Covifenz using electronic health record databases (in Canada, the United Kingdom, the United States, the European Union, and other countries as needed) and one coronavirus disease 2019 (COVID‑19) Vaccine Pregnancy Registry.
  • As a sensitivity analysis, the results of vaccine efficacy including all cases of COVID‑19 occurring before receiving another COVID‑19 vaccine in Study 021.

Additionally, the sponsor is required to:

  • Update the Product Monograph with information on the pregnancy registry.
  • Submit the appropriate reports addressing adverse reactions associated with Covifenz.
  • Submit Monthly Safety Summary Reports for the first 6 months of marketing of Covifenz in Canada.
  • Submit Periodic Safety Update Reports or Periodic Benefit‑Risk Evaluation Reports every 6 months.
  • Submit an updated Core Risk Management Plan with the Canadian Addendum in a timely manner if a safety issue is identified that requires immediate regulatory action, or as requested by Health Canada.
  • Submit final snapshots of all components of the electronic platform, containing Canadian‑specific labelling information for Covifenz in French and English for Health Canada's review and records, prior to launch of the electronic platform.
  • Submit the final reports of the ongoing quality (chemistry and manufacturing) studies.
  • Submit updates on stability studies.
  • Submit investigation reports of the visual inspection issues identified during the review.
  • Provide notification of changes in the Good Manufacturing Practices status for any of the facilities included in the authorization as well as any new facilities relevant to the Canadian supply chain.
  • Submit a summary of batch disposition on a quarterly basis, including all drug substance and drug product lots produced, failed, or aborted, and a brief description of the issue(s) relevant to the disposition determination.
6 What other information is available about drugs?

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

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

The New Drug Submission for Covifenz (virus‑like particles [VLPs] of severe acute respiratory syndrome coronavirus 2 [SARS‑CoV‑2] spike protein) was submitted and reviewed in accordance with the Food and Drug Regulations, which permitted a rolling submission and review process. Following review of the provided information, a Notice of Compliance was issued in relation to Covifenz, with accompanying terms and conditions to manage any uncertainties or mitigate risks related to the product.

Clinical Pharmacology

Covifenz is an adjuvanted vaccine composed of plant‑based VLPs that closely mimic native SARS‑CoV‑2 and activate local innate immune responses. The vaccine then elicits both neutralizing antibody and cellular immune responses to the spike antigen, which may contribute to protection against coronavirus disease 2019 (COVID‑19).

Pharmacokinetic studies to demonstrate absorption, distribution, metabolism, and excretion of coronavirus‑like particles (CoVLPs) were not conducted and are typically not required for vaccines.

The pharmacodynamics of CoVLPs in Studies 019 and 021 (both ongoing, described in the Clinical Efficacy section) is being assessed through evaluations of both humoral and cell‑mediated immunity induced in CoVLP‑immunized subjects.

For further details, please refer to the Covifenz 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

The clinical efficacy of Covifenz was evaluated in Study 021, a randomized, placebo‑controlled Phase II/III study in participants 18 years of age and older. The primary efficacy data were obtained in Phase III, while immunogenicity data were collected in Phase II, and are being collected in Phase III at the time of authorization. Data from a Phase I dose‑finding study, Study 019, were also submitted to support the dosing regimen used in Study 021 (two doses of 3.75 mcg VLPs adjuvanted with adjuvant system 03 [AS03], administered 21 days apart).

Phase III of Study 021 was designed to evaluate the efficacy, immunogenicity, and safety of Covifenz relative to placebo in participants 18 years of age and older. This phase of the study was event‑driven and observer‑blinded, with participants randomized in a 1:1 ratio to receive either Covifenz or placebo. Demographic and baseline characteristics were balanced between the two treatment groups. The date of the first participant visit was March 15, 2021. At the time of authorization, this study was ongoing.

Participants with pre‑existing stable chronic disease (including but not limited to obesity, documented hypertension, and diabetes) were included in the study. Stable chronic disease was defined as no new onset or exacerbation of pre‑existing chronic disease three months prior to vaccination. Individuals who had a previous laboratory‑confirmed diagnosis of COVID‑19 were excluded from the study.

As of the efficacy data cut‑off date of August 20, 2021, 24,141 participants were randomized to receive two doses of either Covifenz (12,074 participants) or placebo (12,067 participants), separated by 21 days (19‑23 days, as per study protocol). At this time point, 24,076 participants (99.7%) had received at least one dose of either Covifenz or placebo. Premature discontinuations occurred in both groups, including 1,508 of the 12,074 participants who received Covifenz (12.5%) and 4,567 of the 12,067 participants who received the placebo (37.9%).

After receiving the second dose, 9,599 participants who received Covifenz (79.8%) and 6,963 participants who received the placebo (57.8%) had received follow‑up for at least two months. The median follow‑up time after the second dose was 3.1 months (range: 0 to 6.8 months) for participants who received Covifenz and 2.5 months (range: 0 to 6.8 months) for participants who received the placebo. Participants will continue to be followed up for 12 months after the second dose to evaluate safety and the persistency of the immune response.

The primary endpoint was the first occurrence of laboratory‑confirmed (by reverse transcription polymerase chain reaction [RT‑PCR]) symptomatic SARS‑CoV‑2 infection (detected 7 days or longer after the second vaccination) at the time of the primary vaccine efficacy analysis. In the per‑protocol population of 20,090 participants, 157 participants had laboratory‑confirmed SARS‑CoV‑2 infection detected 7 days or longer after the second dose. Thirty‑nine cases were confirmed in participants who received Covifenz, and 118 cases were confirmed in participants who received the placebo. Based on these data, the success criteria for vaccine efficacy were met, as the estimate for vaccine efficacy was 71.0% (95% confidence interval [CI]: 58.7, 80.0).

Two participants, both of whom received the placebo, had severe COVID‑19 detected 7 days or longer after the second dose. In healthy adults 65 years of age and older (127 participants), only two cases of COVID‑19 were identified 7 days or longer after the second dose, with one case in each treatment group.

As of December 3, 2021, SARS‑CoV‑2 genome sequencing was completed for 114 of the 157 cases of COVID‑19 (72.6%) detected in the per‑protocol population. Sequencing could not be completed for 21 of the 157 cases (13.4%). In participants who received Covifenz, 11 cases of SARS‑CoV‑2 infection were caused by the Delta variant and 6 cases were caused by the Gamma variant. In participants who received the placebo, 5 cases of COVID‑19 were caused by the Alpha variant, 39 cases were caused by the Delta variant, 46 cases were caused by the Gamma variant, 3 cases were caused by the Lambda variant, and 4 cases were caused by the Mu variant. None of the detected cases of COVID‑19 for which sequencing was completed were caused by the original SARS‑CoV‑2 strain.

At the time of authorization of Covifenz, the Omicron variant was of interest due to its increasing prevalence worldwide. An additional live virus neutralization assay was conducted in participants who received two 3.75 mcg doses of Covifenz to evaluate cross reactivity of neutralizing antibodies against the original SARS‑CoV‑2 strain with the Alpha, Beta, Gamma, Delta, and Omicron variants. The neutralizing antibody geometric mean titers (GMTs) against the various strains were obtained at 21 days and 6 months after the second dose. Limited data showed that the neutralizing antibody GMTs against the Omicron variant at 21 days and 6 months after the second dose were 47‑fold and 12‑fold lower, respectively, than the neutralizing antibody GMTs against the original SARS‑CoV‑2 strain. The exact impact of the lower levels of neutralizing antibodies on vaccine efficacy against the Omicron variant remains unknown. More data are required to assess the efficacy of the vaccine against the Omicron variant.

Immunogenicity

Phase II of Study 021 examined the immunogenicity and safety of Covifenz (3.75 mcg VLPs adjuvanted with AS03) relative to placebo in participants 18 years of age and older. Participants were randomized in a 5:1 ratio to receive either Covifenz or placebo as two intramuscular injections, 21 days apart.

Immunogenicity was assessed through the analysis of GMTs of neutralizing antibodies. Study participants were grouped into three populations:

  • Population 1, consisting of 259 healthy adults 18 to 64 years of age,
  • Population 2, consisting of 235 healthy adults 65 years of age and older, and
  • Population 3, consisting of 138 adults with significant comorbidities 18 years of age and older.

For Covifenz recipients, the baseline levels of GMTs of neutralizing antibodies in Populations 1, 2, and 3 were 5.3, 5.2, and 8.9, respectively. Three weeks after the first dose, GMTs were calculated as 44.3, 29.7, and 49.1. These increased further to 2,033.6, 1,917.7, and 1,962.0 three weeks after the second dose. The seroconversion rates (i.e., the proportions of participants experiencing a rise of 4‑fold or greater in neutralizing antibody titers) in Populations 1, 2, and 3 were 99.2%, 97.7%, and 95.8%, respectively, three weeks after the second dose. Covifenz induced a type 1 cell‑mediated immune response after the first vaccination, which increased three weeks after the second vaccination. A similar type 2 cell‑mediated immune response was observed after the second vaccination, demonstrating that Covifenz induced a balanced cell‑mediated immune response.

Indication

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

  • Covifenz is indicated for active immunization to prevent coronavirus disease 2019 (COVID‑19) cause by severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2), for individuals 18 years and older.

Although the proposed indication was for individuals 18 years of age and older, the available data in individuals 65 years of age and older are not sufficient to demonstrate the efficacy and safety of Covifenz in this population. Accordingly, Health Canada approved the following indication:

  • Covifenz is indicated for active immunization to prevent coronavirus disease 2019 (COVID‑19) caused by severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) in individuals 18 to 64 years of age.

For more information, refer to the Covifenz 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

Evidence of the clinical safety of Covifenz was mainly provided by data from the Phase III portion of Study 021, which is described in the Clinical Efficacy section. As of the safety data cut‑off date of October 25, 2021, the safety analysis set included 24,076 participants who had received at least one injection of either Covifenz (12,036 participants) or the placebo (12,040 participants). A second dose had been administered to 22,087 (91.7%) participants.

Solicited local and systemic adverse reactions were more frequently reported in participants who received Covifenz than in those who received the placebo. In adults 18 to 64 years of age, the most frequently reported solicited local and systemic adverse reactions after receiving the first and/or second dose of Covifenz were pain at the injection site (92.5%), headache (68.5%), muscle aches (67.8%), fatigue (64.7%), feeling of general discomfort (63.8%), chills (46.7%), joint aches (40.0%), swelling at the injection site (38.0%), swelling in the neck (22.2%), erythema at the injection site (20.1%), swelling in the axilla (15.1%) and fever (9.7%). The adverse reactions were usually mild or moderate in intensity and resolved within 1 to 3 days. Solicited local and systemic adverse reactions of Grade 2 or higher intensity were more frequently reported after the second dose than after the first dose. Less than 1.6% of solicited adverse reactions were of Grade 3 or higher intensity.

In the safety analysis set, the 11,933 participants who received Covifenz and the 11,924 participants who received the placebo were between 18 and 64 years old. Unsolicited adverse events (both non‑serious and serious) were reported in 3,140 Covifenz recipients (26.3%) and 2,759 placebo recipients (23.1%). Serious adverse events were reported in 47 participants (0.4%) who received Covifenz and 38 participants (0.3%) who received the placebo. There were no notable patterns or significant numerical imbalances between treatment groups for specific categories of serious adverse events that would suggest a causal relationship to Covifenz. Medically attended adverse events were reported in 5.8% of participants who received Covifenz and 5.6% of participants who received the placebo. Adverse events leading to study withdrawal were reported in five participants (<0.1%) who received Covifenz and 13 participants (0.1%) who received the placebo. No deaths or serious adverse events related to Covifenz were reported.

Potential immune‑mediated diseases (pIMDs) were reported in 21 participants (<0.1%) who received Covifenz and 10 participants who received the placebo (<0.1%). The pIMDs that were reported only in participants who received Covifenz included pharyngeal swelling (5 cases), psoriasis (3 cases), arrhythmia (1 case), and deep vein thrombosis (1 case). Bell’s palsy/facial paralysis was reported in three participants who received Covifenz and one participant who received the placebo. One case of myocarditis was reported in each treatment group. The case of myocarditis in the Covifenz treatment group was in a participant who tested positive for COVID‑19. No cases of anaphylaxis were reported. The information available at the time of authorization was not sufficient to determine whether a causal relationship exists between pIMDs and the Covifenz vaccine.

The efficacy and safety data available in participants 65 years of age and older are limited. The efficacy analysis was based on 20,090 participants in total, 188 of whom were 65 years of age and older. The safety analysis was based on 24,076 participants 18 years of age and older, 219 of whom were 65 years of age and older. As the data were not sufficient to support an indication for individuals in this age group, Health Canada approved Covifenz for individuals 18 to 64 years of age.

Risk Management Plan

A Core Risk Management Plan (RMP) and a Canadian RMP Addendum for Covifenz were submitted by Medicago Inc. to Health Canada as part of the submission for authorization. The RMP is designed to describe known and potential safety issues, to present the monitoring plan and when needed, to describe measures that will be put in place to minimize risks associated with the product.

The following information relates to the RMP submitted by Medicago Inc. as part of the New Drug Submission for Covifenz. It is the sponsor’s responsibility to monitor the safety profile of this vaccine and to submit an update to the RMP if there is a significant change to the benefits, harms or uncertainties associated with this vaccine. Updates to the RMP will be reflected in the Post‑Authorization Activity Table for Covifenz.

Based on results from non‑clinical and clinical studies, the RMP included no important identified risks and three important potential risks: anaphylaxis and severe allergic reactions; vaccine‑associated enhanced disease, including vaccine‑associated enhanced respiratory disease; and pIMDs. There were seven areas of missing (limited/no clinical data) information identified: "use in pregnant and breastfeeding women", "use in pediatric population", "use in immunocompromised subjects", "use in patients with autoimmune or inflammatory disorders", "use in frail subjects with unstable health conditions and comorbidities", "interaction with other vaccines", and "long‑term safety". The proposed routine and additional pharmacovigilance activities for the above risks are considered to be acceptable and the sponsor confirmed that they would be applied in the Canadian context. Additional pharmacovigilance activities include continued safety surveillance of ongoing clinical trials as well as three planned post‑authorization studies: two studies to assess the safety of Covifenz using electronic health record databases, and one pregnancy exposure registry. Routine risk minimization measures (i.e., Product Monograph and labelling) are also considered to be appropriate.

Based on Health Canada’s review of the RMP, it was recommended to add “long‑term effectiveness” as missing (limited/no clinical data) information. The sponsor is expected to provide an updated Core RMP and Canadian Addendum in a timely manner if a signal of safety issue is identified in ongoing post‑authorization surveillance.

In addition, the sponsor will provide the following information in the post‑market period:

  • Older adults: Older adults were included in the clinical development program. The sponsor will submit monthly safety reports to Health Canada, which will include analyses of subpopulations by age and gender.
  • Children: Children were not included in the clinical development program. This subpopulation was identified as missing information in the RMP. The sponsor will submit monthly safety reports to Health Canada. Studies of Covifenz in children are planned.
  • Pregnant women: More information is needed about the use of the vaccine in pregnant women. This subpopulation was identified as missing information in the RMP. The sponsor will monitor and submit monthly safety reports to Health Canada. The sponsor will assess outcomes in pregnancy and lactation as part of ongoing and planned studies, including a pregnancy exposure registry.
  • Breastfeeding women: This subpopulation was identified as missing information in the RMP. The sponsor will submit monthly safety reports to Health Canada. The sponsor will assess outcomes in pregnancy and lactation as part of ongoing and planned studies, including a pregnancy exposure registry.
  • Immunocompromised individuals and patients with chronic or debilitating conditions: These individuals were not included in the clinical development program. The subpopulation was identified as missing information in the RMP. The sponsor will submit monthly safety reports to Health Canada.
  • Anaphylaxis: The risk of anaphylaxis was identified as an important potential risk in the RMP. This risk will be assessed via routine pharmacovigilance activities, and reported in monthly safety reports.
  • Indigenous population in Canada: Adverse drug reactions (ADRs) from all subpopulations, including Indigenous, will be reported as expeditiously as applicable, and will be assessed in the monthly safety reports.

The sponsor is required to promptly report adverse reactions and provide Monthly Safety Summary Reports. These reports will be reflected in the Post‑Authorization Activity Table for Covifenz.

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 the long‑term safety and effectiveness of the vaccine, interactions with other vaccines, and specific subpopulations (e.g., pregnant and breastfeeding women, pediatric populations younger than 18 years of age, patients with autoimmune or inflammatory disorders, immunocompromised patients and frail patients with comorbidities).

Collectively, the results of the clinical safety evaluation demonstrated that the Covifenz 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 to 64 years of age when administered according to the recommended dosage regimen. The Phase III portion of Study 021 is ongoing. A follow‑up period of up to 12 months is planned for all participants in this study, for continued assessments of safety and efficacy of the vaccine. The authorization is accompanied by terms and conditions to manage uncertainties and mitigate risks related to the drug. Appropriate warnings and precautions are in place in the Covifenz Product Monograph to address the identified risks.

For more information, refer to the Covifenz 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 New Drug Submission (NDS) for Covifenz (coronavirus disease 2019 [COVID‑19] vaccine, plant‑based virus‑like particles [VLPs], recombinant, adjuvanted) was submitted and reviewed in accordance with the Food and Drug Regulations, which permitted a rolling submission and review process. Following review of the provided information, a Notice of Compliance was issued in relation to Covifenz, with accompanying terms and conditions to manage any uncertainties or mitigate risks related to the product.

The non‑clinical portion of the NDS for Covifenz included one repeated‑dose toxicity and immunogenicity study in mice, one safety and immunogenicity study in mice, a safety, immunogenicity, and protective efficacy study in non‑human primates (rhesus monkeys), and a reproductive and developmental toxicity study in rats.

Covifenz is an adjuvanted vaccine composed of VLPs (hereafter also referred to as coronavirus‑like particles [CoVLPs]) that closely mimic the native severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) and activate local innate immune responses. The vaccine then elicits both neutralizing antibody and cellular immune responses to the spike (S) antigen, which may contribute to protection against COVID‑19.

Studies in mice and non‑human primates demonstrated that two doses of CoVLPs adjuvanted with the adjuvant system 03 (AS03) (CoVLPs + AS03) induced a humoral immune response (characterized by increasing titers of neutralizing antibodies against the original SARS‑CoV‑2 strain) and a specific CD4 T cell‑mediated immune response. In non‑human primates, an S protein‑specific T helper (Th) 1/Th2 balanced cellular response and an increase in the triple positive (co‑expressing interleukin‑2 [IL‑2], interferon gamma [IFNγ], and tumour necrosis factor alpha [TNFα]) CD4 T cells were observed following two doses of CoVLPs + AS03. No antigen‑specific CD8 T cell response was observed after immunization with adjuvanted or unadjuvanted CoVLPs.

A challenge study demonstrated protection from SARS‑CoV‑2 in non‑human primates immunized with two doses of CoVLPs + AS03 and challenged with the original SARS‑CoV‑2 strain 28 days after the last immunization. There were no indications of vaccine‑associated enhanced disease in any of the endpoints assessed including clinical manifestations, gross pathology, hematology and blood chemistry tests, proinflammatory cytokines and chemotactic factors in bronchoalveolar lavage fluids, or virology and immunology assays. The study showed reduced occurrences of chest radiography findings, reduced viral replication, and reduced SARS‑CoV‑2 positive cells and inflammation in the lungs of non‑human primates in the vaccine group.

Immunogenicity and protection of CoVLPs + AS03 have only been evaluated against the original SARS‑CoV‑2 strain. Consequently, there are no non‑clinical data on the immunogenicity and protection of CoVLPs + AS03 against currently circulating variants of the virus.

Results obtained from the non‑clinical studies did not reveal any safety concerns associated with CoVLPs (unadjuvanted or adjuvanted with AS03). In mice, transient signs of inflammation (erythema and edema) were observed at the injection sites. Histopathology evaluation showed local irritation at the injection sites consisting of subcutaneous mixed or mononuclear cell infiltrate and, in some animals, minimal or mild focal or multifocal necrosis. Secondary reactogenic and transient findings included increased incidence and/or severity of splenic and hepatic extramedullary hematopoiesis and increased spleen weights in animals administered CoVLPs + AS03. The reported findings are consistent with an expected immunostimulatory response following intramuscular administration of an adjuvanted vaccine.

A reproductive and developmental toxicity study evaluated the effects of CoVLPs + AS03 on female fertility, fetal development (including teratogenicity), and postnatal development in Sprague‑Dawley rats. Female rats received 3 mcg (0.2 mL) CoVLPs + AS03 per occasion via intramuscular route, on four occasions: 22 and 8 days prior to cohabitation for mating, and on gestation days 6 and 19. The dose was equivalent to four‑fifths of the full human dose, providing a 224‑fold safety margin. No vaccine‑related adverse effects on female fertility, fetal development, or postnatal development were reported in the study. Immunoglobulin G (IgG) antibodies against SARS‑CoV‑2 S protein were detected in the fetuses and pups indicating transfer of maternal antibodies.

Carcinogenicity and genotoxicity studes are not considered relevant to this vaccine and have not been conducted.

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

For more information, refer to the Covifenz 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

The New Drug Submission (NDS) for Covifenz (COVID‑19 vaccine, plant‑based virus‑like particles, recombinant, adjuvanted) was submitted and reviewed in accordance with the Food and Drug Regulations, which permitted a rolling submission and review process. Following review of the provided information, a Notice of Compliance (NOC) was issued in relation to Covifenz, with accompanying terms and conditions to manage any uncertainties or mitigate risks related to the product.

Covifenz contains two components (antigen and adjuvant) that must be mixed in a ratio of 1:1 prior to administration. The antigen component of Covifenz is purified spike (S) protein of the severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) expressed in virus‑like particles (hereafter referred to as coronavirus‑like particles [CoVLPs]) produced by plant-based technology. The adjuvant system 03 (AS03) is composed of alpha‑tocopherol, squalene, and polysorbate 80 in an oil‑in‑water emulsion. It is manufactured and supplied by GlaxoSmithKline. The AS03 adjuvant has previously been approved as the adjuvant component in the H5N1 influenza vaccine Arepanrix. Therefore, the review of the quality (chemistry and manufacturing) portion of the NDS for Covifenz focused on the data related to the CoVLP drug substance and CoVLP drug product.

Characterization of the Drug Substance

The CoVLPs are enveloped virus‑like particles that consist of recombinant S protein trimers stabilized in a prefusion conformation and embedded in the lipid bilayers of the virus‑like particles. Under the electron microscope, the CoVLPs appear as enveloped virus‑like structures, polymorphic in shape, with typical S protein spikes.

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

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

The CoVLP drug substance is produced by expression of recombinant SARS‑CoV‑2 S protein modified to maintain the prefusion conformation. This is accomplished through vector-mediated transient expression of the modified SARS‑CoV‑2 S protein in plant cells using an Agrobacterium tumefaciens‑based delivery system, resulting in the production of virus‑like particles displaying this antigen.

The manufacturing of the CoVLP drug substance is divided into upstream and downstream processes. The upstream process begins with infiltration of Nicotiana benthamiana plants with Agrobacterium tumefaciens bacteria transformed with the SARS‑CoV‑2 S protein expression vector. Infiltrated plants are placed in a growth chamber for up to 6 days to allow for S protein expression and CoVLP assembly. Plants are then removed and the leaves are harvested and diced before being transferred to an extraction vessel to enter the downstream process, which includes clarification, purification, and filtration/bulk filling. The clarification step comprises enzyme‑assisted CoVLP extraction, low pH treatment, coarse filtration, centrifugation, depth filtration, and microfiltration. This is followed by purification through a series of filtration and chromatography steps. Subsequently, the bulk drug substance is filtered, filled into containers, and stored at 2 °C to 8 °C.

The CoVLP drug product manufacturing process consists of formulation, sterile filtration and filling, and finishing activities (visual inspection, labelling, and packaging). The bulk CoVLP drug product is formulated to deliver 3.75 mcg of S protein per CoVLP vaccine dose.

Based on results from validation studies conducted for the manufacturing process of the drug substance and drug product, the process performance qualification met the acceptance criteria. The results demonstrated consistent process performance suitable for commercial production. Formal comparability protocols including extended characterization analyses were executed to confirm comparability of the drug substance lots manufactured for clinical trials and lots manufactured at commercial scale.

Risk mitigation measures for issues identified during the review are addressed through requirements outlined in the terms and conditions associated with the authorization of Covifenz.

Control of the Drug Substance and Drug Product

The physical characteristics, identity, purity, potency, quality, and safety for each batch of the CoVLP drug substance and drug product are tested for conformance to the release and stability specifications. These specifications were established in accordance with relevant International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines (Q6B Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological Products). The testing is conducted with compendial or in‑house methods.

An in‑house potency assay is employed for the specific and quantitative determination of S protein potency in the CoVLP drug substance and drug product. During the product development, the sponsor initiated transitioning to an alternative potency assay. Based on the data reviewed, Health Canada considers that such a transition is not adequately substantiated, and the sponsor is therefore required to maintain the two potency testing methods and submit data to support the suitability of the alternative potency assay. If supported by the data, a post‑Notice of Compliance change submission would be required to transition to specifications based on the alternative potency assay (see terms and conditions).

Risk mitigation measures are addressed through requirements outlined in the terms and conditions associated with the authorization of Covifenz 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 proposed stability program for the commercial CoVLP drug substance will cover a period of 12 months at the intended storage temperature of 2 °C to 8 °C. Based on the stability data collected to date, an initial 3‑month shelf life is proposed for the CoVLP drug substance, when protected from light.

Similarly, the proposed stability program for the commercial CoVLP drug product will cover a period of 12 months. At present, given the observed stability of the CoVLP drug product over at least 6 months, a 6‑month shelf life is proposed for the CoVLP component, when protected from light.

In‑use storage conditions are outlined in the Covifenz Product Monograph. Once the antigen and adjuvant components are mixed, the vaccine must be used within 6 hours and it must be stored at room temperature (20 °C to 30 °C), protected from light, until administered. If the vaccine is refrigerated, it must be discarded.

The sponsor is required to submit updates on the ongoing stability studies providing information specified in the terms and conditions associated with the authorization of Covifenz.

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.

The submitted information demonstrates that the sites involved in the production are compliant with Good Manufacturing Practices (GMP). As per the terms and conditions associated with the authorization of Covifenz, the sponsor is required to provide notification of any changes in the GMP status for any of the manufacturing facilities.

Adventitious Agents Safety Evaluation

The CoVLP drug substance manufacturing process incorporates adequate control measures to prevent contamination and maintain microbial control.

Due to the incompatibility of typical viral reduction steps with the integrity of the CoVLP drug substance, the current manufacturing process does not include a formal viral clearance operation. Therefore, the risk of contamination with adventitious agents is mitigated by control of raw materials and by implementing appropriate environmental control measures. Additionally, in‑process control tests and release testing of CoVLP drug substance for viral and non‑viral adventitious agents are carried out on each batch intended for commercial use.

Biological raw materials used in the CoVLP manufacturing process are not of animal or human origin. Lactose used in the production of one of the enzymes deployed in the extraction step is compliant with requirements specified in the relevant guidance on minimizing the risk of transmitting animal spongiform encephalopathy agents via medicinal products.

The excipients used in the CoVLP drug product formulation are not of animal or human origin.