Summary Basis of Decision for Comirnaty (previously the Pfizer-BioNTech COVID-19 Vaccine)

The clinical data provided in the application for authorization of the Pfizer‑BioNTech COVID‑19 Vaccine (tozinameran) under the Interim Order Respecting the Importation, Sale, and Advertising of Drugs for Use in Relation to COVID‑19 (Interim Order) included results from the final efficacy analysis from the ongoing Phase III pivotal study (Study C4591001), in which the primary efficacy endpoints have been met. Data from Phases I and II of the pivotal study and from a first‑in‑human study (Study BNT162‑01) have also been submitted in support of the vaccine, dosage regimen, and the safety and immunogenicity of the vaccine. 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 Pfizer‑BioNTech COVID‑19 Vaccine to ascertain the continued quality, safety, and efficacy of the product.

Clinical Pharmacology

The nucleoside‑modified messenger ribonucleic acid (mRNA) in the Pfizer‑BioNTech COVID‑19 Vaccine is formulated in lipid nanoparticles, which enable delivery of the mRNA into the host's cells to allow expression of the severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) spike antigen. The vaccine elicits both neutralizing antibody and cellular immune responses to the spike antigen, which may contribute to protection against COVID‑19 disease.

Immunogenicity was assessed as part of the clinical efficacy evaluation of the Pfizer‑BioNTech COVID‑19 Vaccine.

For further details, please refer to the Pfizer‑BioNTech 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

Evidence of the clinical efficacy of the Pfizer‑BioNTech COVID‑19 Vaccine is based primarily on the available data from the pivotal study (Study C4591001).

Study C4591001 is an adaptive seamless Phase I/II/III randomized, international, placebo‑controlled, observer‑blinded, dose‑finding, vaccine candidate‑selection and efficacy study in healthy individuals. The study consisted of two parts: Phase I/II to identify a promising vaccine candidate and dose to be used for the assessment of safety and immunogenicity, and Phase III as an expanded cohort for efficacy assessment. Tozinameran (also known as BNT162b2) was chosen for further evaluation in Phase III of the study, to be administered as two intramuscular injections of 30 µg (in 0.3 mL) each, 21 days apart.

In Phase III of Study C4591001, 43,651 participants 12 years of age and older were randomized equally into two groups to receive either the Pfizer‑BioNTech COVID‑19 Vaccine (the vaccine group) or placebo (the placebo group). At least 40% of the participants were 56 years of age and older. Participants with pre‑existing stable disease, such as human immunodeficiency virus (HIV), hepatitis C virus (HCV), or hepatitis B virus (HBV) infection, were included in Phase III of the study. Stable disease was defined as disease not requiring significant change in therapy or hospitalization for worsening disease during the six weeks before enrollment. A total of 153 participants 16 to 18 years of age were enrolled in the study (77 in the vaccine group and 76 in the placebo group). The study also included a total of 88 participants that were 12 to 15 years of age (46 in the vaccine and 42 in the placebo group). However, the data analyzed in the final efficacy analysis were from participants 16 years of age and older.

The primary efficacy endpoint was defined as any symptomatic case of COVID‑19 confirmed by reverse transcription‑polymerase chain reaction (RT‑PCR). For analysis of the first primary efficacy endpoint, the studied population included participants who did not have prior infection with SARS‑CoV‑2 through seven days after the administration of Dose 2. For analysis of the second primary efficacy endpoint, the studied population included participants with and without evidence of prior infection with SARS‑CoV‑2 through seven days after the administration of Dose 2. 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. The assessment for the primary analysis was based on posterior probability using a Bayesian model. For the vaccine to be considered superior to placebo, the vaccine efficacy success criteria were predefined for the first and second primary endpoints as follows: a true vaccine efficacy of 60%, and the lower bound of the 95% credible interval (CI) is above 30%.

At the time of the final efficacy analysis, participants had been followed for symptomatic COVID‑19 for a median of 2 months, corresponding to 2,214 person‑years in the vaccine group and 2,222 person‑years in the placebo group.

The Pfizer‑BioNTech COVID‑19 Vaccine met both primary efficacy endpoints of the study, as demonstrated through the results of the final efficacy analysis. With respect to the first primary efficacy endpoint, in participants 16 years of age and older without evidence of prior SARS‑CoV‑2 infection, the data indicate a vaccine efficacy rate of 95.0% (95% CI of 90.3% to 97.6% [p<0.0001]) compared to placebo, through seven days after administration of Dose 2. In participants 65 years of age and older, the vaccine efficacy rate was 94.7% (95% CI of 66.7% to 99.9%). This analysis was based on 170 cases of COVID‑19 (162 in the placebo group and 8 in the vaccine group).

With respect to the second primary efficacy endpoint, the data indicate a vaccine efficacy rate of 94.6% (two‑sided 95% CI of 89.9% to 97.3%) in participants 16 years of age and older with and without prior SARS‑CoV‑2 infection, through seven days after administration of Dose 2. This analysis was based on 178 cases of COVID‑19 (169 in the placebo group and 9 in the vaccine group).

The results of the final efficacy analysis also showed that secondary efficacy endpoints were met. The data indicate a vaccine efficacy rate of 94.4% (95% confidence interval of 89.1% to 97.3%) in participants with and without prior SARS‑CoV‑2 infection, from 14 days after administration of Dose 2. Efficacy was consistent across age, gender, race, and ethnicity demographics. A vaccine efficacy rate of 52.4% was observed after Dose 1 of the vaccine was administered, based on data before Dose 2 was administered.

Ten severe cases of COVID‑19 were identified in total; nine in the placebo group and one in the vaccine group.

Findings from immunogenicity studies 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 RMP and will be monitored through post‑market pharmacovigilance activities.

Immunogenicity

The immunogenicity of the Pfizer‑BioNTech COVID‑19 Vaccine was evaluated in Study BNT162‑01 (Phase I, Part A) and Study C4591001 (Phase I and II).

In Study BNT162‑01, immunogenicity was assessed for two vaccine candidates, BNT162b1 and BNT162b2, and tozinameran (also known as BNT162b2) at a dose of 30 µg was selected as the vaccine candidate for subsequent studies.

Sixty healthy participants 18 to 55 years of age received two injections of BNT162b2 with a 21‑day interval between injections, at different doses. Neutralizing antibody titers, antigen binding antibodies specific to SARS‑CoV‑2 and cell‑mediated immune response (CMI) were assessed at Day 0 (before Dose 1), 7 days and 21 days after Dose 1 (before Dose 2) and at 7, 21 and 28 days after Dose 2.

Results of Study BNT162‑01 showed that a low level of the virus neutralizing antibody geometric mean titers (GMTs) were detected after the first dose of vaccination. The neutralizing antibody level at 7, 21 and 28 days after the second dose showed, in contrast, GMT >4‑fold superior to the baseline (before Dose 1) and superior or comparable to GMT of human convalescent serum level. With regard to the cell‑mediated immune response (CMI), BNT162b2 induced poly‑functional and pro‑inflammatory CD4+/CD8+ T‑cell responses in almost all participants. Two doses of BNT162b2 induced strong SARS‑CoV‑2 receptor binding domain (RBD)‑specific CD4+ and CD8+ T‑cell responses in ≥95% and ≥76% of dosed participants, respectively, compared to the placebo group. The T‑cell responses elicited by BNT162b2 were directed against multiple epitopes of the spike antigen outside the RBD, indicating the induction of multi‑epitopic responses.

In Study C4591001 Phase I, a total of 195 healthy participants 18 to 55 and 65 to 85 years of age were randomized to receive either the placebo or one of two BNT162 vaccine candidates (BNT162b1 or BNT162b2) at different doses. The BNT162b2 vaccine candidate (Pfizer‑BioNTech COVID‑19 Vaccine) at 30 µg was selected as the vaccine candidate for subsequent studies, following review of immunogenicity and safety data.

In Study C4591001 Phase II, a total of 360 participants were enrolled and randomized in a 1:1 ratio to receive either BNT162b2 or placebo. The participants received two injections of the vaccine at the dose of 30 µg separated by a 21‑day interval.

Results obtained from Study C4591001 were similar to those observed in Study BNT162‑01 Phase I, Part A.

Collectively, the results of the final efficacy analysis demonstrated that the Pfizer‑BioNTech COVID‑19 Vaccine met the vaccine efficacy success criteria as specified in Health Canada's Guidance Document, 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 and efficacy. A follow‑up period of up to 24 months is planned for all participants in the study, for continued assessments of safety and efficacy of the vaccine.

Indication

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

• The Pfizer‑BioNTech COVID‑19 Vaccine (COVID‑19 mRNA Vaccine) is indicated for active immunization to prevent coronavirus disease 2019 (COVID‑19) caused by SARS‑CoV‑2 in individuals 16 years of age and older.

For more information, refer to the Pfizer‑BioNTech 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 safety of Pfizer‑BioNTech COVID‑19 Vaccine was evaluated in two clinical studies, Study BNT162‑01 (Phase I) and Study C4591001 (Phase I/II/III) with the data cut‑off date of November 14, 2020 for the present analysis. The study includes 37,706 participants, and safety evaluation in this study is still ongoing. The participants were monitored for solicited local and systemic reactions, unsolicited adverse events and serious adverse events.

A random subset of 8,183 participants 18 years of age and older who received the vaccine were monitored to evaluate reactogenicity. The most frequent solicited adverse events in this subset were: injection site pain (84.1%), fatigue (62.9%), headache (55.1%), muscle pain (38.3%), chills (31.9%), joint pain (23.6%) and fever (14.2%). These were usually mild or moderate in intensity and resolved within a few days after vaccination. The severe cases among these solicited adverse reactions occurred in 0.0% to 4.6% of participants, were more frequent after Dose 2 than after Dose 1, and were generally less frequent in participants 55 years of age and older (≤2.8%) as compared to younger participants (≤4.6%).

The unsolicited adverse event reported in the study was lymphadenopathy (0.3%) with no medical sequelae reported as of the data cut‑off date. The average duration of enlarged lymph nodes was approximately 10 days. A numerical imbalance of three cases of facial paralysis (Bell's palsy) in the vaccine group compared with no cases in the placebo group was observed. The frequency was consistent with the rate in the general population and therefore a causal relationship with the vaccine could not be determined.

A total of 10 severe cases of COVID‑19 were observed in the study, with 9 of the cases occurring in the placebo group and 1 case in the vaccine group. The confinement of the majority of severe cases to the placebo groups suggests no evidence of vaccine‑associated enhanced respiratory disease (VAERD).

A total of 23 pregnant participants, evenly distributed in the placebo and the vaccine group, were recorded in the safety database at the time of the data cut‑off. Safety and efficacy have not been established in pregnant women.

The adverse event profile did not suggest any serious safety concerns. The frequency of serious adverse events was low (<0.5%), without meaningful imbalances between study arms. No life‑threatening adverse events or vaccine‑related deaths were reported in the study. No vaccine-related severe allergic reactions (anaphylaxis) were reported, as of the safety data report cut‑off date in the pivotal study. The vaccine is contraindicated in individuals who are allergic to the active substance or to any ingredient in the vaccine.

Risk Management Plan

A Core (European Union) Risk Management Plan (RMP) for the Pfizer‑BioNTech COVID‑19 Vaccine was submitted by BioNTech Manufacturing GmbH 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 BioNTech Manufacturing GmbH, 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 Pfizer-BioNTech COVID-19 Vaccine.

Based on results from non‑clinical and clinical studies, the RMP included no important identified risks and one important potential risk (vaccine‑associated enhanced disease including VAERD). The RMP also identified "use in pregnant and lactating women" and "vaccine effectiveness" including "real‑world use" as missing information. The proposed routine and additional pharmacovigilance activities for the above safety concerns were considered to be acceptable as outlined in the terms and conditions, and the sponsor confirmed that they would be applied in the Canadian context. Additional pharmacovigilance activities include nine ongoing or planned studies, three interventional studies and six non‑interventional studies (five of which are related to safety and one related to effectiveness of the vaccine). Routine risk minimization measures (i.e., Product Monograph and labelling) were also considered to be appropriate.

Based on Health Canada's review of the RMP, it was recommended to add "long‑term safety", "use in immunocompromised patients and patients with chronic or debilitating conditions", "use in pediatric population younger than 16 years of age" and "interaction with other vaccines" as missing information. 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 submit monthly safety reports to Health Canada, which will include safety information stratified by age group.
• Children: A small number of children under 16 years of age were included in the clinical development program. This sub‑population was identified as important to be added as missing information in the RMP. The sponsor will submit monthly safety reports to Health Canada, which will include safety information stratified by age group. The sponsor is also planning to collect additional information about use in pediatric populations under 16 years of age as part of ongoing studies.
• 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. A study of safety and efficacy of the Pfizer‑BioNTech COVID‑19 Vaccine in pregnant women is planned.
• 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.
• Immunocompromised individuals and patients with chronic or debilitating conditions: These were not included in the clinical development program. Health Canada has requested that this sub‑population be added as missing information in the RMP. The sponsor will submit monthly safety reports to Health Canada.
• Anaphylaxis: This was identified as a very rare potential risk for all vaccines and is well known to healthcare professionals. This will be assessed via routine pharmacovigilance activities, and reported in monthly summary safety reports.
• Indigenous populations in Canada: Adverse events following immunization (AEFIs) 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 AEFIs in the indigenous sub‑populations.

The sponsor will also provide prompt reporting of adverse reactions and monthly safety summary reports. In addition, the sponsor is required to provide, prior to distribution, patient information cards to vaccination sites, which will include elements such as manufacturer name, space for recording dates of first and second doses and associated batch/lot numbers. 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 monthly safety summary reports and results from these studies are expected to address data gaps related to specific sub-populations, such as pediatric populations less than 16 years of age, pregnant and lactating 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 Pfizer‑BioNTech 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 16 years of age and older when administered according to the recommended dosage regimen. This Phase III study is ongoing. A follow‑up period of up to 24 months is planned for all participants in this study, for continued assessments of safety and efficacy of the vaccine.

For more information, refer to the Pfizer‑BioNTech 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.