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

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

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

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

Clinical Pharmacology

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

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

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

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

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

Clinical Efficacy

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

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

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

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

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

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

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

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

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

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

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

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

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

Immunogenicity

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

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

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

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

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

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

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

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

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

Indication

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

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

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

Clinical Safety

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Risk Management Plan

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

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

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

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

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

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

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

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

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

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

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

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