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

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.