FDA Briefing Document Pfizer-BioNTech COVID-19 Vaccine

Vaccines and Related Biological Products Advisory Committee Meeting December 10, 2020

FDA Briefing Document Pfizer-BioNTech COVID-19 Vaccine

Sponsor: Pfizer and BioNTech

Table of Contents

List of Tables …………………………………………………………………………………………………………….. 3 List of Figures ……………………………………………………………………………………………………………. 4 Glossary……………………………………………………………………………………………………………………. 5 1. Executive Summary ………………………………………………………………………………………………… 6 2. Background……………………………………………………………………………………………………………. 7

2.1. SARS-CoV-2 Pandemic …………………………………………………………………………………… 7

2.2. EUA Request for the Pfizer and BioNTech COVID-19 Vaccine BNT162b2……………….. 8

2.3. U.S. Requirements to Support Issuance of an EUA for a Biological Product…………………………………………………………………………………………………………… 8

2.4. Applicable Guidance for Industry……………………………………………………………………….. 9

2.5. Safety and Effectiveness Information Needed to Support an EUA…………………………… 9

2.6. Continuation of clinical trials following issuance of an EUA for a COVID-
19 vaccine ………………………………………………………………………………………………………10

2.7. Previous Meetings of the VRBPAC to Discuss Vaccines to Prevent COVID-19……………………………………………………………………………………………………….10

3. Topics for VRBPAC Discussion…………………………………………………………………………………11 4. Pfizer-BioNTech COVID-19 Vaccine (BNT162b2)………………………………………………………..11 4.1. Vaccine Composition, Dosing Regimen………………………………………………………………11 4.2. Proposed Use Under EUA………………………………………………………………………………..12 5. FDA Review of Clinical Safety and Effectiveness Data …………………………………………………12 5.1. Overview of Clinical Studies ……………………………………………………………………………..12 5.2. Study C4591001……………………………………………………………………………………………..12 5.2.1. Design …………………………………………………………………………………………………….12 5.2.2. FDA Assessment of Phase 2/3 Follow-Up Duration ………………………………………..17 5.2.3. Subject Disposition and Inclusion in Analysis Populations ……………………………….17 5.2.4. Demographics and Other Baseline Characteristics …………………………………………19 5.2.5. Vaccine Efficacy………………………………………………………………………………………..24 5.2.6. Safety ……………………………………………………………………………………………………..33 6. Sponsor’s Plans for Continuing Blinded, Placebo-Controlled Follow-Up…………………………..44 7. Pharmacovigilance Activities…………………………………………………………………………………….44

8. Benefit/Risk Assessment in the Context of Proposed Indication and Use Under
EUA …………………………………………………………………………………………………………………….46

8.1. Known Benefits ………………………………………………………………………………………………46 8.2. Unknown Benefits/Data Gaps……………………………………………………………………………46 8.3. Known Risks ………………………………………………………………………………………………….48 8.4. Unknown Risks/Data Gaps……………………………………………………………………………….49

Pfizer-BioNTech COVID-19 Vaccine VRBPAC Briefing Document

9. References ……………………………………………………………………………………………………………49 10. Appendix A. Study BNT162-01………………………………………………………………………………..51 11. Appendix B. Charlson Comorbidity Index ………………………………………………………………….52 12. Appendix C. Guidance for Industry: Emergency Use Authorization for

Vaccines to Prevent COVID-19………………………………………………………………………………..53

List of Tables

Table 1: Clinical Trials Submitted in Support of Efficacy and Safety Determinations of the Pfizer-BioNTech COVID-19 Vaccine………………………………………………………………………12

Table 2. Efficacy Populations, Treatment Groups as Randomized ……………………………………..18

Table 3. Disposition of All Randomized Participants, Phase 2/3 Safety Population ……………….19

Table 4. Demographic Characteristics, Participants With or Without Evidence of Infection Prior to 7 Days After Dose 2, Evaluable Efficacy (7 Days) Population …………………………………20

Table 5. Demographics and Other Baseline Characteristics, Phase 2/3 Safety Population …….21

Table 6. Final Analysis of Efficacy of BNT162b2 Against Confirmed COVID-19 From 7 Days After Dose 2 in Participants Without Evidence of Prior SARS-CoV-2 Infection – Evaluable Efficacy Population ……………………………………………………………………………………………..24

Table 7. Efficacy of BNT162b2 Against Confirmed COVID-19 From 7 Days After Dose 2 in Participants With And Without Evidence of Prior SARS-CoV-2 Infection, Evaluable Efficacy Population………………………………………………………………………………………………………….25

Table 8: Subgroup Analyses of Second Primary Endpoint: First COVID-19 Occurrence From 7 Days After Dose 2, by Subgroup, Participants With and Without Evidence of Infection Prior to 7 Days After Dose 2, Evaluable Efficacy (7 Days) Population …………………………………26

Table 9. Demographic Characteristics, Participants With Protocol Defined Case (Without Evidence of Infection Prior to 7 Days After Dose 2)…………………………………………………..28

Table 10. Vaccine Efficacy: First COVID-19 Occurrence From 7 Days After Dose 2, by Comorbidity Status, Among Participants Without Evidence of Infection Prior to 7 Days After Dose 2, Evaluable Efficacy (7 Days) Population ………………………………………………………29

Table 11. First Severe COVID-19 Occurrence from 7 Days after Dose 2 – Evaluable Efficacy Population………………………………………………………………………………………………………….31

Table 12. First Severe COVID-19 Occurrence After Dose 1 – Dose 1 All-Available Efficacy Population………………………………………………………………………………………………………….31

Table 13. Primary Efficacy Endpoint –All-Available Efficacy Population ………………………………32

Table 14. Study C4591001 Safety Overview- Ages 16 years and older ………………………………33

Table 15. Frequency of Solicited Local Reactions Within 7 Days After Each Vaccination, Reactogenicity Subset of the Phase 2/3 Safety Population*, 18 to 55 Years of Age……….34

Table 16. Frequency of Solicited Local Reactions Within 7 Days After Each Vaccination, Reactogenicity Subset of the Phase 2/3 Safety Population*, >55 Years of Age and Older 35

Table 17. Frequency of Solicited Systemic Adverse Events Within 7 Days After Each Vaccination- Reactogenicity Subset of the Phase 2/3 Safety Population*, 18 to 55 Years of Age …………………………………………………………………………………………………………………..35

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Pfizer-BioNTech COVID-19 Vaccine VRBPAC Briefing Document

Table 18. Frequency of Solicited Systemic Adverse Events Within 7 Days After Each Vaccination- Reactogenicity Subset of the Phase 2/3 Safety Population*, >55 Years of Age and Older…………………………………………………………………………………………………………..37

Table 19. Frequency of Unsolicited AEs with Occurrence in ≥1% of Participants in any Treatment Group from Dose 1 to 1-month After Dose 2, Phase 2/3 Safety Population*, 16 Years of Age and Older………………………………………………………………………………………..39

Table 20. Frequency of Unsolicited AEs with Occurrence in ≥1% of Participants in any Treatment Group from Dose 1 to 1 Month After Dose 2, Phase 2/3 Safety Population*, 16 and 17 Years of Age ……………………………………………………………………………………………39

Table 21. Frequency of Unsolicited AEs with Occurrence in ≥1% of Participants in any Treatment Group from Dose 1 to 1 Month After Dose 2, Phase 2/3 Safety Population*, 65 Years and Older………………………………………………………………………………………………….40

List of Figures

Figure 1. Safety Monitoring Plan, Study C4591001………………………………………………………….15

Figure 2. Cumulative Incidence Curves for the First COVID-19 Occurrence After Dose 1, Dose 1 All-Available Efficacy Population ……………………………………………………………………………30

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Pfizer-BioNTech COVID-19 Vaccine VRBPAC Briefing Document

Glossary

AE adverse event
AIDS acquired immunodeficiency syndrome
ARDS acute respiratory distress syndrome
BNT162b2 Pfizer-BioNTech COVID-19 Vaccine
CBRN chemical, biological, radiological, or nuclear
CDC Centers for Disease Control and Prevention
CMC Che
EUA Emergency Use Authorization
FDA Food and Drug Administration
hACE2 human angiotensin converting enzyme 2
HHS Health and Human Services
HIV human immunodeficiency virus
IM intramuscular
LNP lipid nanoparticle
MERS-CoV Middle Eastern respiratory syndrome
modRNA nucleoside-modified messenger RNA
NAAT nucleic acid amplification-based test
PVP Pharmacovigilance Plan
RBD receptor binding domain
RT-PCR reverse transcription-polymerase chain reaction
SAE serious adverse event
SARS-CoV-2 severe acute respiratory syndrome coronavirus 2
VE vaccine efficacy
VRBPAC Vaccines and Related Biological Products Advisory Committee

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Pfizer-BioNTech COVID-19 Vaccine VRBPAC Briefing Document

1. Executive Summary

On November 20, 2020, Pfizer and BioNTech (the Sponsor) submitted an Emergency Use Authorization (EUA) request to FDA for an investigational COVID-19 vaccine (BNT162b2) intended to prevent COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The vaccine is based on the SARS-CoV-2 spike glycoprotein (S) antigen encoded by RNA and formulated in lipid nanoparticles (LNPs). The proposed use under an EUA is “for active immunization for the prevention of COVID-19 caused by SARS-CoV-2 in individuals 16 years of age and older.” The proposed dosing regimen is 2 doses, 30 μg each, administered 21 days apart.

The EUA request includes safety and efficacy data from an ongoing phase 3 randomized, double-blinded and placebo-controlled trial of BNT162b2 in approximately 44,000 participants. The primary efficacy endpoint is incidence of COVID-19 among participants without evidence of SARS-CoV-2 infection before or during the 2-dose vaccination regimen. In a mid-November analysis of 36,621 participants randomized 1:1 to vaccine or placebo who were included in the per-protocol efficacy analysis population of participants without evidence of SARS-CoV-2 infection prior to 7 days after completion of the vaccination regimen, efficacy in preventing confirmed COVID-19 occurring at least 7 days after the second dose of vaccine was 95.0%, with 8 COVID-19 cases in the vaccine group and 162 COVID-19 cases in the placebo group. Subgroup analyses of the primary efficacy endpoint showed similar efficacy point estimates across age groups, genders, racial and ethnic groups, and participants with medical comorbidities associated with high risk of severe COVID-19. Secondary efficacy analyses suggested benefit of the vaccine in preventing severe COVID-19, in preventing COVID-19 following the first dose, and in preventing COVID-19 in individuals with prior SARS-CoV-2 infection, although available data for these outcomes did not allow for firm conclusions.

Safety data from approximately 38,000 participants ≥16 years of age randomized 1:1 to vaccine or placebo with a median of 2 months of follow up after the second dose suggest a favorable safety profile, with no specific safety concerns identified that would preclude issuance of an EUA. Available safety data from all participants enrolled through the November 14, 2020 data cut-off (N=43,252, which includes late enrollment of additional adolescent and adult participants), was consistent with the safety profile for the approximately 38,000 participants with median follow-up of 2 months and also did not raise specific safety concerns. The most common solicited adverse reactions were injection site reactions (84.1%), fatigue (62.9%), headache (55.1%), muscle pain (38.3%), chills (31.9%), joint pain (23.6%), fever (14.2%); severe 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 (≤ 2.8%) as compared to younger participants (≤4.6%). The frequency of serious adverse events was low (<0.5%), without meaningful imbalances between study arms. Among non-serious unsolicited adverse events, there was a numerical imbalance of four cases of Bell’s palsy in the vaccine group compared with no cases in the placebo group, though the four cases in the vaccine group do not represent a frequency above that expected in the general population. Otherwise, there were no notable patterns or numerical imbalances between treatment groups for specific categories of non-serious adverse events (including other neurologic, neuro- inflammatory, and thrombotic events) that would suggest a causal relationship to BNT162b2 vaccine. With the exception of more frequent, generally mild to moderate reactogenicity in participants <55 years of age, the safety profile of BNT162b2 was generally similar across age groups, genders, ethnic and racial groups, participants with or without medical comorbidities, and participants with or without evidence of prior SARS-CoV-2 infection at enrollment.

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Pfizer-BioNTech COVID-19 Vaccine VRBPAC Briefing Document

This meeting of the Vaccines and Related Biological Products Advisory Committee (VRBPAC) is being convened to discuss and provide recommendations on whether:

• based on the totality of scientific evidence available, it is reasonable to believe that the Pfizer-BioNTech COVID-19 Vaccine may be effective in preventing COVID-19 in individuals 16 years of age and older, and

• the known and potential benefits of the Pfizer-BioNTech COVID-19 Vaccine outweigh its known and potential risks for use in individuals 16 years of age and older.
The committee will also discuss what additional studies should be conducted by the vaccine manufacturer following issuance of the EUA to gather further data on the safety and effectiveness of this vaccine.
2. Background
2.1. SARS-CoV-2 Pandemic

The SARS-CoV-2 pandemic presents an extraordinary challenge to global health and, as of November 30, 2020, has caused more than 60 million cases of COVID-19 and claimed the lives of 1.5 million people worldwide. In the United States, over 13 million cases have been reported to the Centers for Disease Control and Prevention (CDC), with over 260,000 deaths. Confirmed cases and mortality continue to rise globally. On January 31, 2020, the U.S. Secretary of Health and Human Services (HHS) declared a public health emergency related to COVID-19 and mobilized the Operating Divisions of HHS. Following the World Health Organization’s declaration of the novel coronavirus pandemic on March 11, 2020, the U.S. President declared a national emergency in response to COVID-19 on March 13, 2020. Vaccines to protect against COVID-19 are critical to mitigate the current SARS-CoV-2 pandemic and to prevent future disease outbreaks.
SARS-CoV-2 is a novel, zoonotic coronavirus that emerged in late 2019 in patients with pneumonia of unknown cause.1 The virus was named SARS-CoV-2 because of its similarity to the coronavirus responsible for severe acute respiratory syndrome (SARS-CoV, a lineage B betacoronavirus).2 SARS-CoV-2 is an enveloped, positive sense, single stranded RNA virus sharing more than 70% of its sequence with SARS-CoV, and ~50% with the coronavirus responsible for Middle Eastern respiratory syndrome (MERS-CoV).3 The SARS-CoV-2 spike glycoprotein (S), which is a main target for neutralizing antibody, binds to its receptor human angiotensin converting enzyme 2 (hACE2) to initiate infection.4 SARS-CoV-2 is the cause of COVID-19, an infectious disease with respiratory and systemic manifestations. Disease symptoms vary, with many persons presenting with asymptomatic or mild disease and some progressing to severe respiratory tract disease including pneumonia and acute respiratory distress syndrome (ARDS), leading to multiorgan failure and death.
In an attempt to prevent the spread of disease and to control the pandemic, numerous COVID- 19 vaccine candidates are in development. These vaccines are based on different platforms including mRNA and DNA technologies and include viral vectored, subunit, inactivated, and live attenuated vaccines. Most COVID-19 candidate vaccines express the spike protein or parts of the spike protein, i.e., the receptor binding domain (RBD), as the immunogenic determinant.

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Pfizer-BioNTech COVID-19 Vaccine VRBPAC Briefing Document

2.2. EUA Request for the Pfizer and BioNTech COVID-19 Vaccine BNT162b2

Pfizer, in partnership with BioNTech Manufacturing GmbH, is developing a vaccine to prevent COVID-19 which is based on the SARS-CoV-2 spike glycoprotein (S) antigen encoded by RNA and formulated in lipid nanoparticles (LNP). The Pfizer-BioNTech COVID-19 Vaccine (also referred to as BNT162b2) is administered intramuscularly as a 2-dose series spaced 21 days apart at a dose of 30 μg each. The vaccine is supplied as a multi-dose vial (5 doses) containing a frozen suspension (-80°C to -60°C) of BNT162b2 that must be thawed and diluted with 1.8 mL of sterile 0.9% sodium chloride, allowing for five 0.3 mL doses. The vaccine is preservative free.

A phase 3 randomized and placebo-controlled trial using BNT162b2 in approximately 44,000 participants is currently ongoing to evaluate the vaccine’s safety and efficacy. Vaccine efficacy for the primary endpoint against confirmed COVID-19 occurring at least 7 days after the second dose was 95.0% with 8 COVID-19 cases in the vaccine group compared to 162 COVID-19 cases in the placebo group. Data from about 38,000 participants randomized 1:1 with a median of 2 months of follow-up after the second dose of vaccine showed a favorable safety profile at a dose of 30 μg in participants 16 years of age and older. On November 20, 2020, Pfizer and BioNTech submitted an EUA request to FDA for its investigational COVID-19 vaccine (BNT162b2) intended to prevent COVID-19 caused by SARS-CoV-2.

2.3. U.S. Requirements to Support Issuance of an EUA for a Biological Product

Based on the declaration by the Secretary of HHS that the COVID-19 pandemic constitutes a public health emergency with a significant potential to affect national security or the health and security of United States citizens living abroad, FDA may issue an EUA after determining that certain statutory requirements are met (section 564 of the FD&C Act (21 U.S.C. 360bbb-3)).5

• The chemical, biological, radiological, or nuclear (CBRN) agent referred to in the March 27, 2020 EUA declaration by the Secretary of HHS (SARS-CoV-2) can cause a serious or life- threatening disease or condition.

• Based on the totality of scientific evidence available, including data from adequate and well- controlled trials, if available, it is reasonable to believe that the product may be effective to prevent, diagnose, or treat such serious or life-threatening disease or condition that can be caused by SARS-CoV-2, or to mitigate a serious or life-threatening disease or condition caused by an FDA-regulated product used to diagnose, treat, or prevent a disease or condition caused by SARS-CoV-2.

• The known and potential benefits of the product, when used to diagnose, prevent, or treat the identified serious or life-threatening disease or condition, outweigh the known and potential risks of the product.

• There is no adequate, approved, and available alternative to the product for diagnosing, preventing, or treating the disease or condition.
If these criteria are met, under an EUA, FDA can allow unapproved medical products (or unapproved uses of approved medical products) to be used in an emergency to diagnose, treat, or prevent serious or life-threatening diseases or conditions caused by threat agents. FDA has been providing regulatory advice to COVID-19 vaccine manufacturers regarding the data needed to determine that a vaccine’s benefit outweigh its risks. This includes demonstrating that manufacturing information ensures product quality and consistency along with data from at least one phase 3 clinical trial demonstrating a vaccine’s safety and efficacy in a clear and compelling manner.

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Pfizer-BioNTech COVID-19 Vaccine VRBPAC Briefing Document

In the event an EUA is issued for this product, it would still be considered unapproved and it would be under further investigation (under an Investigational New Drug Application) until it is licensed under a Biologics License Application (BLA). Licensure of a COVID-19 vaccine will be based on review of additional manufacturing, efficacy, and safety data, providing greater assurance of the comparability of licensed product to product tested in the clinical trials, greater assurance of safety based on larger numbers of vaccine recipients who have been followed for a longer period of time, and additional information about efficacy that addresses, among other questions, the potential for waning of protection over time.

2.4. Applicable Guidance for Industry

Risk and benefit considerations are unique for COVID-19 vaccines, given that an EUA may be requested to allow for a vaccine’s rapid and widespread deployment for administration to millions of individuals, including healthy people. FDA published in October 2020 guidance for industry entitled “Emergency Use Authorization for Vaccines to Prevent COVID-19” (Appendix C, page 53) describing FDA’s current recommendations regarding the manufacturing, nonclinical, and clinical data and information needed under section 564 of the FD&C Act to support the issuance of an EUA for an investigational vaccine to prevent COVID-19, including a discussion of FDA’s current thinking regarding the circumstances under which an EUA for a COVID-19 vaccine would be appropriate.

2.5. Safety and Effectiveness Information Needed to Support an EUA Effectiveness data

Issuance of an EUA requires a determination that the known and potential benefits of the vaccine outweigh the known and potential risks. For a preventive COVID-19 vaccine to be potentially administered to millions of individuals, including healthy individuals, data adequate to inform an assessment of the vaccine’s benefits and risks and support issuance of an EUA would include meeting the prespecified success criteria for the study’s primary efficacy endpoint, as described in the guidance for industry entitled “Development and Licensure of Vaccines to Prevent COVID-19” (i.e., a point estimate for a placebo-controlled efficacy trial of at least 50%, with a lower bound of the appropriately alpha-adjusted confidence interval around the primary efficacy endpoint point estimate of >30%).6

Safety data

An EUA request for a COVID-19 vaccine should include all safety data accumulated from studies conducted with the vaccine, with data from phase 1 and 2 focused on serious adverse events, adverse events of special interest, and cases of severe COVID-19 among study participants. Phase 3 safety data should include characterization of reactogenicity (common and expected adverse reactions shortly following vaccination) in a sufficient number of participants from relevant age groups and should include a high proportion of enrolled participants (numbering well over 3,000) followed for serious adverse events and adverse events of special interest for at least one month after completion of the full vaccination regimen. The phase 1 and 2 safety data likely will be of a longer duration than the available safety data from the phase 3 trial at the time of submission of an EUA request and thus, are intended to complement the available data from safety follow-up from ongoing phase 3 studies.

   

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Pfizer-BioNTech COVID-19 Vaccine VRBPAC Briefing Document

Phase 3 Follow-up

Data from phase 3 studies should include a median follow-up duration of at least 2 months after completion of the full vaccination regimen to help provide adequate information to assess a vaccine’s benefit-risk profile. From a safety perspective, a 2-month median follow-up following completion of the full vaccination regimen will allow identification of potential adverse events that were not apparent in the immediate postvaccination period. Adverse events considered plausibly linked to vaccination generally start within 6 weeks of vaccine receipt.7 Therefore, a 2- month follow-up period may allow for identification of potential immune-mediated adverse events that began within 6 weeks of vaccination. From the perspective of vaccine efficacy, it is important to assess whether protection mediated by early responses has not started to wane. A 2-month median follow-up is the shortest follow-up period to achieve some confidence that any protection against COVID-19 is likely to be more than short-lived. The EUA request should include a plan for active follow-up for safety (including deaths, hospitalizations, and other serious or clinically significant adverse events) among individuals administered the vaccine under an EUA in order to inform ongoing benefit-risk determinations to support continuation of the EUA.

2.6. Continuation of clinical trials following issuance of an EUA for a COVID-19 vaccine

FDA does not consider availability of a COVID-19 vaccine under EUA, in and of itself, as grounds for immediately stopping blinded follow-up in an ongoing clinical trial or grounds for offering vaccine to all placebo recipients. To minimize the risk that use of an unapproved vaccine under EUA will interfere with long-term assessment of safety and efficacy in ongoing trials, it is critical to continue to gather data about the vaccine even after it is made available under EUA. An EUA request should therefore include strategies that will be implemented to ensure that ongoing clinical trials of the vaccine are able to assess long-term safety and efficacy (including evaluating for vaccine-associated enhanced respiratory disease and decreased effectiveness as immunity wanes over time) in sufficient numbers of participants to support vaccine licensure. These strategies should address how ongoing trial(s) will handle loss of follow-up information for study participants who choose to withdraw from the study in order to receive the vaccine under an EUA.

FDA is aware that some COVID-19 vaccine developers may wish to immediately unblind their trials upon issuance of an EUA in order to rapidly provide vaccine to trial participants who received placebo. Some developers have proposed maintaining blinding in a crossover design that provides vaccine to previous placebo recipients and placebo to previous vaccine recipients. Such strategies would impact collection of longer-term placebo-controlled safety data and evaluation of the duration of vaccine efficacy. Ethical and scientific issues associated with offering vaccination to placebo recipients have been discussed in recent statements and articles.8-10

2.7. Previous Meetings of the VRBPAC to Discuss Vaccines to Prevent COVID-19

On October 22, 2020, the VRBPAC met in open session, to discuss, in general, the development, authorization and/or licensure of vaccines to prevent COVID-19. No specific application was discussed at this meeting. Topics discussed at the meeting included:

• FDA’s approach to safety and effectiveness, and chemistry, manufacturing and control

(CMC) data as outlined in the respective guidance documents

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Pfizer-BioNTech COVID-19 Vaccine VRBPAC Briefing Document

• Considerations for continuation of blinded Phase 3 clinical trials if an EUA has been issued for an investigational COVID-19 vaccine

• Studies following licensure and/or issuance of an EUA for COVID-19 vaccines to: o Furtherevaluatesafety,effectivenessandimmunemarkersofprotection o Evaluatethesafetyandeffectivenessinspecificpopulations.
3. Topics for VRBPAC Discussion
The Vaccines and Related Biological Products Advisory Committee will convene on December 10, 2020, to discuss and provide recommendations on whether:

• based on the totality of scientific evidence available, it is reasonable to believe that the Pfizer-BioNTech COVID-19 Vaccine may be effective in preventing COVID-19 in individuals 16 years of age and older, and

• the known and potential benefits of the Pfizer-BioNTech COVID-19 Vaccine outweigh its known and potential risks for use in individuals 16 years of age and older.
The committee will also discuss what additional studies should be conducted by the vaccine manufacturer following issuance of the EUA to gather further data on the safety and effectiveness of this vaccine.
4. Pfizer-BioNTech COVID-19 Vaccine (BNT162b2) 4.1. Vaccine Composition, Dosing Regimen
The Pfizer-BioNTech COVID-19 Vaccine is a white to off-white, sterile, preservative-free, frozen suspension for intramuscular injection. The vaccine contains a nucleoside-modified messenger RNA (modRNA) encoding the viral spike glycoprotein (S) of SARS-CoV-2. The vaccine also includes the following ingredients: lipids ((4-hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)bis(2- hexyldecanoate), 2-[(polyethylene glycol)-2000]-N,N-ditetradecylacetamide, 1,2-distearoyl-sn- glycero-3-phosphocholine, and cholesterol), potassium chloride, monobasic potassium phosphate, sodium chloride, dibasic sodium phosphate dihydrate, and sucrose.
The Pfizer-BioNTech COVID-19 Vaccine is supplied as a frozen [between -80°C to -60°C (- 112°F to -76°F)] multi-dose (5-dose) vial. The vaccine must be thawed and diluted in its original vial with 1.8 mL of sterile 0.9% Sodium Chloride Injection, USP prior to administration. After dilution, the vial contains 5 doses of 0.3 mL per dose. After dilution, the multiple-dose vials must be stored between 2°C to 25°C (35°F to 77°F) and used within 6 hours from the time of dilution.
The Pfizer-BioNTech COVID-19 Vaccine, BNT162b2 (30 μg), is administered intramuscularly (IM) as a series of two 30 μg doses (0.3 mL each) 21 days apart.
FDA has reviewed the CMC data submitted to date for this vaccine and has determined that the CMC information is consistent with the recommendations set forth in FDA’s Guidance on Emergency Use Authorization for Vaccines to Prevent COVID-19. As such, FDA has determined that the Sponsor has provided adequate information to ensure the vaccine’s quality and consistency for authorization of the product under an EUA.

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4.2. Proposed Use Under EUA

The proposed indication and use of the vaccine under an EUA is “for active immunization for the prevention of COVID-19 caused by SARS-CoV-2 in individuals 16 years of age and older.”

5. FDA Review of Clinical Safety and Effectiveness Data 5.1. Overview of Clinical Studies

Data from two ongoing clinical studies were included in the EUA request, which are summarized in Table 1 below. Study C4591001 is a multi-center, multi-national Phase 1,2,3 randomized, blinded, placebo-controlled safety, immunogenicity, and efficacy study that is the focus of the EUA review. Study BNT162-01 is a Phase 1 study that explored various vaccine candidates and dose levels and will not be discussed in detail. A brief summary of the BNT162-01 study design and results to date is found in Appendix A, page 51.

Table 1: Clinical Trials Submitted in Support of Efficacy and Safety Determinations of the

 

Pfizer-BioNTech COVID-19 Vaccine

BNT162b2 (30 μg)*

Placebo participants (N)

Phase 1: 6 Phase 2/3: 21828

0

      

Study Number/
Country
C4591001   
Phase 1,2,3 randomized,

Study Status

Ongoing Ongoing

participants Description  (N)

 

USA, Argentina, Brazil, Germany, S. Africa, Turkey

placebo-controlled, observer- blind; to evaluate safety, immunogenicity and efficacy of COVID-19 vaccine

Phase 1: 24 Phase 2/3: 21823

12

BNT162-01   Phase 1/2 randomized, open-

   

Germany

label; to evaluate safety and

immunogenicity, dose escalation
N= total number of randomized participants as of November 14, 2020. Placebo: saline.

*Phase 1 studies included additional participants vaccinated with other dose levels and other mRNA vaccine candidates. Studies C4591001 and BNT162-01 started in April 2020 (first participant, first visit).

5.2. Study C4591001 5.2.1. Design

Study C4591001 is an ongoing, randomized, placebo-controlled, phase 1/2/3 study being conducted in the US, Argentina, Brazil, Germany, South Africa and Turkey. Initially the study was designed as a phase 1/2 study in healthy adults in the US for vaccine candidate and dosage selection, immunogenicity and preliminary efficacy, but the protocol was revised to expand the study design for inclusion of a phase 2/3 portion to evaluate clinical disease endpoint efficacy in individuals 12 years of age and older in the US and additional sites outside of the US.

In phase 1, two age groups were evaluated in separate cohorts, younger participants 18 through 55 years of age (N=45) and older participants 65 through 85 years of age (N=45). The study population included healthy men and women and excluded participants at high risk of SARS- CoV-2 infection or with serological evidence of prior or current SARS-CoV-2 infection. Two different vaccine candidates were evaluated, and younger participants received escalating dose levels with progression to subsequent dose levels and evaluation of escalating dose levels in the older age group (65 through 85 years), based on recommendations from an internal review committee that reviewed safety and immunogenicity data. For each vaccine candidate and dose

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level, participants were randomized 4:1, such that 12 participants received the vaccine candidate and 3 participants received placebo. Review of the safety and immunogenicity from phase 1, in combination with data from Study BNT162-01 (See Section 10), supported the final vaccine candidate and dose level (BNT162b2 at 30 μg, given 21 days apart) to proceed into phase 2/3.

In phase 2/3, participants were enrolled with stratification by age (younger adults: 18 through 55 years of age; older adults: over 55 years of age) and a goal of 40% enrollment in the older adult age group. Adolescents were added to the protocol, based on review of safety data in younger adults enrolled in the ongoing study, so the age strata were revised as follows: 12 through 15 years of age, 16 through 54 years of age, and 55 years of age and older. The study population for phase 2/3 includes participants at higher risk for acquiring COVID-19 and at higher risk of severe COVID-19 disease, such as participants working in the healthcare field, participants with autoimmune disease, and participants with chronic but stable medical conditions such as hypertension, asthma, diabetes, and infection with HIV, hepatitis B or hepatitis C. Participants were randomized 1:1 to receive 2 doses of either BNT162b2 or placebo, 21 days apart. The phase 2 portion of the study evaluated reactogenicity and immunogenicity for 360 participants enrolled early-on, and these participants also contribute to the overall efficacy and safety data in the phase 3 portion. The ongoing phase 3 portion of the study is evaluating the safety and efficacy of BNT162b2 for the prevention of COVID-19 disease occurring at least 7 days after the second dose of vaccine. Efficacy is being assessed throughout a participant’s follow-up in the study through surveillance for potential cases of COVID-19. If, at any time, a participant develops acute respiratory illness, an illness visit occurs. Assessments for illness visits include a nasal (midturbinate) swab, which is tested at a central laboratory using a reverse transcription- polymerase chain reaction (RT-PCR) test (e.g., Cepheid; FDA authorized under EUA), or other sufficiently validated nucleic acid amplification-based test (NAAT), to detect SARS-CoV-2. The central laboratory NAAT result is used for the case definition, unless it is not possible to test the sample at the central laboratory. In that case, the following NAAT results are acceptable: Cepheid Xpert Xpress SARS-CoV-2Roche cobas SARS-CoV-2 real-time RT-PCR test (EUA200009/A001) Abbott Molecular/RealTime SARS-CoV-2 assay (EUA200023/A001).

The study design includes planned interim analyses of the first primary efficacy endpoint at pre- specified numbers of COVID-19 cases (at least 62, 92, and 120 cases), and all primary and secondary efficacy endpoints were analyzed in the final efficacy analysis after at least 164 COVID-19 cases were accrued (see Statistical Analysis section, below). Participants are expected to participate for a maximum of approximately 26 months.

Primary Efficacy Endpoints

Study C4591001 has two primary endpoints:

First primary endpoint: COVID-19 incidence per 1000 person-years of follow-up in participants without serological or virological evidence of past SARS-CoV-2 infection before and during vaccination regimen – cases confirmed ≥7 days after Dose 2

Second primary endpoint: COVID-19 incidence per 1000 person-years of follow-up in participants with and without evidence of past SARS-CoV-2 infection before and during vaccination regimen – cases confirmed ≥7 days after Dose 2

Secondary Efficacy Endpoints

Study C4591001 has secondary endpoints based on different approaches to COVID-19 case evaluation criteria as follows:

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COVID-19 confirmed at least 14 days after Dose 2: COVID-19 incidence per 1000 person- years of follow up in participants either (1) without or (2) with and without serological or virological evidence of past SARS-CoV-2 infection before and during vaccination regimen – cases confirmed ≥14 days after Dose 2

Severe COVID-19: incidence per 1000 person-years of follow-up in participants either
(1) without or (2) with and without evidence of past SARS-CoV-2 infection before and during vaccination regimen – cases confirmed either (1) ≥7 days after Dose 2 or (2) ≥14 days after Dose 2

CDC-defined COVID-19: incidence per 1000 person-years of follow-up in participants either (1) without or (2) with and without evidence of past SARS-CoV-2 infection before and during vaccination regimen – cases confirmed either (1) ≥7 days after Dose 2 or (2) ≥14 days after Dose 2.

For the primary efficacy endpoint, the case definition for a confirmed COVID-19 case was the presence of at least one of the following symptoms and a positive SARS-CoV-2 NAAT within 4 days of the symptomatic period:

• Fever;

• New or increased cough;

• New or increased shortness of breath;

• Chills;

• New or increased muscle pain;

• New loss of taste or smell;

• Sore throat;

• Diarrhea;

• Vomiting.
For a secondary efficacy endpoint, a second definition, which may be updated as more is learned about COVID-19, included the following additional symptoms defined by CDC (listed at https://www.cdc.gov/coronavirus/2019-ncov/symptoms-testing/symptoms.html):

• Fatigue;

• Headache;

• Nasal congestion or runny nose;

• Nausea.
For another secondary endpoint, the case definition for a severe COVID-19 case was a confirmed COVID-19 case with at least one of the following:

• Clinical signs at rest indicative of severe systemic illness (RR ≥30 breaths per minute, HR ≥125 beats per minute, SpO2 ≤93% on room air at sea level, or PaO2/FiO2 <300 mm Hg);

• Respiratory failure (defined as needing high-flow oxygen, noninvasive ventilation, mechanical ventilation, or ECMO);

• Evidence of shock (SBP <90 mm Hg, DBP <60 mm Hg, or requiring vasopressors)

• Significant acute renal, hepatic, or neurologic dysfunction;

• Admission to an ICU;

• Death.

      

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Evaluation of Safety

The primary safety objective for all phases was to describe the safety of BNT162 vaccine(s) in healthy adults after 1 or 2 doses. All phase 1 participants (n=30), and then 6653 U.S. participants (360 phase 2, 6293 phase 3) and the first ~500 phase 3 participants/per country with enrollment through October 9, 2020 (Argentina, Brazil and South Africa) recorded local reactions, systemic events, and antipyretic/pain medication usage from Day 1 through Day 7 after each dose. Unsolicited adverse events (AEs) are collected from Dose 1 to 1 month after the last dose and serious AEs (SAEs) from Dose 1 to 6 months after the last dose. Figure 1 below shows the study safety monitoring plan.

Figure 1. Safety Monitoring Plan, Study C4591001

 

Reactogenicity assessments included solicited injection site reactions (pain, redness, swelling) and systemic AEs (fever, fatigue, headache, chills, vomiting, diarrhea, new or worsened muscle pain, and new or worsened joint pain), and antipyretic/pain medication use were recorded in an e-diary. At the data cutoff date for the EUA, reactogenicity events were not collected from adolescents 16 to 17 years of age (enrolled prior to the implementation of Protocol Amendment 9, finalized on 29 October 2020) using an e-diary but were detected and reported as unsolicited AEs. For any phase 3 participants who were not in the reactogenicity subset, local reactions and systemic events consistent with reactogenicity were detected and reported as unsolicited AEs. HIV-positive participants and adolescents 12 through 15 years of age were included in the reactogenicity subset with implementation of protocol amendment 6 (finalized on September 8, 2020) and amendment 7 (finalized on October 6, 2020), respectively. Solicited reactogenicity data in adolescents 16-17 years of age are not available for the reporting period. Reactogenicity data from a total of 100 adolescents 12 through 15 years of age enrolled in C4591001 phase 2/3 were provided in the EUA submission. However, the Sponsor did not request inclusion of this age group in the EUA because the available data, including number of participants and follow-up duration, were insufficient to support favorable a benefit-risk determination at this time. Therefore, the reactogenicity data for participants 12 through 15 years of age are not presented in this document.

Clinical laboratory tests were assessed in phase 1 at 1-week postvaccination. The planned safety follow-up for currently enrolled adolescents and adults is through 24 months after vaccination #2.

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Potential COVID-19 illnesses and their sequelae were not to be reported as AEs, with the exception of illnesses that met regulatory criteria for seriousness and were not confirmed to be COVID-19. These illnesses were evaluated and reported as SAEs.

In phase 2/3, monitoring for risk of vaccine-enhanced disease was performed by an unblinded team supporting the Data Monitoring Committee that reviewed cases of severe COVID-19 as they were received and reviewed AEs at least weekly for additional potential cases of severe COVID-19. The stopping rule was triggered when the 1-sided probability of observing the same or a more extreme case split was 5% or less when the true incidence of severe disease was the same for vaccine and placebo participants, and alert criteria were triggered when this probability was less than 11%.

Analysis Populations

For the purposes of analysis, the following populations are defined:

Population   Description

Enrolled   All participants who have a signed informed consent document. Randomized   All participants who are assigned a randomization number. Evaluable efficacy   All eligible randomized participants who receive all vaccination(s) as

randomized within the predefined window and have no other important

protocol deviations as determined by the clinician.
All-available efficacy   1. All randomized participants who receive at least 1 vaccination.

2. All randomized participants who complete 2 vaccination doses. Phase 2/3 safety analysis populations were as follows:

• Phase 2/3 all-enrolled population: composed of a total of 43,448 (21720 vaccine, 21728 placebo) participants >16 years of age, regardless of duration of follow-up, for whom written informed consent was obtained. Initial enrollment included individuals 18 years and older, then included individuals as young as 16 years of age and individuals with known HIV (protocol amendment 6; finalized on September 8, 2020). As of November 14, 2020, 43.9% and 79.5% of vaccine recipients completed at least 2 months (>8 weeks) and at least 1 month (>4 weeks), respectively, of safety follow-up after Dose 2. The percentages of placebo recipients completing at least 2 months (>8 weeks) and at least 1 month (>4 weeks) were similar to the vaccine group.

• Phase 2/3 safety population (median follow-up time of 2 months after vaccination #2): comprised of a total of 37586 (18801 vaccine,18785 placebo) participants >16 years of age enrolled by October 9, 2020 and received at least 1 dose of study vaccine or placebo; overall, 98.1% of participants completed the 2-dose series. As of November 14, 2020, 50.6% and 91.6% of vaccine recipients completed at least 2 months (>8 weeks) and at least 1 month (>4 weeks), respectively, of safety follow-up after Dose 2. The percentages of placebo recipients completing at least 2 months (>8 weeks) and at least 1 month (>4 weeks) were similar to the vaccine group. A total of 283 (138 vaccine,145 placebo) individuals were 16 to <18 years of age. HIV-positive individuals were included in the all-enrolled population, but not the phase 2/3 safety population because the number of participants enrolled by October 9, 2020 was small (n=120) and the median duration of safety follow-up was short.

      

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5.2.2. FDA Assessment of Phase 2/3 Follow-Up Duration

Study C4591001 initially enrolled approximately 30,000 participants and then several months later began enrollment of approximately 14,000 additional participants, including adolescents and participants with chronic, stable HIV, hepatitis B, or hepatitis C infections. Because of the gap in enrollment, the entire enrolled study population had a median follow-up of less than 2 months as of the EUA submission data cut-off date of November 14, 2020. However, the analyses submitted to support this EUA request meet the expectation for median duration of follow-up time, as follows:

• Submitted safety analyses for participants enrolled through October 9, 2020, and followed through November 14, 2020 (referred to by Pfizer and in this document as the phase 2/3 safety population and including a total of 37,586 participants), represent a median follow-up of 2 months. Additionally, this safety database is larger than for the initial planned enrollment of approximately 30,000 participants.

• The date for data cut-off for the first interim analysis for efficacy was November 4, 2020, when a total of 94 confirmed COVID-19 cases were accrued. All of the participants included in the first interim efficacy analysis had at least 7 days of follow-up after Dose 2, and thus were enrolled no later than October 7, 2020. All participants in the first interim efficacy analysis were therefore included in the phase 2/3 safety population defined above. Although the median follow-up duration for participants included in the first interim efficacy analysis was slightly less than 2 months as of November 4, 2020, these participants were also included in the final efficacy analyses with data cut-off of November 14, 2020, which extended the median follow-up for these participants to greater than 2 months. The results of the final efficacy analysis on data to November 14, 2020, indicate that the conclusions from the first interim efficacy analysis would not change when including additional follow-up to November 14, 2020.
The date for data cut-off for the final efficacy analysis was November 14, 2020, when a total of 170 confirmed COVID-19 cases were accrued. As noted above, the median follow-up duration after completion of the full vaccination regimen for all participants enrolled at that time was less than 2 months for both safety and efficacy populations, due to a gap in enrollment. Because the data for the final efficacy analysis could be submitted in support of the EUA request and could provide data from a greater number of participants than from the interim analysis, FDA has focused its review on the efficacy data from the final efficacy analyses. Additional safety analyses from this larger database of all enrolled participants were also reviewed to evaluate for differences compared with the smaller phase 2/3 safety population.
5.2.3. Subject Disposition and Inclusion in Analysis Populations
Disposition tables are presented below in Table 2 (efficacy analysis populations) and Table 3 (phase 2/3 safety population). Overall, few participants were discontinued or lost to follow-up, and these and other analysis population exclusions were generally balanced between treatment groups. Of 43,448 participants in the phase 2/3 all-enrolled population, 94.2% of vaccine recipients and 94.1% of placebo recipients completed 2 doses (data not shown).

 

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Table 2. Efficacy Populations, Treatment Groups as Randomized BNT162b2

Randomizedb
Dose 1 all-available efficacy population

Participants without evidence of infection before Dose

1
Participants excluded from Dose 1 all-available efficacy population
Reason for exclusionc

Did not receive at least 1 vaccination

Did not provide informed consent Dose 2 all-available efficacy population

Participants without evidence of infection prior to 7 days after Dose 2
Participants without evidence of infection prior to 14 days after Dose 2

Participants excluded from Dose 2 all-available efficacy population
Reason for exclusionc

Did not receive 2 vaccinations

Did not provide informed consent
Evaluable efficacy (7 days) population
Evaluable efficacy (14 days) population
Participants excluded from evaluable efficacy (7 days) population
Participants excluded from evaluable efficacy (14 days) population
Reason for exclusionc

Randomized but did not meet all eligibility criteria
Did not provide informed consent
Did not receive all vaccinations as randomized or did not receive Dose 2 within the predefined window (19- 42 days after Dose 1)

Had other important protocol deviations on or prior to 7 days after Dose 2
Had other important protocol deviations on or prior to 14 days after Dose 2

     

Total na (%) 21823 (100.0)  21828 (100.0)  43651 (100.0) 21768 (99.7)  21783 (99.8)  43551 (99.8) 20314 (93.1)  20296 (93.0)  40610 (93.0)

55 (0.3)  45 (0.2)  100 (0.2)

54 (0.2)  45 (0.2)  99 (0.2) 1 (0.0)  0  1 (0.0) 20566 (94.2)  20536 (94.1)  41102 (94.2) 18701 (85.7)  18627 (85.3)  37328 (85.5)

18678 (85.6)  18563 (85.0)  37241 (85.3) 1257 (5.8)  1292 (5.9)  2549 (5.8)

1256 (5.8)  1292 (5.9)  2548 (5.8) 1 (0.0)  0  1 (0.0) 20033 (91.8)  20244 (92.7)  40277 (92.3) 20033 (91.8)  20243 (92.7)  40276 (92.3) 1790 (8.2)  1584 (7.3)  3374 (7.7)

1790 (8.2)  1585 (7.3)  3375 (7.7)

36 (0.2)  26 (0.1)  62 (0.1) 1 (0.0)  0  1 (0.0) 1550 (7.1)  1561 (7.2)  3111 (7.1)

311 (1.4)  60 (0.3)  371 (0.8) 311 (1.4)  61 (0.3)  372 (0.9)

(30 μg) na (%)

Placebo na (%)

                                                           

an = Number of participants with the specified characteristic.
bThese values are the denominators for the percentage calculations.
cParticipants may have been excluded for more than 1 reason.
Note: 100 participants 12 through 15 years of age with limited follow-up are included in the randomized population (49 in the vaccine group and 51 in the placebo group). Some of these subjects were included in the denominators of efficacy analyses, depending on the population analyzed, but did not contribute primary endpoint cases and do not affect efficacy conclusions for ages 16 years and above.

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Table 3. Disposition of All Randomized Participants, Phase 2/3 Safety Population

Treatment Group

Randomized Vaccinated

Completed 1 dose

Completed 2 doses Withdrawn from Study Reason for Withdrawal

Adverse Event
Death
Withdrawal by Subject Lost to Follow-up

No longer meets eligibility criteria

Refused further study procedures
Source: EUA 27036, amendment 3, Table 2; c4591001-safety-tables-cos-reacto.pdf, page 43.
Note: One participant was randomized but did not sign informed consent and therefore not included in any analysis population. Note: 120 HIV-positive participants included in this table. HIV population analyses were summarized separately from analyses based on the phase 2/3 safety population, but included in the all-enrolled poplation analyses presented in this briefing document. %:n/N. n = number of subjects with the specified characteristic. N = number of participants >16 years of age enrolled by October 9, 2020, including 120 HIV-positive participants, and received at least 1 dose of study vaccine or placebo. N is the denominator used for the percentage calculations.
Data analysis cutoff date: November 14, 2020

The numbers of randomized participants contributing to efficacy analyses presented in this document include 100 participants 12 through 15 years of age (49 in the vaccine group and 51 in the placebo group) who had limited follow-up at the time of the November 14, 2020 data cut- off. However, the sponsor did not include this age group in the EUA request. The numbers of participants presented and used as denominators for efficacy calculations were not adjusted to remove participants 12 through 15 years of age. Because the number of participants 12 through 15 years of age is very small relative to the overall efficacy analysis populations, and no primary endpoint COVID-19 cases occurred in this age group, the vaccine efficacy conclusions are not impacted. No participants 12 through 15 years of age are included in the safety analyses. However, the safety disposition table includes 120 HIV-positive participants who were not included in the phase 2/3 safety population analyses.

5.2.4. Demographics and Other Baseline Characteristics

Overall, the phase 2/3 evaluable efficacy population included 49.4% females, 81.9% White, 9.8% African American, 4.4% Asian participants, and <3% from other racial groups; 26.2% of participants were Hispanic/Latino; 21.4% of participants were >65 years of age. The median age was 51 years. The most frequently reported comorbidities were obesity (35.1%), diabetes (with and without chronic complications, 8.4%) and pulmonary disease (7.8%). Geographically, 76.7% of participants were from the US, 15.3% from Argentina, 6.1% from Brazil, and 2% from South Africa.

The demographic characteristics among vaccine and placebo participants in the all-available efficacy population were similar to the evaluable efficacy population. Please refer to the table below.

BNT162b2 N=18904 n (%)

Total N=37796 n (%) 37796 (100.0)

Placebo N=18892) n (%) 18904 (100.0)    18892 (100.0)

             

18858 (99.8)  18849 (99.8) 18555 (98.2)  18533 (98.1) 180 (1.0)  259 (1.4)

37707 (99.8) 37088 (98.1) 439 (1.2)   8 (0.0)  5 (0.0) 13 (0.0) 2 (0.0)  4 (0.0)  6 (0.0) 84 (0.4)  157 (0.8)  241 (0.6) 80 (0.4)  86 (0.5)  166 (0.4) 1 (0.0)  2 (0.0)  3 (0.0) 0  1 (0.0)  1 (0.0)

                                

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Table 4. Demographic Characteristics, Participants With or Without Evidence of Infection Prior to

7 Days After Dose 2, Evaluable Efficacy (7 Days) Population BNT162b2

Placebo (Na=20244) Nb (%) 10107 (49.9) 10137 (50.1) 50.1 (15.78) 51.0 (12, 91) 76 (0.4) 11743 (58.0) 8454 (41.8) 4319 (21.3) 852 (4.2) 122 (0.6) 883 (4.4) 1972 (9.7) 29 (0.1)

Total (Na=40277) Nb (%) 19901 (49.4) 20376 (50.6) 50.2 (15.76) 51.0 (12, 91) 153 (0.4) 23332 (57.9) 16850 (41.8) 8613 (21.38) 1712 (4.3) 253 (0.6) 1763 (4.4) 3929 (9.8) 83 (0.2)

  

Characteristic

Sex: Female
Sex: Male
Age at Vaccination: Mean years (SD) Age at Vaccination: Median (years)
Age at Vaccination: Min, max (years) Age Group: 16 to <18 years
Age Group: 16 to 55 years
Age Group: >55 years
Age Group: ≥65 years
Age Group: ≥75 years
Race: American Indian or Alaska Native Race: Asian
Race: Black or African American
Race: Native Hawaiian or Other Pacific Islander
Race: White
Race: Multiracial
Race: Not reported
Ethnicity: Hispanic or Latino
Ethnicity: Not Hispanic or Latino Ethnicity: Not reported
Comorbiditiesc: Yes
Comorbidities: No

Comorbidity: Obesity
a.N = number of participants in the specified group, or the total sample. This value is the denominator for the percentage calculations.
b.n = number of participants with the specified characteristic.
c. Number of participants who have 1 or more comorbidities that increase the risk of severe COVID-19 disease: defined as patients who had at least one of the Charlson comorbidity index (Appendix B, page 52) category or obesity only (BMI ≥30 kg/m2).

(Na=20033) Nb (%) 9794 (48.9) 10239 (51.1) 50.3 (15.73) 51.0 (12, 89) 77 (0.4) 11589 (57.8) 8396 (41.9) 4294 (21.4) 860 (4.3) 131 (0.7) 880 (4.4) 1957 (9.8) 54 (0.3)

                                         

16387 (81.8) 523 (2.6) 101 (0.5) 5272 (26.3) 14652 (73.1) 109 (0.5) 9278 (46.3) 10755 (53.7) 6934 (34.6)

16619 (82.1) 493 (2.4) 126 (0.6) 5281 (26.1) 14847 (73.3) 116 (0.6) 9314 (46.0) 10930 (54.0) 7093 (35.0)

33006 (81.9) 1016 (2.5) 227 (0.6) 10553 (26.2) 29499 (73.2) 225 (0.6) 18592 (46.2) 21685 (53.8) 14027 (34.8)

                            

Overall, the phase 2/3 safety population included 83.1% White, 9.1% African American, 4.3% Asian participants, and <3% from other racial groups; 28.0% of participants were Hispanic/Latino; 21.6% of participants were >65 years of age. The median age was 52 years, and safety data from a total of 103 participants 16 and 17 years of age were included in this submission. The most frequently reported comorbidities were obesity (35.1%), diabetes (without chronic complications, 7.8%) and chronic pulmonary disease (7.8%). Geographically, 76.7% of participants were from the US, 15.3% from Argentina, 6.1% from Brazil, and 2.0% from South Africa.

The demographic characteristics among vaccine and placebo participants in the all-enrolled population were similar and were also enrolled from sites in Germany (1%) and Turkey (1%). There were no significant imbalances in demographic and other baseline characteristics between the all-enrolled population and phase 2/3 safety population with median 2-month follow-up.

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Table 5. Demographics and Other Baseline Characteristics, Phase 2/3 Safety Population

BNT162b2 N=18801 Characteristic n (%) Age (years)      16 to <18

Age (years)
Mean 16.40 [SD] [0.49] Median 16 Min, max      16-17

Sex
Male   33 (0.2) Female      20 (0.1)

Race
White   37 (0.2) African   11 (0.1) American
Asian   0 (0.0) Multiracial   3 (0.0) Not reported   0 (0.0) American   0 (0.0) Indian or
Alaska native
Nat. HI or   2 (0.0) other Pac. Isl.

Ethnicity
Hispanic or   6 (0.0) Latino
Non-   47 (0.2) Hispanic/non-
Latino
Not reported      0 (0.0)

Baseline Body Mass Index (BMI)

Obese   3 (0.0)
Overweight      14 (0.1)  4901 (26.1)  1278 (6.8)  368 (2.0)  9 (0.0)

            

BNT162b2 n (%) 18 to <65

44.99 [12.66] 46 18-64

7385 (39.3) 7305 (38.9)

11895 (63.3) 1477 (7.9)

693 (3.7) 417 (2.2) 82 (0.4) 84 (0.4)

42 (0.2)

4595 (24.4) 10009 (53.2)

86 (0.5)

BNT162b2 n (%) 65 to <75

68.84 [2.80] 68 65-74

1714 (9.1) 1513 (8.0)

2908 (15.5) 186 (1.0)

81 (0.4) 21 (0.1) 11 (0.1) 15 (0.1)

5 (0.0)

549 (2.9) 2658 (14.1)

20 (0.1)

BNT162b2 n (%) >75

78.07 [2.78] 77 75-89

470 (2.5) 361 (1.9)

775 (4.1) 20 (0.1)

26 (0.1) 7 (0.0) 0 (0.0) 2 (0.0)

1 (0.0)

103 (0.5) 722 (3.8)

6 (0.0)

Placebo N=18785 n (%) 16 to <18

16.36 [0.48] 16 16-17

24 (0.1) 26 (0.1)

38 (0.2) 7 (0.0)

0 (0.0) 3 (0.0) 1 (0.0) 1 (0.0)

0 (0.0)

5 (0.0) 44 (0.2)

1 (0.0)

Total N=37586 n (%)

50.38 [15.70] 52 16-91

19001 (50.6) 18585 (49.4)

31230 (83.1) 3416 (9.1)

1606 (4.3) 853 (2.3) 207 (0.6) 198 (0.5)

76 (0.2)

10522 (28.0) 26843 (71.4)

221 (0.6)

5242 (27.9)  1147 (6.1)  235 (1.3)
4857 (25.9)     1255 (6.7)    340 (1.8)  13022 (34.6)

Placebo n (%) 18 to <65    65 to <75     >75

44.78  68.84  78.10

Placebo n (%)

Placebo n (%)

                     

[12.72]
46  69  77

18-64    65-74    75-91

7153 (38.1)  1724 (9.2)  498 (2.7)

7539 (40.1)    1511 (8.0)    310 (1.7)

11891 (63.3)  2930 (15.6)  756 (4.0) 1505 (8.0)  189 (1.0)  21 (0.1)

715 (3.8)  72 (0.4)  19 (0.1) 379 (2.0)  18 (0.1)  5 (0.0) 98 (0.5)  10 (0.1)  5 (0.0) 83 (0.4)  11 (0.1)  2 (0.0)

21 (0.1)  5 (0.0)  0 (0.0)

4616 (24.6)  558 (3.0)  90 (0.5) 10004 (53.3)  2652 (14.1)  707 (3.8)

72 (0.4)    25 (0.1)    11 (0.1)

[2.78]

[2.81]

                                                                                                                     

5200 (27.7)

1079 (5.7)

248 (1.3)

14 (0.1)

13168 (35.0)

            

Pfizer-BioNTech COVID-19 Vaccine VRBPAC Briefing Document

BNT162b2 N=18801 n (%) Age (years)      16 to <18

Baseline Evidence of Prior SARS- CoV-2 Infection

Negative   48 (0.3)

Positive   3 (0.0)

Missing      2 (0.0) Comorbidities

No   48 (0.3)

Yes   5 (0.0) Diabetes   0 (0.0) Without
Chronic

BNT162b2 n (%) 18 to <65

13879 (73.8%)

473 (2.5%) 338 (1.8%)

12353 (65.7%)

2337 (12.4%) 814 (4.3%)

BNT162b2 n (%) 65 to <75

3109 (16.5)

53 (0.3) 65 (0.3)

2081 (11.1)

1146 (6.1) 497 (2.6)

BNT162b2 n (%) >75

805 (4.3)

16 (0.1) 10 (0.1)

444 (2.4)

387 (2.1) 156 (0.8)

Placebo N=18785 n (%) 16 to <18

47 (0.3%)

3 (0.0%) 0 (0.0%)

37 (0.2%)

13 (0.1%) 1 (0.0%)

Placebo n (%) 18 to <65    65 to <75     >75

13858 (73.8%)  3115 (16.6%)  788 (4.2%)

520 (2.8%)  52 (0.3%)  5 (0.0%) 314 (1.7%)    68 (0.4%)    15 (0.1%)

12412 (66.1%)  2118 (11.3%)  470 (2.5%)

2280 (12.1%)  1117 (5.9%)  338 (1.8%) 849 (4.5%)  491 (2.6%)  132 (0.7%)

Total N=37586 n (%)

35649 (94.8%) 1125 (3.0%) 812 (2.2%)

29963 (79.7%) 7623 (20.3%) 2940 (7.8%)

            

Characteristic

Placebo n (%)

Placebo n (%)

                                                      

Complication
Chronic   5 (0.0)
Pulmonary
Disease
Myocardial   0 (0.0)
Infarction
Peripheral   0 (0.0)
Vascular
Disease
Liver Disease   0 (0.0)
(mild,
moderate or
severe)
Diabetes   0 (0.0)
With Chronic
Complication
Congestive   0 (0.0)
Heart Failure
AIDS/HIV      0 (0.0)  0 (0.0%)  0 (0.0)  0 (0.0)  0 (0.0%)  1 (0.0%)    0 (0.0%)    0 (0.0%)  1 (0.0%)

22

1093 (5.8%)

82 (0.4%) 26 (0.1%)

83 (0.4%)

47 (0.2%) 44 (0.2%)

286 (1.5)

71 (0.4) 67 (0.4)

34 (0.2)

36 (0.2) 26 (0.1)

89 (0.5)

41 (0.2) 31 (0.2)

7 (0.0)

15 (0.1) 17 (0.1)

12 (0.1%)

0 (0.0%) 0 (0.0%)

0 (0.0%)

0 (0.0%) 0 (0.0%)

1060 (5.6%)  309 (1.6%)  66 (0.4%)

67 (0.4%)  17 (0.1%)  6 (0.0%)

2920 (7.8%)

381 (1.0%) 238 (0.6%)

214 (0.6%)

210 (0.6%) 169 (0.4%)

     

73 (0.4%)  83 (0.4%)  31 (0.2%) 29 (0.2%)  52 (0.3%)  33 (0.2%)

                 

47 (0.3%)  47 (0.3%)  18 (0.1%) 36 (0.2%)  30 (0.2%)  16 (0.1%)

                 

Pfizer-BioNTech COVID-19 Vaccine VRBPAC Briefing Document

BNT162b2 N=18801 n (%) Age (years)   16 to <18 Hypertension   0 (0.0)

BNT162b2 n (%) 18 to <65 2569 (13.7%)

BNT162b2 n (%) 65 to <75 1528 (8.1)

BNT162b2 n (%) >75 488 (2.6)

Placebo N=18785 n (%) 16 to <18 1 (0.0%)

Placebo n (%) 18 to <65  65 to <75   >75 2621 (14.0%)  1569 (8.4%)  432 (2.3%)

Total N=37586 n (%)

9208 (24.5%)

            

Characteristic

Placebo n (%)

Placebo n (%)

            

only
Source: FDA-generated table.
Abbreviations: n = number of participants with the specified characteristic; N = number of participants >16 years of age enrolled by October 9, 2020 and received at least 1 dose of vaccine or placebo, N is denominator for the percentage calculations; SD = standard deviation; min, max = minimum, maximum; Nat. HI = Native Hawaiian; Pac. Isl. = Pacific Islander Data analysis cutoff date: November 14, 2020.

                   

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5.2.5. Vaccine Efficacy Primary Efficacy Analyses

Efficacy Results – Primary Endpoint (Evaluable Efficacy Population)

For the first primary efficacy endpoint, vaccine efficacy (VE) for BNT162b2 against confirmed COVID-19 was evaluated in participants without evidence of prior SARS-CoV-2 infection prior to 7 days after Dose 2. For the second primary efficacy endpoint, VE for BNT162b2 against confirmed COVID-19 was evaluated in participants with and without evidence of prior SARS- CoV-2 infection prior to 7 days after Dose 2. Cases were counted from 7 days after Dose 2 for both endpoints. The criterion for success was met if the posterior probability that true vaccine efficacy >30% conditioning on the available data was >99.5% at the final analysis.

For participants without evidence of SARS-CoV-2 infection prior to 7 days after Dose 2, VE against confirmed COVID-19 occurring at least 7 days after Dose 2 was 95.0%. The case split was 8 COVID-19 cases in the BNT162b2 group compared to 162 COVID-19 cases in the placebo group (Table 6). The 95% credible interval for the vaccine efficacy was 90.3% to 97.6%, indicating that the true VE is at least 90.3% with a 97.5% probability, which met the pre- specified success criterion.

Table 6. Final Analysis of Efficacy of BNT162b2 Against Confirmed COVID-19 From 7 Days After Dose 2 in Participants Without Evidence of Prior SARS-CoV-2 Infection – Evaluable Efficacy

   

Population

Pre-specified Age Group

All participants
16 to 55 years
> 55 years and older

BNT162b2 Na = 18198 Cases n1b Surveillance Timec (n2d) 8 2.214 (17411) 5 1.234 (9897) 3 0.980 (7500)

Placebo Na =18325 Cases n1b Surveillance Timec (n2d) 162 2.222 (17511) 114 1.239 (9955) 48 0.983 (7543)

Met Vaccine Predefined Efficacy % Success (95% CI) Criterion* 95.0 Yes

(90.3, 97.6)e
95.6 NA

(89.4, 98.6)f
93.7 NA

                       

(80.6, 98.8)f
*Success criterion: the posterior probability that true vaccine efficacy > 30% conditioning on the available data is >99.5% at the final

analysis
a N = number of participants in the specified group.
b n1 = Number of participants meeting the endpoint definition.
c Total surveillance time in 1000 person-years for the given endpoint across all participants within each group at risk for the endpoint. Time period for COVID-19 case accrual is from 7 days after Dose 2 to the end of the surveillance period.
d n2 = Number of participants at risk for the endpoint.
e Credible interval for VE was calculated using a beta-binomial model with prior beta (0.700102, 1) adjusted for surveillance time. f Confidence interval (CI) for VE is derived based on the Clopper and Pearson method adjusted to the surveillance time.

For participants with and without evidence of SARS-CoV-2 infection before and during vaccination regimen, VE against confirmed COVID-19 occurring at least 7 days after Dose 2 was 94.6%, with 9 and 169 cases in the BNT162b2 and placebo groups respectively (Table 7). The posterior probability was >99.99% for the true VE being greater than 30%. The 95% credible interval for the vaccine efficacy was 89.9% to 97.3%, indicating that the true VE is at least 89.9% with a 97.5% probability given the available data.

Pfizer-BioNTech COVID-19 Vaccine VRBPAC Briefing Document

Table 7. Efficacy of BNT162b2 Against Confirmed COVID-19 From 7 Days After Dose 2 in Participants With And Without Evidence of Prior SARS-CoV-2 Infection, Evaluable Efficacy

Population

Pre-specified Age Group

All participants
16 to 55 years
>55 years and older

BNT162b2 Na = 19965 Cases n1b Surveillance Timec (n2d) 9 2.332 (18559) 6 1.309 (10653) 3 1.022 (7892)

Placebo Na =20172 Cases n1b

Surveillance Timec (n2d) 169 2.345 (18708) 120 1.317 (10738) 49 1.028 (7956)

Met Vaccine Predefined Efficacy % Success (95% CI) Criterion* 94.6 Yes

(89.9, 97.3)e
95.0 NA

(88.7, 98.2)f
93.8 NA

                       

(80.9, 98.8)f
*Success criterion: the posterior probability that true vaccine efficacy >30% conditioning on the available data is >99.5% at the final

analysis
a N = number of participants in the specified group.
b n1 = Number of participants meeting the endpoint definition.
c Total surveillance time in 1000 person-years for the given endpoint across all participants within each group at risk for the endpoint. Time period for COVID-19 case accrual is from 7 days after Dose 2 to the end of the surveillance period.
d n2 = Number of participants at risk for the endpoint.
e Credible interval for VE was calculated using a beta-binomial model with prior beta (0.700102, 1) adjusted for surveillance time. f Confidence interval (CI) for VE is derived based on the Clopper and Pearson method adjusted to the surveillance time.

Subgroup Analyses of Vaccine Efficacy

Subgroup analyses of the second primary efficacy endpoint provide additional information about the VE for participants with and without evidence of infection prior to vaccination in specific populations enrolled, which is the endpoint considered to represent the general population who may receive the vaccine, as baseline evidence of prior infection may not be known by all people who might receive the vaccine. The results are displayed below in Table 8. The VE point estimates for the subgroup analyses were comparable to results for the first primary efficacy endpoint.

VE point estimates were uniformly high across the subgroups examined with the exception of participants identifying as multiracial and participants with evidence of prior SARS-CoV-2 infection at enrollment, for which too few COVID-19 cases occurred to interpret efficacy data for these subgroups. Additionally, the numbers of participants and cases in some other specific subgroups, such as the adolescent age group and racial subgroups, limits the interpretability of the VE results because of the wide credible intervals, but are displayed for completeness.

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Table 8: Subgroup Analyses of Second Primary Endpoint: First COVID-19 Occurrence From 7 Days After Dose 2, by Subgroup, Participants With and Without Evidence of Infection Prior to 7

Days After Dose 2, Evaluable Efficacy (7 Days) Population BNT162b2 Na=19965 Cases n1b Efficacy Endpoint Surveillance Timec Subgroup (n2d) Overall 9 2.332 (18559)

Age group (years)
16 to 17 0

0.003 (58) 18to64 8

Placebo Na=20172 Cases n1b Surveillance Timec (n2d)

169 2.345 (18708)

1 0.003 (61) 149 1.811 (14566) 14 0.423 (3255) 5 0.109 (812)

87 1.084 (8609) 82 1.261 (10099)

75 1.019 (8239) 75 0.794 (6388) 7 0.241 (1849) 12 0.290 (2218)

68 0.832 (6582) 101 1.513 (12120)

89 1.162 (9422) 61 0.651 (5199) 12 0.351 (2685) 7 0.180 (1382)

84 1.176 (9366) 85 1.170 (9342)

55 0.638 (5090)

Vaccine Efficacy % (95% CI)e 94.6 (89.6, 97.6)

100.0 (-3969.9, 100.0) 94.6 (89.1, 97.7)

92.9 (53.2, 99.8) 100.0 (-12.1, 100.0)

95.4 (87.8, 98.8) 93.8 (85.0, 98.1)

93.3 (83.6, 97.9)

96.0 (87.8, 99.2) 100.0 (29.5, 100.0) 91.7 (44.2, 99.8)

95.5 (86.2, 99.1) 94.1 (86.7, 97.9)

94.4 (86.4, 98.2) 95.0 (84.6, 99.0) 91.8 (44.7, 99.8)

100.0 (27.4, 100.0)

93.9 (85.2, 98.1) 95.3 (87.6, 98.8)

94.5 (83.2, 98.9)

                        

65 to 74

≥75

At riskf Yes

No

Age group (years) and at risk 16-64 and not at risk

16-64 and at risk ≥65 and not at risk ≥65 and at risk

Obeseg Yes

No

Age group (years) and obese 16-64 and not obese

16-64 and obese ≥65 and not obese ≥65 and obese

Sex Female

Male

Ethnicity
Hispanic or Latino

1.799 (14443) 1 0.424 (3239) 0 0.106 (805)

4 1.083 (8584) 5 1.250 (9975)

5 1.012 (8172) 3 0.790 (6329) 0 0.238 (1794) 1 0.293 (2250)

3 0.810 (6445) 6 1.522 (12108)

5 1.163 (9380) 3 0.637 (5116) 1 0.358 (2715) 0 0.172 (1328)

5 1.149 (9102) 4 1.183 (9457)

3 0.637 (5074)

                                                                                                                   

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Efficacy Endpoint Subgroup

Not Hispanic or Latino

BNT162b2 Na=19965 Cases n1b Surveillance Timec (n2d)

6 1.681 (13380)

0 0.011 (104) Asian 1 0.095 (796) 0 0.187 (1758) 0 0.006 (50) White 7 1.975 (15294) Multiracial 1 0.047 (467) Not reported 0 0.010 (90)

Baseline SARS-CoV-2 Status
Positiveh 1

Placebo Na=20172 Cases n1b Surveillance Timec (n2d)

114 1.693 (13509)

1 0.010 (104) 4 0.097 (808) 7 0.188 (1758) 1 0.003 (29) 153 1.990 (15473) 1 0.042 (424) 2 0.013 (112)

1 0.060 (567) 164 2.242 (17720) 4 0.043 (421)

Vaccine Efficacy % (95% CI)e 94.7 (88.1, 98.1)

100.0 (-3511.0, 100.0) 74.4 (-158.7, 99.5)

100.0 (30.4, 100.0)

100.0 (-2112.1, 100.0) 95.4 (90.3, 98.2)

10.4 (-6934.9, 98.9) 100.0 (-581.6, 100.0)

-7.1 (-8309.9, 98.6) 95.1 (90.1, 97.9) 100.0 (-68.9, 100.0)

         

Race
American Indian or Alaska native

              

Black or African American

    

Native Hawaiian or other Pacific Islander

                             

Negativei

Unknown

0.056 (526) 8 2.237 (17637) 0 0.039 (396)

         

a. N = number of participants in the specified group.
b. n1 = Number of participants meeting the endpoint definition.
c. Total surveillance time in 1000 person-years for the given endpoint across all participants within each group at risk for the endpoint. Time period for COVID-19 case accrual is from 7 days after Dose 2 to the end of the surveillance period.
d. n2 = Number of participants at risk for the endpoint.
e. Confidence interval (CI) for VE is derived based on the Clopper and Pearson method adjusted to the surveillance time.
f. At risk is defined as having at least one of the Charlson comorbidity index (Appendix B, page 52) category or obesity (BMI ≥30 kg/m2).
g. Obese is defined as BMI ≥30 kg/m2.

The demographics of the participants with confirmed COVID-19 cases contributing to the primary efficacy analysis are displayed below in Table 9.

 

h. Positive N-binding antibody result at Visit 1, positive NAAT result at Visit 1, or medical history of COVID-19.

i. Negative N-binding antibody result at Visit 1, negative NAAT result at Visit 1, and no medical history of COVID-19.

 

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Table 9. Demographic Characteristics, Participants With Protocol Defined Case (Without Evidence

of Infection Prior to 7 Days After Dose 2) Characteristic

Sex: Female
Sex: Male
Age at Vaccination: Mean years (SD)
Age at Vaccination: Median (years)
Age at Vaccination: Min, max (years)
Age Group: 16 to < 18 years
Age Group: 18 to < 65 years
Age Group: ≥ 65 to < 75 years
Age Group: ≥ 75 years
Race: American Indian or Alaska Native
Race: Asian
Race: Black or African American
Race: Native Hawaiian or Other Pacific Islander Race: White
Race: Multiracial
Race: Not reported
Ethnicity: Hispanic or Latino
Ethnicity: Not Hispanic or Latino
Ethnicity: Not reported
Comorbiditiesc: Yes
Comorbidities: No
Comorbidity: Obesity

BNT162b2 (Na=8) Nb (%) 5 (62.5) 3 (37.5) 51.4 (12.47) 51 (30, 69) 0 7 (87.5) 1 (12.5) 0 0 1 (12.5) 0 0 7 (87.5) 0 0 3 (37.5) 5 (62.5) 0 4 (50.0) 4 (50.0) 3 (37.5)

Placebo  Total

  

(Na=170) Nb (%) 81 (50.0)  86 (50.6) 81 (50.0)  84 (49.4) 47.4 (15.21)  47.6 (15.09) 48  48 (18, 79)  (18, 79) 0  0 143 (88.3)  150 (88.2) 14 (8.6)  15 (8.8) 5 (3.1)  5 (2.9) 1 (0.6)  1 (0.6) 4 (2.5)  5 (2.9) 7 (4.3)  7 (4.1) 1 (0.6)  1 (0.6) 146 (90.1)  153 (90.0) 1 (0.6)  1 (0.6) 2 (1.2)  2 (1.2) 53 (32.7)  56 (32.9) 109 (67.3)    114 (67.1)

(Na=162) Nb (%)

                                                     

0 86 (53.1) 76 (46.9) 67 (41.4)

0 90 (52.9) 80 (47.1) 70 (41.2)

                 

a N = number of participants in the specified group, or the total sample. This value is the denominator for the percentage calculations.
b n = Number of participants with the specified characteristic.
c Number of participants who have 1 or more comorbidities that increase the risk of severe COVID-19 disease: defined as patients who had at least one of the Charlson comorbidity index (Appendix B, page 52) category or obesity only (BMI ≥30 kg/m2).

Only 3% of participants had evidence of prior infection at study enrollment, and additional analyses showed that very few COVID-19 cases occurred in these participants over the course of the entire study (9 in the placebo group and 10 in the BNT162b2 group, only 1 of which occurred 7 days or more after completion of the vaccination regimen – data not shown). The placebo group attack rate from enrollment to the November 14, 2020, data cut-off date was 1.3% both for participants without evidence of prior infection at enrollment (259 cases in 19,818 participants) and for participants with evidence of prior infection at enrollment (9 cases in 670 participants). While limited, these data do suggest that previously infected individuals can be at risk of COVID-19 (i.e., reinfection) and could benefit from vaccination.

Additional analyses of the first primary efficacy endpoint were conducted to evaluate the vaccine efficacy, by comorbidity status. VE point estimates were uniformly high across the comorbidities examined, though for some interpretation of the results is limited by small numbers of participants and/or cases.

 

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Table 10. Vaccine Efficacy: First COVID-19 Occurrence From 7 Days After Dose 2, by Comorbidity Status, Among Participants Without Evidence of Infection Prior to 7 Days After Dose 2, Evaluable

Efficacy (7 Days) Population

BNT162b2 (30 μg) Na=18198 Cases n1b Surveillance Timec Subgroup (n2d)

Placebo Na=18325 Cases n1b Surveillance Timec (n2d)

162 2.222 (17511)

76 1.197 (9482) 86 1.025 (8029)

4 0.090 (681)

5 0.062 (492) 14 0.171 (1358) 19 0.176 (1374) 67 0.782 (6103) 44 0.567 (4437) 20 0.178 (1384)

Vaccine Efficacy % (95% CIe) 95.0 (90.0, 97.9)

94.7 (85.9, 98.6) 95.3 (87.7, 98.8) 75.7 (-145.8, 99.5) 100.0 (-0.8, 100.0) 93.0 (54.1, 99.8) 94.7 (66.8, 99.9) 95.4 (86.0, 99.1) 95.4 (82.6, 99.5) 95.0 (68.7, 99.9)

    

Efficacy Endpoint

Overall

8 2.214 (17411)

4 1.189 (9381) 4 1.025 (8030) 1 0.092 (704) 0 0.067 (534) 1 0.175 (1374) 1 0.176 (1372) 3 0.763 (6000) Hypertension   2 0.567 (4413) Diabetes (including   1

    

Comorbidity
No comorbidity

    

Any comorbidityf Any malignancy Cardiovascular

Chronic pulmonary disease
Diabetes

Obese (BMI≥30.0 kg/m2)

   

gestational diabetes)
Abbreviations: N-binding = SARS-CoV-2 nucleoprotein–binding; NAAT = nucleic acid amplification test; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; VE = vaccine efficacy.
Note: Participants who had no serological or virological evidence (prior to 7 days after receipt of the last dose) of past SARS-CoV-2 infection (i.e., N-binding antibody [serum] negative at Visit 1 and SARS-CoV-2 not detected by NAAT [nasal swab] at Visits 1 and 2), and had negative NAAT (nasal swab) at any unscheduled visit prior to 7 days after Dose 2 were included in the analysis.
a N = number of participants in the specified group.
bn1 = Number of participants meeting the endpoint definition.
c Total surveillance time in 1000 person-years for the given endpoint across all participants within each group at risk for the endpoint. Time period for COVID-19 case accrual is from 7 days after Dose 2 to the end of the surveillance period.
d n2 = Number of participants at risk for the endpoint.
e Confidence interval (CI) for VE is derived based on the Clopper and Pearson method adjusted for surveillance time.
f Subject who had 1 or more comorbidities that increase the risk of severe COVID-19 disease: defined as participants who had at least one of the Charlson comorbidity index (Appendix B, page 52) category or BMI ≥30 kg/m2.

Cumulative Incidence Curves

0.177 (1381)

 

Based on the cumulative incidence curve for the all-available efficacy population after Dose 1, (Figure 2), COVID-19 disease onset appears to occur similarly for both BNT162b2 and placebo groups until approximately 14 days after Dose 1, at which time point, the curves diverge, with more cases accumulating in the placebo group than in the BNT162b2 group, and there does not appear to be evidence of waning protection during the follow-up time of approximately 2 months following the second dose that is being evaluated at this point in time.

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Figure 2. Cumulative Incidence Curves for the First COVID-19 Occurrence After Dose 1, Dose 1 All-Available Efficacy Population

Secondary Efficacy Analyses

The secondary efficacy endpoints evaluate the VE of BNT162b2 for the prevention of COVID-19 disease from 14 days after Dose 2 and based on the CDC’s definition of COVID-19 disease from 7 and 14 days after Dose 2. The case splits and VE for each of these secondary efficacy endpoints were each similar to the primary efficacy endpoints described above.

Severe COVID-19 Cases

In the final analysis of the evaluable efficacy population (7 days), four participants had severe COVID-19 disease at least 7 days after Dose 2 (one subject who received BNT162b2 and three participants who received placebo). The vaccine recipient who had severe COVID-19 disease met the severe case definition because oxygen saturation at the COVID-19 illness visit was 93% on room air. The subject was not hospitalized, did not seek further medical care, and did not have risk factors for severe disease. The three placebo recipients who had severe COVID- 19 disease met the severe case definition for the following reasons: one subject had an oxygen saturation of 92% on room air without other severe disease criteria, one subject was

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hospitalized for noninvasive positive pressure ventilation with bilateral pneumonia, and one subject had an oxygen saturation of 92% and ICU admission for heart block. One of these placebo recipients with severe disease also had a body mass index > 30 kg/m2 as a risk factor, while the other two participants did not have any risk factors for severe disease. The vaccine efficacy of this secondary efficacy endpoint is shown in Table 11.

Table 11. First Severe COVID-19 Occurrence from 7 Days after Dose 2

– Evaluable Efficacy

Population

BNT162b2 Na=18198 Cases n1b Secondary Efficacy Surveillance Timec Endpoint (n2d)

Placebo Na=18325 Cases n1b Surveillance Timec

Met Predefined Success Criterion* No

     

First severe COVID-19 occurrence from 7 days after Dose 2 in participants without evidence of prior SARS-CoV-2 infection

Vaccine Efficacy % (n2d) (95% CI)

1
2.215 (17411) 2.232 (17511)

3

66.4 (-124.8, 96.3)e

       

*Success criterion: the posterior probability that true vaccine efficacy > 30% conditioning on the available data is >98.6% at the final analysis.
a. N = number of participants in the specified group.
b. n1 = Number of participants meeting the endpoint definition.

c.Total surveillance time in 1000 person-years for the given endpoint across all participants within each group at risk for the endpoint. Time period for COVID-19 case accrual is from 7 or 14 days after Dose 2 to the end of the surveillance period depending on specified endpoint.
d. n2 = Number of participants at risk for the endpoint.

e Credible interval for VE was calculated using a beta-binomial model with prior beta (0.700102, 1) adjusted for surveillance time. f Confidence interval (CI) for VE is derived based on the Clopper and Pearson method adjusted to the surveillance time.

In the all-available efficacy population, ten participants had severe COVID-19 disease after Dose 1 (one subject who received BNT162b2 and nine participants who received placebo). Five of the remaining six placebo recipients who had severe COVID-19 disease were hospitalized, two of whom were admitted to an intensive care unit. Five of these remaining six placebo recipients who had severe disease had at least one risk factor for severe disease. The total number of severe cases is small, which limits the overall conclusions that can be drawn; however, the case split does suggest protection from severe COVID-19 disease.

Table 12. First Severe COVID-19 Occurrence After Dose

1 – Dose 1 All-Available Efficacy

Population

Secondary Efficacy Endpoint

First severe case occurrence after Dose 1

BNT162b2 Na=21669 Cases n1b Surveillance Timec (n2d)

Placebo Na=21686 Cases n1b Surveillance Timec (n2d)

9 4.006 (21259) 4 1 4

Vaccine Efficacy % (95% CI) 88.9 (20.1, 99.7)f 100.0 (-51.5, 100.0) 100.0 (-3800.0, 100.0) 75.0 (-152.6, 99.5)

   

1 4.021 (21314) 0 Dose2to7daysafterDose2 0 ≥7 Days after Dose 2 1

   

After Dose 1 to before Dose 2

           

a N = number of participants in the specified group.
b n1 = Number of participants meeting the endpoint definition.
c Total surveillance time in 1000 person-years for the given endpoint across all participants within each group at risk for the endpoint. Time period for COVID-19 case accrual is from 7 or 14 days after Dose 2 to the end of the surveillance period depending on specified endpoint.
d n2 = Number of participants at risk for the endpoint.
e Credible interval for VE was calculated using a beta-binomial model with prior beta (0.700102, 1) adjusted for surveillance time.
f Confidence interval (CI) for VE is derived based on the Clopper and Pearson method adjusted to the surveillance time.

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Additional Efficacy Analyses

Additional analyses of the first primary efficacy endpoint were conducted to evaluate the all- available efficacy population, for all participants regardless of evidence of prior infection through 7 days after Dose 2 (Table 13).

Table 13. Primary Efficacy Endpoint –All-Available Efficacy Population

BNT162b2 Na=21669 Cases n1b Surveillance Timec (n2d)

50 4.015 (21314) 39 2 9

Placebo Na=21686 Cases n1b Surveillance Timec (n2d)

     

Efficacy Endpoint

First COVID-19 occurrence after Dose 1 – Dose 1

After Dose 1 to before Dose 2 Dose 2 to 7 days after Dose 2 ≥7 Days after Dose 2

Vaccine Efficacy % (95% CI) 275  82.0

   

3.982 (21258)
82  52.4 (29.5, 68.4)

21  90.5 (61, 98.9) 172  94.8 (89.8, 97.6)

(75.6, 86.9)f

           

a N = number of participants in the specified group.
b n1 = Number of participants meeting the endpoint definition.
c Total surveillance time in 1000 person-years for the given endpoint across all participants within each group at risk for the endpoint. Time period for COVID-19 case accrual is from 7 or 14 days after Dose 2 to the end of the surveillance period depending on specified endpoint.
d n2 = Number of participants at risk for the endpoint.
e Credible interval for VE was calculated using a beta-binomial model with prior beta (0.700102, 1) adjusted for surveillance time.
f Confidence interval (CI) for VE is derived based on the Clopper and Pearson method adjusted to the surveillance time.

VE in participants in the all-available efficacy population was similar to results in the evaluable efficacy population. The VE for the prevention of COVID-19 disease after Dose 1 is 82%, in the all-available efficacy population. Based on the number of cases accumulated after Dose 1 and before Dose 2, there does seem to be some protection against COVID-19 disease following one dose; however, these data do not provide information about longer term protection beyond 21 days after a single dose.

Efficacy Summary

The data submitted in this EUA request were consistent with the recommendations set forth in the FDA Guidance on Emergency Use Authorization for Vaccines to Prevent COVID-19 and met the prespecified success criteria established in the protocol. In the planned interim and final analyses, vaccine efficacy after 7 days post Dose 2 was 95%, (95% CI 90.3; 97.6) in participants without prior evidence of SARS-CoV-2 infection and >94% in the group of participants with or without prior infection. Efficacy outcomes were consistently robust (≥93%) across demographic subgroups.

Efficacy against severe COVID-19 occurring after the first dose was 88.9% (95% CI 20.1, 99.7), with an estimated VE of 75.0% (95% CI -152.6, 99.5) (1 case in BNT162b2 group and 4 cases in placebo group) against severe COVID-19 occurring at least 7 days after Dose 2.

Among all participants (regardless of evidence of infection before or during the vaccination regimen), 50 cases of COVID-19 occurred after Dose 1 in the BNT162b2 group compared with 275 cases in the placebo group, indicating an estimated VE of 82% (95% CI: 75.6%, 86.9%) against confirmed COVID-19 occurring after Dose 1, with VE of 52.4% (95% CI: 29.5%, 68.4%) between Dose 1 and Dose 2. The efficacy observed after Dose 1 and before Dose 2, from a post-hoc analysis, cannot support a conclusion on the efficacy of a single dose of the vaccine, because the time of observation is limited by the fact that most of the participants received a

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second dose after three weeks. The trial did not have a single-dose arm to make an adequate comparison.

5.2.6. Safety

Overview of Adverse Events

Table 14 below presents an overview of all adverse events in the phase 2/3 safety population. A higher proportion of vaccine recipients reported adverse events compared with placebo recipients, and this imbalance was driven by reactogenicity (solicited adverse events) reported in the 7 days following vaccination and unsolicited adverse events corresponding to reactogenicity symptoms among participants not in the reactogenicity subset (see presentation of unsolicited adverse events in a later section). Proportions of participants with serious adverse events, deaths, and withdrawals due to adverse events were balanced between treatment groups.

Table 14. Study C4591001 Safety Overview- Ages 16 years and older

  

Participants Experiencing at Least One:

Immediate unsolicited AE Within 30 minutes after vaccinationa

Dose #1

Dose #2
Solicited injection site reaction within 7 daysb

Dose #1

Dose #2
Solicited systemic AE within 7 daysb

Dose #1

Dose #2
From Dose 1 through 1 month after Dose 2a

Unsolicited non-serious AE

SAE
From Dose 1 through cutoff date (safety population)

SAE
From Dose 1 through cutoff date (all-enrolled)c

Withdrawal due AEs SAE
Deaths

BNT162b2 n/N (%)

78/18801 (0.4) 52/18494 (0.3)

3216/4093 (78.6) 2748/3758 (73.1)

2421/4093 (59.1) 2627/3758 (69.9)

5071/18801 (27.0) 103/18801 (0.5)

124/18801 (0.7)

37/21621 (0.6) 126/21621 (0.6) 2/21621 (0.0)

Placebo n/N (%)

66/18785 (0.4) 39/18470 (0.2)

525/4090 (12.8) 396/3749 (10.6)

1922/4090 (47.0) 1267/3749 (33.8)

2356/18785 (12.5) 81/18785 (0.4)

101/18785 (0.5)

30/21631 (0.5) 111/21631 (0.5) 4/21631 (0.0)

                 

Source: c4591001-safety-tables-ae3.pdf pages 216,446,459,463; c4591001-safety-tables-cos-reacto.pdf, pages 113-114. n= number of participants with the specified reaction or AE.
a N: number of participants in the phase 2/3 safety population.
b N: number of participants in the reactogenicity subset of the phase 2/3 safety population.

b N: number of participants in the all-enrolled population. Data analysis cutoff date: November 14, 2020.

Solicited Local Reactions and Systemic Adverse Events

As of the cutoff date, solicited reactogenicity data in participants 16 and 17 years of age were not collected by e-diary and are not available. Symptoms consistent with solicited reactogenicity that were reported by these participants were collected and analyzed as unsolicited adverse events and are discussed with review of those data.

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Solicited Local Reactions

For each age group in the reactogenicity subset (younger: 18 to 55 years, older: >55 years) and overall (18 years and older), the median onset of local reactions in the vaccine group was 0 (day of vaccination) to 2 days after either dose and lasted a median duration between 1 and 2 days.

For both age groups, injection site pain was the most frequent solicited local adverse reaction. After dose 2, the younger age group reported any pain more frequently than the older age group (77.8% vs 66.1%) and pain characterized as moderate (27.1% vs. 18.0%); a similar pattern was observed after Dose 1. Injection site redness and swelling after each dose were generally similar for both age groups.

 

Subgroup analyses by age

Table 15. Frequency of Solicited Local Reactions Within 7 Days After Each Vaccination, Reactogenicity Subset of the Phase 2/3 Safety Population*, 18 to 55 Years of Age

BNT162b2 Dose 1 N=2238 Local Reaction   n (%)

Placebo Dose 1 N=2248 n (%)

322 (14.0) 308 (13.4) 12 (0.5) 2 (0.1)

26 (1.1) 16 (0.7) 6 (0.3) 4 (0.2)

11 (0.5) 3 (0.1) 5 (0.2) 3 (0.1)

BNT162b2 Dose 2 N=2045 n (%)

1632 (77.8) 1039 (49.5) 568 (27.1) 25 (1.2)

123 (5.9) 73 (3.5) 40 (1.9) 10 (0.5)

132 (6.3) 80 (3.8) 45 (2.1)

Placebo Dose 2 N=2053 n (%)

245 (11.7) 225 (10.7) 20 (1.0) 0 (0.0)

14 (0.7) 8 (0.4) 6 (0.3) 0 (0.0)

5 (0.2) 3 (0.1) 2 (0.1) 0 (0.0)

     

Paina Any

  

1904 (83.1) 1170 (51.1) 710 (31.0) Severe   24 (1.0)

Rednessb Any

Mild
Moderate
Severe   6 (0.3)

Mild Moderate

  

Swellingb Any Mild

Moderate

132 (5.8) 88 (3.8) 39 (1.7)

104 (4.5) 70 (3.1) 28 (1.2)

  

Severe
Source: adapted from EUA 27034, amendment 3, Table 17.
n = number of participants with the specified reaction.
N = number of participants reporting at least 1 yes or no response for the specified reaction after the specified dose.
a Mild: does not interfere with activity; moderate: interferes with activity; severe: prevents daily activity.
b Mild: 2.0 to <5.0 cm; moderate: 5.0 to <10.0 cm; severe: >10.0 cm.
* Participants in the reactogenicity subset of the safety population >16 years of age enrolled by October 9, 2020 and received at least 1 dose of vaccine or placebo.
Data analysis cutoff date: November 14, 2020.

5 (0.2)

7 (0.3)

   

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Table 16. Frequency of Solicited Local Reactions Within 7 Days After Each Vaccination, Reactogenicity Subset of the Phase 2/3 Safety Population*, >55 Years of Age and Older

BNT162b2 Dose 1 N=1802 Local Reaction   n (%)

Placebo Dose 1 N=1792 n (%)

166 (9.3) 160 (8.9) 6 (0.3) 0 (0.0)

19 (1.1) 12 (0.7) 5 (0.3) 2 (0.1)

21 (1.2) 10 (0.6) 11 (0.6)

BNT162b2 Dose 2 N=1660 n (%)

1098 (66.1) 792 (47.7) 298 (18.0)

8 (0.5)

120 (7.2) 59 (3.6) 53 (3.2)

8 (0.5)

124 (7.5) 68 (4.1) 53 (3.2)

Placebo Dose 2 N=1646 n (%)

127 (7.7) 125 (7.6) 2 (0.1) 0 (0.0)

12 (0.7) 8 (0.5) 3 (0.2) 1 (0.1)

11 (0.7) 5 (0.3) 5 (0.3) 1 (0.1)

For each age group in the reactogenicity subset (younger: 18 to 55 years, older: >55 years) and overall (18 years and older), the median onset of systemic AEs in the vaccine group in general was 1 to 2 days after either dose and lasted a median duration of 1 day.

The frequency and severity of systemic AEs were higher in the younger than the older age groups. Within each age group, the frequency and severity of systemic AEs was higher after Dose 2 than Dose 1, except for vomiting and diarrhea, which was generally similar regardless of dose. For both age groups, fatigue, headache and new/worsened muscle pain were most common.

Subgroup analyses by age

Table 17. Frequency of Solicited Systemic Adverse Events Within 7 Days After Each Vaccination-

      

Paina Any

   

1282 (71.1) 1008 (55.9) 270 (15.0) Severe   4 (0.2)

Rednessb Any

Mild
Moderate
Severe   3 (0.2)

Mild Moderate

   

Swellingb Any Mild

Moderate

118 (6.5) 71 (3.9) 45 (2.5)

85 (4.7) 55 (3.1) 27 (1.5)

   

Severe
Source: EUA 27036, amendment 3, Table 21.
n = number of participants with the specified reaction.
N = number of participants reporting at least 1 yes or no response for the specified reaction after the specified dose.
a Mild: does not interfere with activity; moderate: interferes with activity; severe: prevents daily activity.
b Mild: 2.0 to <5.0 cm; moderate: 5.0 to <10.0 cm; severe: >10.0 cm.
* Participants in the reactogenicity subset of the safety population >16 years of age enrolled by October 9, 2020 and received at least 1 dose of vaccine or placebo.
Data analysis cutoff date: November 14, 2020.

Solicited Systemic AEs

2 (0.1)

0 (0.0)

3 (0.2)

     

Reactogenicity Subset of the Phase 2/3 Safety Population*, 18 to 55 Years of Age

   

Adverse Event

BNT162b2 Dose 1 N=2238 n (%)

85 (3.7) 64 (2.8) 15 (0.7)

6 (0.3) 0 (0.0)

Placebo Dose 1 N=2248 n (%)

20 (0.9) 10 (0.4) 5 (0.2) 3 (0.1) 2 (0.1)

BNT162b2 Dose 2 N=2045 n (%)

331 (15.8) 194 (9.2) 110 (5.2)

26 (1.2) 1 (0.0)

Placebo Dose 2 N=2053 n (%)

10 (0.5) 5 (0.2) 3 (0.1) 2 (0.1) 0 (0.0)

Fever ≥38.0°C

   

>38.0°C to 38.4°C >38.4°C to 38.9°C >38.9°C to 40.0°C >40.0°C

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Adverse Event

Fatiguea Any Mild

Moderate

Severe Headachea

Any
Mild Moderate Severe

Chillsa Any Mild

Moderate

Severe Vomitingb

Any
Mild Moderate Severe

Diarrheac Any Mild

Moderate

Severe
New or worsened muscle paina

Any
Mild Moderate Severe

New or worsened joint paina

Any
Mild Moderate Severe

Use of antipyretic or pain medication

BNT162b2 Dose 1 N=2238 n (%)

1085 (47.4) 597 (26.1) 455 (19.9)

33 (1.4)

959 (41.9) 628 (27.4) 308 (13.4)

23 (1.0)

321 (14.0) 230 (10.0) 82 (3.6) 9 (0.4)

28 (1.2) 24 (1.0) 4 (0.2) 0 (0.0)

255 (11.1) 206 (9.0) 46 (2.0) 3 (0.1)

487 (21.3) 256 (11.2) 218 (9.5) 13 (0.6)

251 (11.0) 147 (6.4) 99 (4.3) 5 (0.2) 638 (27.8)

Placebo Dose 1 N=2248 n (%)

767 (33.4) 46 (20.3) 289 (12.6) 11 (0.5)

775 (33.7) 505 (22.0) 251 (10.9)

19 (0.8)

146 (6.4) 111 (4.8) 33 (1.4) 2 (0.1)

28 (1.2) 22 (1.0) 5 (0.2) 1 (0.0)

270 (11.7) 217 (9.4) 52 (2.3) 1 (0.0)

249 (10.8) 175 (7.6) 72 (3.1) 2 (0.1)

138 (6.0) 95 (4.1) 43 (1.9)

0 (0.0) 332 (14.4)

BNT162b2 Dose 2 N=2045 n (%)

1247 (59.4) 442 (21.1) 708 (33.7)

97 (4.6)

1085 (51.7) 538 (25.6) 480 (22.9)

67 (3.2)

737 (35.1) 359 (17.1) 333 (15.9)

45 (2.1)

40 (1.9) 28 (1.3) 8 (0.4) 4 (0.2)

219 (10.4) 179 (8.5) 36 (1.7) 4 (0.2)

783 (37.3) 326 (15.5) 410 (19.5)

47 (2.2)

459 (21.9) 205 (9.8) 234 (11.2) 20 (1.0) 945 (45.0)

Placebo Dose 2 N=2053 n (%)

479 (22.8) 248 (11.8) 217 (10.3)

14 (0.7)

506 (24.1) 321 (15.3) 170 (8.1) 15 (0.7)

79 (3.8) 65 (3.1) 14 (0.7)

0 (0.0)

25 (1.2) 16 (0.8) 9 (0.4) 0 (0.0)

177 (8.4) 144 (6.8) 32 (1.5) 1 (0.0)

173 (8.2) 111 (5.3) 59 (2.8) 3 (0.1)

109 (5.2) 54 (2.6) 51 (2.4)

4 (0.2) 266 (12.6)

                               

Source: adapted from EUA 27036, amendment 3, Table 19.
n = number of participants with the specified reaction.
N = number of participants in the reactogenicity subset reporting at least 1 yes or no response for the specified reaction after the specified dose.
a Mild: does not interfere with activity; moderate: some interference with activity; severe: prevents daily activity.
b Mild: 1 to 2 times in 24 hours; moderate: >2 times in 24 hours; severe: requires intravenous hydration.
c Mild: 2 to 3 loose stools in 24 hours; moderate: 4 to 5 loose stools in 24 hours; severe: 6 or more loose stools in 24 hours.
* Participants in the reactogenicity subset of the safety population >16 years of age enrolled by October 9, 2020 and received at least 1 dose of vaccine or placebo.
Data analysis cutoff date: November 14, 2020.

 

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Table 18. Frequency of Solicited Systemic Adverse Events Within 7 Days After Each Vaccination-

Reactogenicity Subset of the Phase 2/3 Safety Population*, >55 Years of Age and Older

Placebo Dose 1 N=1792

Placebo Dose 2 N=1646 n (%)

4 (0.2) 2 (0.1) 1 (0.1) 1 (0.1) 0 (0.0)

277 (16.8) 161 (9.8) 114 (6.9)

2 (0.1)

229 (13.9) 165 (10.0) 60 (3.6) 4 (0.2)

46 (2.8) 35 (2.1) 11 (0.7)

0 (0.0)

5 (0.3) 5 (0.3) 0 (0.0) 0 (0.0)

99 (6.0) 73 (4.4) 22 (1.3)

4 (0.2)

87 (5.3) 57 (3.5) 29 (1.8)

1 (0.1)

61 (3.7) 35 (2.1) 25 (1.5)

1 (0.1)

BNT162b2 Dose 1 N=1802 Adverse Event   n (%)

BNT162b2 Dose 2 N=1660 n (%)  n (%)

      

Fever ≥38.0°C

 

>38.0°C to 38.4°C >38.4°C to 38.9°C >38.9°C to 40.0°C

26 (1.4) 23 (1.3) 1 (0.1) 1 (0.1) >40.0°C   1 (0.1)

7 (0.4) 2 (0.1) 3 (0.2) 2 (0.1) 0 (0.0)

405 (22.6) 252 (14.1) 150 (8.4) 3 (0.2)

325 (18.1) 242 (13.5) 80 (4.5) 3 (0.2)

57 (3.2) 40 (2.2) 16 (0.9)

1 (0.1)

9 (0.5) 9 (0.5) 0 (0.0) 0 (0.0)

118 (6.6) 100 (5.6) 17 (0.9) 1 (0.1)

149 (8.3) 100 (5.6) 46 (2.6) 3 (0.2)

109 (6.1) 68 (3.8) 40 (2.2)

1 (0.1)

181 (10.9) 131 (7.9) 45 (2.7) 5 (0.3) 0 (0.0)

839 (50.5) 351 (21.1) 442 (26.6)

46 (2.8)

647 (39.0) 422 (25.4) 216 (13.0)

9 (0.5)

377 (22.7) 199 (12.0) 161 (9.7) 17 (1.0)

11 (0.7) 9 (0.5) 1 (0.1) 1 (0.1)

137 (8.3) 114 (6.9) 21 (1.3) 2 (0.1)

477 (28.7) 202 (12.2) 259 (15.6)

16 (1.0)

313 (18.9) 161 (9.7) 145 (8.7)

7 (0.4)

Fatiguea Any Mild

615 (34.1) 373 (20.7) 240 (13.3)

   

Moderate
Severe   2 (0.1)

Headachea Any

   

454 (25.2) 348 (19.3) 104 (5.8) Severe   2 (0.1)

Mild Moderate

Chillsa Any Mild

113 (6.3) 87 (4.8) 26 (1.4)

   

Moderate
Severe   0 (0.0)

Vomitingb Any Mild

Moderate
Severe   0 (0.0)

   

Diarrheac Any Mild

9 (0.5) 8 (0.4) 1 (0.1)

   

147 (8.2) 118 (6.5) 26 (1.4) Severe   3 (0.2)

New or worsened muscle paina

Any
Mild
Moderate
Severe   1 (0.1)

Moderate

   

New or worsened joint paina

Any
Mild Moderate Severe

155 (8.6) 101 (5.6) 52 (2.9) 2 (0.1)

251 (13.9) 168 (9.3) 82 (4.6)

    

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BNT162b2 Dose 1 N=1802 n (%)

358 (19.9)

Placebo Dose 1 N=1792

Placebo Dose 2 N=1646 n (%)

161 (9.8)

      

Adverse Event

Use of antipyretic or

BNT162b2 Dose 2 N=1660 n (%)  n (%)

    

pain medication
Source: EUA 27036, amendment 3, Table 23.

213 (11.9)

625 (37.7)

n = number of participants with the specified reaction.
N = number of participants in the reactogenicity subset reporting at least 1 yes or no response for the specified reaction after the specified dose.
a Mild: does not interfere with activity; moderate: some interference with activity; severe: prevents daily activity.
b Mild: 1 to 2 times in 24 hours; moderate: >2 times in 24 hours; severe: requires intravenous hydration.
c Mild: 2 to 3 loose stools in 24 hours; moderate: 4 to 5 loose stools in 24 hours; severe: 6 or more loose stools in 24 hours.
* Participants in the reactogenicity subset of the safety population >16 years of age enrolled by October 9, 2020 and received at least 1 dose of vaccine or placebo.
Data analysis cutoff date: November 14, 2020.

Unsolicited (non-serious) AEs

A higher frequency of unsolicited, non-serious adverse events was reported in the vaccine group compared to placebo group and was primarily attributed to local reactions and systemic adverse events in subjects not in the reactogenicity subset and are consistent with solicited reactions/events reported by reactogenicity subset participants during the first 7 days following vaccination. Table 19 below presents unsolicited adverse events reported by at least 1% of participants in any treatment group for the phase 2/3 safety population.

Reports of lymphadenopathy were imbalanced with notably more cases in the vaccine group (64) vs. the placebo group (6), which is plausibly related to vaccination. Bell’s palsy was reported by four vaccine participants and none in the placebo group. These cases occurred at 3, 9, 37, and 48 days after vaccination. One case (onset at 3 days postvaccination) was reported as resolved with sequelae within three days after onset, and the other three were reported as continuing or resolving as of the November 14, 2020 data cut-off with ongoing durations of 10, 15, and 21 days, respectively. The observed frequency of reported Bell’s palsy in the vaccine group is consistent with the expected background rate in the general population, and there is no clear basis upon which to conclude a causal relationship at this time, but FDA will recommend surveillance for cases of Bell’s palsy with deployment of the vaccine into larger populations. There were no other notable patterns or numerical imbalances between treatment groups for specific categories (system organ class or preferred term) of non-serious adverse events, including other neurologic, neuro-inflammatory, and thrombotic events, that would suggest a causal relationship to BNT162b2 vaccine.

 

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Table 19. Frequency of Unsolicited AEs with Occurrence in ≥1% of Participants in any Treatment Group from Dose 1 to 1-month After Dose 2, Phase 2/3 Safety Population*, 16 Years of Age and

Older

System Organ Class Preferred Term

General disorders and administration site conditions

Injection site pain Fatigue
Pyrexia
Chills

Pain
Musculoskeletal and connective tissue disorders

Myalgia

Arthralgia
Nervous system disorders

Headache Gastrointestinal disorders

Diarrhoea

Nausea Source: FDA analysis.

BNT162b2 N=18801 n (%) 3521 (18.7)

2125 (11.3) 1029 (5.5) 1146 (6.1) 999 (5.3) 455 (2.4) 1387 (7.4)

909 (4.8) 212 (1.1) 1158 (6.2) 973 (5.2) 565 (3.0) 194 (1.0) 216 (1.1)

Placebo N=18785 n (%) 737 (3.9)

286 (1.5) 260 (1.4) 61 (0.3) 87 (0.5) 36 (0.2) 401 (2.1)

126 (0.7) 82 (0.4) 460 (2.4) 304 (1.6) 368 (2.0) 149 (0.8) 63 (0.3)

Total N=37586 n (%) 4258 (11.3)

2411 (6.4) 1289 (3.4) 1207 (3.2) 1086 (2.9) 491 (1.3) 1788 (4.8)

1035 (2.8) 294 (0.8) 1618 (4.3) 1277 (3.4) 933 (2.5) 343 (0.9) 279 (0.7)

                         

Adverse events in any PT = at least one adverse event experienced (regardless of the MedDRA Preferred Term)
%: n/N. n = number of participants reporting at least 1 occurrence of the specified event.
of any event. N = number of participants in the specified group. This value is the denominator for the percentage calculations. * Participants >16 years of age enrolled by October 9, 2020 and received at least 1 dose of vaccine or placebo.
Data analysis cutoff date: November 14, 2020.

Subgroup analyses by age

16 and 17 years of age: the table below represents an FDA-generated summary of unsolicited AEs consistent with reactogenicity and AEs that occurred at ≥1% and higher in the BNT162b2 Vaccine Group, classified by MedDRA System Organ Class and Preferred Term.

Table 20. Frequency of Unsolicited AEs with Occurrence in ≥1% of Participants in any Treatment Group from Dose 1 to 1 Month After Dose 2, Phase 2/3 Safety Population*, 16 and 17 Years of Age

     

System Organ Class Preferred Term

General disorders and administration site conditions

Injection site pain Pyrexia
Pain
Chills

Injury, poisoning and procedural complications Concussion

Facial bones fracture

Road traffic accident Investigations

Body temperature increased Source: FDA analysis.

BNT162b2 N=53 n (%) 7 (13.2)

Placebo N=50 n (%) 3 (6.0)

Total N=103 n (%) 10 (9.7)

7 (6.8) 5 (4.9) 2 (1.9) 1 (1.0) 1 (1.0) 1 (1.0) 1 (1.0) 1 (1.0) 1 (1.0) 1 (1.0)

   

5 (9.4) 2 (4.0) 5 (9.4) 0

2 (3.8) 1 (1.9) 1 (1.9) 1 (1.9) 1 (1.9) 1 (1.9) 1 (1.9) 1 (1.9)

0

0

0

0

0

0

0

0

        

Adverse events in any PT = at least one adverse event experienced (regardless of the MedDRA Preferred Term)
%: n/N. n = number of participants reporting at least 1 occurrence of the specified event.
of any event. N = number of participants in the specified group. This value is the denominator for the percentage calculations. * Participants >16 years of age enrolled by October 9, 2020 and received at least 1 dose of vaccine or placebo.
Data analysis cutoff date: November 14, 2020.

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Table 21. Frequency of Unsolicited AEs with Occurrence in ≥1% of Participants in any Treatment Group from Dose 1 to 1 Month After Dose 2, Phase 2/3 Safety Population*, 65 Years and Older

Placebo (N=4043) n (%) 577 (14.2)   118 (2.9)

Total (N=8101) n (%) 695 (8.6)

400 (4.9) 219 (2.7) 162 (2.0) 158 (2.0) 67 (0.8) 314 (3.9)

148 (1.8) 63 (0.8) 43 (0.5) 266 (3.3) 172 (2.1) 199 (2.5) 75 (0.9) 53 (0.7)

    

System Organ Class Preferred Term

General disorders and administration site conditions

Injection site pain Fatigue
Chills
Pyrexia

Pain Musculoskeletal and connective tissue disorders

Myalgia Arthralgia
Pain in extremity

Nervous system disorders Headache

Gastrointestinal disorders Diarrhea

Nausea Source: FDA analysis.

BNT162b2 (N=4058) n (%)

  

361 (8.9)
175 (4.3)
143 (3.5)
148 (3.6)
60 (1.5)
231 (5.7)   83 (2.1)

39 (1.0) 44 (1.1) 19 (0.5) 10 (0.2) 7 (0.2)

  

125 (3.1)
42 (1.0)
33 (0.8)
179 (4.4)   87 (2.2)

23 (0.6) 21 (0.5) 10 (0.2)

  

127 (3.1)
127 (3.1)   72 (1.8)

45 (1.1)

  

49 (1.2) 40 (1.0)

26 (0.6) 13 (0.3)

Adverse events in any PT = at least one adverse event experienced (regardless of the MedDRA Preferred Term)
%: n/N. n = number of participants reporting at least 1 occurrence of the specified event.
of any event. N = number of participants in the specified group. This value is the denominator for the percentage calculations. * Participants >16 years of age enrolled by October 9, 2020 and received at least 1 dose of vaccine or placebo.
Data analysis cutoff date: November 14, 2020.

FDA independently conducted standard MedDRA queries (SMQs) using FDA-developed software (MAED) to evaluate for constellations of unsolicited adverse event preferred terms that could represent various diseases and conditions, including but not limited to allergic, neurologic, inflammatory, and autoimmune conditions. The SMQs, conducted on the phase 2/3 all-enrolled safety population, revealed a slight numerical imbalance of adverse events potentially representing allergic reactions, with more participants reporting hypersensitivity-related adverse events in the vaccine group (137 [0.63%]) compared with the placebo group (111 [0.51%]). No imbalances between treatment groups were evident for any of the other SMQs evaluated.

Immediate AEs (phase 2/3 safety population)
The frequency of immediate AEs reported in the vaccine group was 0.4% after Dose 1 and <0.3% after Dose 2 and were mainly consistent with solicited reactogenicity events. In both study groups, the most frequently reported immediate AE was injection site pain (BNT162b2 vaccine 0.3%, placebo 0.2%).

Study Withdrawals due to an AE (all-enrolled population)
Of 43,448 enrolled participants, 37 (0.2%) vaccine recipients and 30 (0.1%) placebo recipients (0.1%), and no adolescents 16 to <18 years of age, withdrew from the study due to an AE. AEs in the SOC of General Disorders and Administration Site Conditions (7 vaccine, 3 placebo) was common, with injection site pain the most frequent (2 vaccine, 0 placebo).

  

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Serious Adverse Events

Deaths

A total of six (2 vaccine, 4 placebo) of 43,448 enrolled participants (0.01%) died during the reporting period from April 29, 2020 (first participant, first visit) to November 14, 2020 (cutoff date). Both vaccine recipients were >55 years of age; one experienced a cardiac arrest 62 days after vaccination #2 and died 3 days later, and the other died from arteriosclerosis 3 days after vaccination #1. The placebo recipients died from myocardial infarction (n=1), hemorrhagic stroke (n=1) or unknown causes (n=2); three of the four deaths occurred in the older group (>55 years of age). All deaths represent events that occur in the general population of the age groups where they occurred, at a similar rate.

Non-fatal SAEs

In the all-enrolled population of (total N=43,448), the proportions of participants who reported at least 1 SAE during the time period from Dose 1 to the data cutoff date (November 14, 2020) were 0.6% in the BNT162b2 vaccine group and 0.5% in the placebo group. The most common SAEs in the vaccine group which were numerically higher than in the placebo group were appendicitis (0.04%), acute myocardial infarction (0.02%), and cerebrovascular accident (0.02%), and in the placebo arm numerically higher than in the vaccine arm were pneumonia (0.03%), atrial fibrillation (0.02%), and syncope (0.02%). Occurrence of SAEs involving system organ classes and specific preferred terms were otherwise balanced between treatment groups, including no imbalance overall in cardiovascular serious adverse events.

Appendicitis was reported as a SAE for 12 participants, and numerically higher in the vaccine group: 8 vaccine participants ([appendicitis [n=7], appendicitis perforated [n=1]) and 4 placebo participants (appendicitis [n=2], appendicitis perforated [n=1], complicated appendicitis [n=1]). All of the vaccine participants (n=8) and 2 placebo participants were younger than 65 years of age. The cases were considered unrelated to vaccination by the study investigators and occurred no more frequently than expected in the given age groups. FDA agrees that there is no clear basis upon which to suspect that this imbalance represents a vaccine-related risk.

Three SAEs reported in the BNT162 group were considered by the investigator as related to vaccine or vaccine administration: shoulder injury, ventricular arrhythmia, and lymphadenopathy. The investigator and the sponsor thought that the shoulder injury was related to vaccine administration. Two SAEs in the BNT162b2 group and none in the placebo group were considered by the investigator, but not the Sponsor, as related to study vaccination: shoulder injury (n=1), ventricular arrhythmia in a participant with known cardiac conditions (n=1), and lymphadenopathy temporally following vaccination (n=1). In FDA’s opinion following review of the adverse event narratives, two of these events were considered as possibly related to vaccine: shoulder injury possibly related to vaccine administration or to the vaccine itself, and lymphadenopathy involving the axilla contralateral to the vaccine injection site. For lymphadenopathy, the event was temporally associated and biologically plausible.

Among participants 16 to 17 years of age, there was 1 participant in the vaccine group who experienced an SAE of facial bones fracture, which was not considered related to study intervention by the investigator.

 

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Suspected COVID-19 Cases

As specified in the protocol, suspected cases of symptomatic COVID-19 that were not PCR- confirmed were not recorded as adverse events unless they met regulatory criteria for seriousness. Two serious cases of suspected but unconfirmed COVID-19 were reported, both in the vaccine group, and narratives were reviewed. In one case, a 36-year-old male with no medical comorbidities experienced fever, malaise, nausea, headache and myalgias beginning on the day of Dose 2 and was hospitalized 3 days later for further evaluation of apparent infiltrates on chest radiograph and treatment of dehydration. A nasopharyngeal PCR test for SARS-CoV-2 was negative on the day of admission, and a chest CT was reported as normal. The participant was discharged from the hospital 2 days after admission. With chest imaging findings that are difficult to reconcile, it is possible that this event represented reactogenicity following the second vaccination, a COVID-19 case with false negative test that occurred less than 7 days after completion of the vaccination series, or an unrelated infectious process. In the other case, a 66-year-old male with no medical comorbidities experienced fever, myalgias, and shortness of breath beginning 28 days post-Dose 2 and was hospitalized one day later with abnormal chest CT showing a small left-sided consolidation. He was discharged from the hospital 2 days later, and multiple nasopharyngeal PCR tests collected over a 10-day period beginning 2 days after symptom onset were negative. It is possible, though highly unlikely, that this event represents a COVID-19 case with multiple false negative tests that occurred more than 7 days after completion of the vaccination regimen, and more likely that it represents an unrelated infectious process.

Among 3410 total cases of suspected but unconfirmed COVID-19 in the overall study population, 1594 occurred in the vaccine group vs. 1816 in the placebo group. Suspected COVID-19 cases that occurred within 7 days after any vaccination were 409 in the vaccine group vs. 287 in the placebo group. It is possible that the imbalance in suspected COVID-19 cases occurring in the 7 days postvaccination represents vaccine reactogenicity with symptoms that overlap with those of COVID-19. Overall though, these data do not raise a concern that protocol-specified reporting of suspected, but unconfirmed COVID-19 cases could have masked clinically significant adverse events that would not have otherwise been detected.

Subgroup Analyses

There were no specific safety concerns identified in subgroup analyses by age, race, ethnicity, medical comorbidities, or prior SARS-CoV-2 infection, and occurrence of solicited, unsolicited, and serious adverse events in these subgroups were generally consistent with the overall study population.

Pregnancies

Female study participants of childbearing potential were screened for pregnancy prior to each vaccination, with a positive test resulting in exclusion or discontinuation from study vaccination. The study is collecting outcomes for all reported pregnancies that occur after vaccination, or before vaccination and not detected by pre-vaccination screening tests. Twenty-three pregnancies were reported through the data cut-off date of November 14, 2020 (12 vaccine, 11 placebo). Study vaccination occurred prior to the last menstrual period (LMP) in 5 participants (4 vaccine, 2 placebo), within 30 days after LMP in 8 participants (4 vaccine, 6 placebo), >30 days after LMP in 1 participant (0 vaccine, 2 placebo), and date of LMP not known in 5 participants (4 vaccine, 1 placebo). Unsolicited AEs related to pregnancy include spontaneous abortion and retained products of conception, both in the placebo group. Pregnancy outcomes are otherwise

 

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unknown at this time.

Clinical Laboratory Evaluations

Clinical laboratory tests (hematology, chemistries) were assessed in study BNT162-01 and C4591001 phase 1. The only common laboratory abnormality reported throughout the studies was transient decreases in lymphocytes 1-3 days after Dose 1, which increased in frequency with increasing dose, were mostly Grade 1-2, generally normalized at the next laboratory assessment 6-8 days after Dose 1 and did not occur after Dose 2. Among C4591001 phase 1 participants who received the 30 μg dose of BNT162b2, transient decreases in lymphocytes post-Dose 1 occurred in 5 of 12 participants 18-55 years of age and in 4 of 12 participants 65-85 years of age. These transient hematological changes were not associated with clinical symptoms.

Safety Summary

The information provided by the Sponsor was adequate for review and to make conclusions about the safety of BNT162b2 in the context of the proposed indication and population for intended use under EUA. The number of participants in the phase 2/3 safety population (N=37586; 18801 vaccine,18785 placebo) meets the expectations in FDA’s Guidance on Development and Licensure of Vaccines to Prevent COVID-19 for efficacy, and the median duration of at least 2 months follow-up after completion of the 2-dose primary vaccination series meets the agency’s expectations in FDA’s Guidance on its Emergency Use Authorization for Vaccines to Prevent COVID-19. The all-enrolled population contained more participants >16 years of age, regardless of duration of follow-up (43448; 21720 vaccine, 21728 placebo). The demographic and baseline characteristics of the all-enrolled population and the safety population were similar. Although the overall median duration of follow-up in the all-enrolled population was less than 2 months, because the protocol was amended to include subpopulations such as individuals with HIV and adolescents, the data from both populations altogether provide a comprehensive summary of safety.

Local site reactions and systemic solicited events after vaccination were frequent and mostly mild to moderate. The most common solicited adverse reactions were injection site reactions (84.1%), fatigue (62.9%), headache (55.1%), muscle pain (38.3%), chills (31.9%), joint pain (23.6%), fever (14.2%); severe 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 adults ≥55 years of age (≤2.8%) as compared to younger participants (≤4.6%). Among adverse events of special interest, which could be possibly related to vaccine, lymphadenopathy was reported in 64 participants (0.3%): 54 (0.5%) in the younger (16 to 55 years) age group; 10 (0.1%) in the older (>55 years) age group; and 6 in the placebo group. The average duration of these events was approximately 10 days, with 11 events ongoing at the time of the data cutoff. Bell’s palsy was reported by four vaccine participants. From Dose 1 through 1 month after Dose 2, there were three reports of Bell’s palsy in the vaccine group and none in the placebo group. This observed frequency of reported Bell’s palsy is consistent with the expected background rate in the general population. There were no other notable patterns or numerical imbalances between treatment groups for specific categories of non-serious adverse events (including other neurologic, neuro-inflammatory, and thrombotic events) that would suggest a causal relationship to BNT162b2 vaccine.

A total of six deaths occurred in the reporting period (2 deaths in the vaccine group, 4 in placebo). In the vaccine group, one participant with baseline obesity and pre-existing atherosclerosis died 3 days after Dose 1, and the other participant experienced cardiac arrest

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60 days after Dose 2 and died 3 days later. Of the four deaths in the placebo arm, the cause was unknown for two of them, and the other two participants died from hemorrhagic stroke (n=1) and myocardial infarction (n=1), respectively; three deaths occurred in the older group (>55 years of age). All deaths represent events that occur in the general population of the age groups where they occurred, at a similar rate.

The frequency of non-fatal serious adverse events was low (<0.5%), without meaningful imbalances between study arms. The most common SAEs in the vaccine arm which were numerically higher than in the placebo arm were appendicitis (0.04%), acute myocardial infarction (0.02%), and cerebrovascular accident (0.02%), and in the placebo arm numerically higher than in the vaccine arm were pneumonia (0.03%), atrial fibrillation (0.02%), atrial fibrillation (0.02%) and syncope (0.02%). Appendicitis was the most common SAE in the vaccine arm. There were 12 participants with SAEs of appendicitis; 8 in the BNT162b2 group. Of the 8 total appendicitis cases in the BNT162b2 group, 6 occurred in the younger (16 to 55 years) age group and 2 occurred in the older (>55 years) age group (one of the cases in the older age group was perforated). One of the 6 participants with appendicitis in the younger age group also had a peritoneal abscess. Cases of appendicitis in the vaccine group were not more frequent than expected in the general population.

6. Sponsor’s Plans for Continuing Blinded, Placebo-Controlled Follow-Up

The Sponsor plans to offer vaccination to participants ≥16 years of age who originally received placebo and who become eligible for receipt of BNT162b2 according to local or national recommendations. The Sponsor proposes that these participants will be unblinded upon request and will have the opportunity to receive BNT162b2 as part of the study. The Sponsor also proposes that all placebo recipients ≥16 years of age will be offered BNT162b2 after completing 6 months of follow-up after Dose 2, if they did not request and receive vaccine previously. The participants will provide consent to receive vaccination and to continue follow- up. For these participants, the Sponsor plans a total follow up period of 18 months, with one visit 1-month postvaccination and subsequent phone contacts at 1, 6, and 18 months postvaccination. Safety and efficacy monitoring during this period will include collection of AEs, SAEs, and screening and diagnosing COVID-19 cases.

7. Pharmacovigilance Activities

Pfizer submitted a Pharmacovigilance Plan (PVP) to monitor safety concerns that could be associated with Pfizer-BioNTech COVID-19 Vaccine. The Sponsor identified vaccine-associated enhanced disease including vaccine-associated enhanced respiratory disease as an important potential risk. Use in pregnancy and lactation and vaccine effectiveness are areas the Sponsor identified as missing information. In addition to the safety concerns specified by the Sponsor, FDA requested that the Sponsor update their PVP to include missing information in pediatric participants less than 16 years of age.

The Sponsor will conduct both passive and active surveillance activities for continued vaccine safety monitoring. Passive surveillance activities will include submitting spontaneous reports of the following events to the Vaccine Adverse Event Reporting System (VAERS) within 15 days:

• Vaccine administration errors whether or not associated with an adverse event • Serious adverse events (irrespective of attribution to vaccination)
• Cases of Multisystem Inflammatory Syndrome in children and adults
• Cases of COVID-19 that result in hospitalization or death

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The Sponsor will also conduct periodic aggregate review of safety data and submit periodic safety reports at monthly intervals. Each periodic safety report is required to contain descriptive information which includes:

• A narrative summary and analysis of adverse events submitted during the reporting interval, including interval and cumulative counts by age groups, special populations (e.g., pregnant women), and adverse events of special interest

• Newly identified safety concerns in the interval

• Actions taken since the last report because of adverse experiences (e.g., changes made
to Vaccination Provider fact sheets, changes made to studies or studies initiated)
Sponsor studies will include completion of long-term follow-up from ongoing clinical trials as well as the following three planned active surveillance studies. Of note, the Sponsor will submit plans for a clinical study to assess safety and immunogenicity in pregnant women and has proposed active surveillance studies designed to monitor vaccination during pregnancy within populations expected to receive the vaccine under EUA.

• Study Protocol Number C4591008. The Sponsor proposes to survey 20,000 U.S. health care workers enrolled in the COVID-19 HERO registry as well as health care workers in certain participating health care facilities about adverse events of special interest, and other clinically significant events of interest after vaccination with the Pfizer-BioNTech COVID-19 Vaccine. Incidence rates of these events in this cohort will be compared to expected rates. The respondents would receive follow-up surveys for a 30-month period.

• Study Protocol Number C4591011. This study is an active safety surveillance evaluation conducted within the Department of Defense Health System Databases using data derived from electronic health records and medical service claims among covered U.S. military and their families. Rates of safety events of interest in vaccinated participants will be compared to unvaccinated comparators. The study will be conducted for 30 months.

• Study Protocol Number C4591012. This study is an active surveillance study for adverse events of special interest and other clinically significant events associated with the Pfizer-BioNTech COVID-19 Vaccine using the Veteran’s Health Administration electronic medical record database. Vaccinated participants will be compared to unvaccinated participants or to recipients of seasonal influenza vaccine. The study will be conducted for 30 months.
Currently, the primary objective of all three proposed studies above is descriptive, and the list of adverse events in the studies has not been finalized. FDA will provide feedback on these studies after further review.
Reporting to VAERS and Pfizer, Inc.
Providers administering the Pfizer-BioNTech COVID-19 Vaccine must report to VAERS (as required by the National Childhood Vaccine Injury Act) and to Pfizer the following information associated with the vaccine of which they become aware:
• Vaccine administration errors whether or not associated with an adverse event • Serious adverse events (irrespective of attribution to vaccination)
• Cases of Multisystem Inflammatory Syndrome in children and adults
• Cases of COVID-19 that result in hospitalization or death

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Additional VAERS Reporting

An additional source of VAERS reports will be through a program administered by the CDC known as v-safe. V-safe is a new smartphone-based opt-in program that uses text messaging and web surveys from CDC to check in with vaccine recipients for health problems following COVID-19 vaccination. The system also will provide telephone follow-up to anyone who reports medically significant (important) adverse events. Responses indicating missed work, inability to do normal daily activities, or that the recipient received care from a doctor or other healthcare professional will trigger the VAERS Call Center to reach out to the participant and collect information for a VAERS report, if appropriate.

8. Benefit/Risk Assessment in the Context of Proposed Indication and Use Under EUA 8.1. Known Benefits

The known benefits among recipients of the proposed vaccine relative to placebo are:

• Reduction in the risk of confirmed COVID-19 occurring at least 7 days after Dose 2

• Reduction in the risk of confirmed COVID-19 after Dose 1 and before Dose 2

• Reduction in the risk of confirmed severe COVID-19 any time after Dose 1
The protocol-specified 2-dose vaccination regimen was highly effective in preventing PCR- confirmed COVID-19 occurring at least 7 days after completion of the vaccination regimen. Additional primary efficacy analyses in the all-available efficacy population, including participants who had protocol violations, showed consistency with outcomes in the primary analysis population. Efficacy findings were also consistent across various subgroups, including racial and ethnic minorities, participants aged 65 years and older, and those with one or more of the following conditions: obesity, diabetes, hypertension, and chronic cardiopulmonary diseases. While limited, available data suggest that individuals with previous SARS-CoV-2 infection can be at risk of COVID-19 (i.e., re-infection) and may benefit from vaccination.
Among participants with no evidence of COVID-19 prior to vaccination, the vaccine was effective in reducing the risk of COVID-19 and severe COVID-19 after Dose 1. Fewer severe cases were also observed in the vaccine recipients relative to recipients of placebo during the follow up period after Dose 1. The findings post Dose 1, from a post-hoc analysis, cannot be the basis to assess the potential efficacy of the vaccine when administered as a single dose because the period of observation is limited by the fact that most participants received a second dose three weeks after the first one.
8.2. Unknown Benefits/Data Gaps Duration of protection
As the interim and final analyses have a limited length of follow-up, it is not possible to assess sustained efficacy over a period longer than 2 months.
Effectiveness in certain populations at high-risk of severe COVID-19
Although the proportion of participants at high risk of severe COVID-19 is adequate for the overall evaluation of safety in the available follow-up period, the subset of certain groups such as immunocompromised individuals (e.g., those with HIV/AIDS) is too small to evaluate efficacy outcomes.

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Effectiveness in individuals previously infected with SARS-CoV-2

The primary endpoint was evaluated in individuals without prior evidence of COVID-19 disease, and very few cases of confirmed COVID-19 occurred among participants with evidence of infection prior to vaccination (although more cases occurred in the placebo group compared with the vaccine group). Therefore, available data are insufficient to make conclusions about benefit in individuals with prior SARS-CoV-2 infection. However, available data, while limited, do suggest that previously infected individuals can be at risk of COVID-19 (i.e., reinfection) and could benefit from vaccination.

Effectiveness in pediatric populations

The representation of pediatric participants in the study population is too limited to adequately evaluate efficacy in pediatric age groups younger than 16 years. No efficacy data are available from participants ages 15 years and younger. Although adolescents 16 to 17 years of age were included in the overall efficacy analysis, only one confirmed COVID-19 case was reported in this age group. However, it is biologically reasonable to extrapolate that effectiveness in ages 16 to 17 years would be similar to effectiveness in younger adults. Efficacy surveillance continued beyond November 14, 2020, and the Sponsor has represented that additional data will be provided in a BLA.

Future vaccine effectiveness as influenced by characteristics of the pandemic, changes in the virus, and/or potential effects of co-infections

The study enrollment and follow-up occurred during the period of July 27 to November 14, 2020, in various geographical locations. The evolution of the pandemic characteristics, such as increased attack rates, increased exposure of subpopulations, as well as potential changes in the virus infectivity, antigenically significant mutations to the S protein, and/or the effect of co- infections may potentially limit the generalizability of the efficacy conclusions over time. Continued evaluation of vaccine effectiveness following issuance of an EUA and/or licensure will be critical to address these uncertainties.

Vaccine effectiveness against asymptomatic infection

Data are limited to assess the effect of the vaccine against asymptomatic infection as measured by detection of the virus and/or detection of antibodies against non-vaccine antigens that would indicate infection rather than an immune response induced by the vaccine. Additional evaluations will be needed to assess the effect of the vaccine in preventing asymptomatic infection, including data from clinical trials and from the vaccine’s use post-authorization.

Vaccine effectiveness against long-term effects of COVID-19 disease

COVID-19 disease may have long-term effects on certain organs, and at present it is not possible to assess whether the vaccine will have an impact on specific long-term sequelae of COVID-19 disease in individuals who are infected despite vaccination. Demonstrated high efficacy against symptomatic COVID-19 should translate to overall prevention of COVID-19- related sequelae in vaccinated populations, though it is possible that asymptomatic infections may not be prevented as effectively as symptomatic infections and may be associated with sequelae that are either late-onset or undetected at the time of infection (e.g., myocarditis). Additional evaluations will be needed to assess the effect of the vaccine in preventing long-term effects of COVID-19, including data from clinical trials and from the vaccine’s use post- authorization.

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Vaccine effectiveness against mortality

A larger number of individuals at high risk of COVID-19 and higher attack rates would be needed to confirm efficacy of the vaccine against mortality. However, non-COVID vaccines (e.g., influenza) that are efficacious against disease have also been shown to prevent disease- associated death.11-14 Benefits in preventing death should be evaluated in large observational studies following authorization.

Vaccine effectiveness against transmission of SARS-CoV-2

Data are limited to assess the effect of the vaccine against transmission of SARS-CoV-2 from individuals who are infected despite vaccination. Demonstrated high efficacy against symptomatic COVID-19 may translate to overall prevention of transmission in populations with high enough vaccine uptake, though it is possible that if efficacy against asymptomatic infection were lower than efficacy against symptomatic infection, asymptomatic cases in combination with reduced mask-wearing and social distancing could result in significant continued transmission. Additional evaluations including data from clinical trials and from vaccine use post-authorization will be needed to assess the effect of the vaccine in preventing virus shedding and transmission, in particular in individuals with asymptomatic infection.

8.3. Known Risks

The vaccine has been shown to elicit increased local and systemic adverse reactions as compared to those in the placebo arm, usually lasting a few days. The most common solicited adverse reactions were injection site reactions (84.1%), fatigue (62.9%), headache (55.1%), muscle pain (38.3%), chills (31.9%), joint pain (23.6%), fever (14.2%). Adverse reactions characterized as reactogenicity were generally mild to moderate. The number of subjects reporting hypersensitivity-related adverse events was numerically higher in the vaccine group compared with the placebo group (137 [0.63%] vs. 111 [0.51%]). Severe adverse reactions occurred in 0.0-4.6% of participants, were more frequent after Dose 2 than after Dose 1 and were generally less frequent in older adults (>55 years of age) (<2.8%) as compared to younger participants (≤4.6%). Among reported unsolicited adverse events, lymphadenopathy occurred much more frequently in the vaccine group than the placebo group and is plausibly related to vaccination.

Serious adverse events, while uncommon (<1.0%), represented medical events that occur in the general population at similar frequency as observed in the study. Three SAEs in the BNT162b2 group were considered related by the investigator, but not the Sponsor, as related to study vaccination: shoulder injury (n=1), ventricular arrhythmia in a participant with known cardiac conditions (n=1), and lymphadenopathy temporally related following vaccination (n=1). We considered two of the events as possibly related to vaccine: the shoulder injury possibly due to vaccine administration or the vaccine itself and lymphadenopathy. Lymphadenopathy was temporally associated and biologically plausible.

No specific safety concerns were identified in subgroup analyses by age, race, ethnicity, medical comorbidities, or prior SARS-CoV-2 infection. Although participants 16 to 17 years of age were enrolled in the phase 3 trial, safety data for this age group is limited. However, available data are consistent with the safety profile in the adult population, and it is biologically reasonable to extrapolate the greater safety experience in adults, in particular younger adults, to the oldest pediatric age group of 16 to 17 years.

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8.4. Unknown Risks/Data Gaps Safety in certain subpopulations

There are currently insufficient data to make conclusions about the safety of the vaccine in subpopulations such as children less than 16 years of age, pregnant and lactating individuals, and immunocompromised individuals.

Adverse reactions that are very uncommon or that require longer follow-up to be detected

Following authorization of the vaccine, use in large numbers of individuals may reveal additional, potentially less frequent and/or more serious adverse events not detected in the trial safety population of nearly 44,000 participants over the period of follow up at this time. Active and passive safety surveillance will continue during the post authorization period to detect new safety signals.

A numerically greater number of appendicitis cases occurred in the vaccine group but occurred no more frequently than expected in the given age groups and do not raise a clear concern at this time for a causal relationship to study vaccination. Although the safety database revealed an imbalance of cases of Bell’s palsy (4 in the vaccine group and none in the placebo group), causal relationship is less certain because the number of cases was small and not more frequent than expected in the general population. Further signal detection efforts for these adverse events will be informative with more widespread use of the vaccine.

Vaccine-enhanced disease

Available data do not indicate a risk of vaccine-enhanced disease, and conversely suggest effectiveness against severe disease within the available follow-up period. However, risk of vaccine-enhanced disease over time, potentially associated with waning immunity, remains unknown and needs to be evaluated further in ongoing clinical trials and in observational studies that could be conducted following authorization and/or licensure.

9. References

1. Zhu N, Zhang D, Wang W, et al. A Novel Coronavirus from Patients with Pneumonia in China, 2019. The New England journal of medicine. 2020;382(8):727-733.

2. Coronaviridae Study Group of the International Committee on Taxonomy of V. The species Severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2.

3. Lu R, Zhao X, Li J, et al. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet (London, England). 2020;395(10224):565-574.

4. Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. 2020;181(2):271-280.e278.

5. Federal Food, Drug and Cosmetic Act, 21 U.S.C. § 360bbb–3 and 360bbb-3b. (2011).

6. FDA. Guidance for Industry: Development and Licensure of Vaccines to Prevent COVID-
19. June 2020. https://www.fda.gov/regulatory-information/search-fda-guidance- documents/development-and-licensure-vaccines-prevent-covid-19.

 

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7. National Vaccine Injury Compensation Program. Vaccine Injury Table, Revised and Effective March 21, 2017. https://www.hrsa.gov/sites/default/files/hrsa/vaccine- compensation/vaccine-injury-table.pdf.

8. International Coalition of Medicines Regulatory Authorities. Statement on continuation of vaccine trials. http://www.icmra.info/drupal/en/covid-
19/statement on continuation of vaccine trials. 2020.

9. Krause PR, Fleming TR, Longini IM, et al. Placebo-Controlled Trials of Covid-19 Vaccines – Why We Still Need Them. The New England journal of medicine. 2020.

10. Wendler D, Ochoa J, Millum J, Grady C, Taylor HA. COVID-19 vaccine trial ethics once we have efficacious vaccines. Science. 2020:eabf5084.

11. Roush SW, Murphy TV, Vaccine-Preventable Disease Table Working Group, the. Historical Comparisons of Morbidity and Mortality for Vaccine-Preventable Diseases in the United States. JAMA. 2007;298(18):2155-2163.

12. Verhees RAF, Dondorp W, Thijs C, Dinant GJ, Knottnerus JA. Influenza vaccination in the elderly: Is a trial on mortality ethically acceptable? Vaccine. 2018;36(21):2991-2997.

13. Flannery B, Reynolds SB, Blanton L, et al. Influenza Vaccine Effectiveness Against Pediatric Deaths: 2010–2014. 2017;139(5):e20164244.

14. Rolfes MA, Flannery B, Chung JR, et al. Effects of Influenza Vaccination in the United States During the 2017-2018 Influenza Season. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2019;69(11):1845-1853.

   

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10. Appendix A. Study BNT162-01

Design

Study BNT162-01 is an ongoing, first-in-human, phase 1 dose-level finding study conducted in Germany to evaluate the safety and immunogenicity of several different candidate vaccines, including BNT162b2. Twelve adults 18 to 55 years of age received 30ug BNT162b2.

Secondary and exploratory objectives were specified to describe the immune response, measured by functional antibody titer, antibody binding assay, and cell-mediated immune responses (cytokines associated with Th1 and Th2 responses to assess for the induction of a balanced versus Th1 or Th2 dominant immune response) at baseline and various time points after vaccination, specifically 7 days post Dose 2. Adverse event monitoring was the same as in study C4591001.

Results

No SAEs were reported in the BNT162-01 safety database included in the EUA submission, and the safety profile for BNT162b2 in this study was similar to that in the much larger study, C4591001.

Evaluable ELISPOT data were available from 39 participants across dose levels of BNT162b2 (data cutoff date was 17 September 2020). Evaluable intracellular cytokine staining and FACS data were available from 36 participants across dose levels of BNT162b2 (cutoff date was 04 September 2020). Data for serology results for serum neutralizing titers were available for 45 participants across dose levels of BNT162b2 (data cutoff date was 18 September 2020).

Most participants who received both doses of BNT162b2 had evidence of SARS-CoV-2 S protein-specific CD4+ (39/39, 100%) and CD8+ (35/39, 89.7%) T cell responses. These T cell responses were directed against different parts of the antigen, including epitopes in the RBD, indicating the induction of multi-epitope responses by BNT162b2. Functionality and polarization of S-specific BNT162b2-induced SARS-CoV-2 T cells were assessed by intracellular accumulation of cytokines IFNγ, IL-2, and IL-4 measured after stimulation with overlapping peptide pools representing the full-length sequence of the whole SARS-CoV-2 S protein. For benchmarking, PBMC fractions from 15 convalescent patients with virologically confirmed COVID-19 were used. The Th1 polarization of the T helper response was characterized by the IFNγ and IL-2 production, and only minor IL-4, production upon antigen-specific (SARS-CoV-2 S protein peptide pools) re-stimulation. The SARS-CoV-2 neutralizing geometric mean titer (GMTs) increased over baseline after Dose 1, with a boost effect after Dose 2 that was most pronounced at the 30 μg dose level.

Thus, the immunogenicity results from Study BNT162-01 showed evidence of antibody- mediated SARS-CoV-2 neutralization and a Th1 polarization in the cell-mediated cellular immune responses in healthy adults 18 to 55 years of age, which supports the final dose selection and prospect of benefit for the enrollment of larger numbers of participants in Study C4591001.

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Pfizer-BioNTech COVID-19 Vaccine VRBPAC Briefing Document

11. Appendix B. Charlson Comorbidity Index

This index is based on a list of 19 conditions identified from diagnoses in hospital and physician data. Each condition is assigned a weight from 1 to 6. The index score is the sum of the weights for all identified conditions (Charlson et al., 1987). An index score of 0 indicates no comorbid conditions, while higher scores indicate a greater level of comorbidity.

Charlson Index Diagnoses: Cancer, Chronic Pulmonary Disease, Diabetes without Complications, Congestive Heart Failure, Cerebrovascular Disease, Dementia, Renal Disease, Peripheral Vascular Disease, Myocardial Infarction, Diabetes with Complications, Paraplegia and Hemiplegia, Connective Tissue Disease-Rheumatic Disease, Peptic Ulcer Disease, Mild Liver Disease, Metastatic Carcinoma, Moderate or Severe Liver Disease, HIV/AIDS.

Reference: Charlson ME, Pompei P, Ales KL, et al. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987; 40(5):373– 383. [PubMed: 3558716]

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Pfizer-BioNTech COVID-19 Vaccine VRBPAC Briefing Document

12. Appendix C. Guidance for Industry: Emergency Use Authorization for Vaccines to Prevent COVID-19

Emergency Use Authorization for Vaccines to Prevent COVID-19

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