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Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
STN:125742
i
BLA Clinical Review Memorandum *
Application Type Biologics Licen se Application (BLA)
STN 125742 /0
CBER Received Date May 18, 2021
PDUFA Goal Date January 16, 2022
Division / Office DVRPA / OVRR
Priority Review (Yes/No) Yes
Reviewer Name(s)
Susan Wollersheim, MD
Ann Schwartz, MD
Review Completion Date /
Stamped Date August 23, 2021
Supervisory Concurrence
Lucia Lee, M.D.; Team Leader
CRB1/DVRPA/OVRR
Maria Allende, M.D.; Chief,
CRB1/DVRPA/OVRR
Applicant BioNTech Manufacturing GmbH (in partnership
with Pfizer, Inc.)
Established Name COVID -19 Vaccine , mRNA
(Proposed) Trade Name COMIRNATY
Pharmacologic Class Vaccine
Formulation, including Adjuvants Each 0.3 mL dose contains 30ug modified
mRNA encoding SARS -CoV -2 spike
glycoprotein, encapsulat ed in lipid nanoparticles
(LNP)
Dosage Form and Route of
Administration Suspension for intramu scular injection
Dosing Regimen Two 0.3 mL doses, 3 weeks apart
Indication(s) and Intended
Population(s) Active immunization to prevent coronavirus
disease 2019 (COVID -19) caused by severe
acute respiratory syndrome coronavirus 2
(SARS- CoV-2) in individuals 16 years of age
and older
Orphan Desi gnated (Yes/No) No
*Updated version of the previously uploaded memo corrected to add safety information
to Sections 6.1.12. 2, 6.1.12.4, and 6.1.12.7 that was inadv ertently omitted but does not
change overall conclusions .
Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
STN:125742
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TABLE OF CONTENTS
GLOSSARY ......................................................................................................................... 4
1. EXECUTIVE SUMMARY ..................................................................................................... 5
1.1 Demographic Information: Subgroup Demographics and Analysis Summary .................... 7
1.2 Patient Experience Data ................................ ................................ ................................ ..... 8
2. CLINICAL AND REGULATORY BACKGROUND .................................................................... 9
2.1 Disease or Health -Related Condition(s) Studied ................................ ................................ 9
2.2 Currently Available, Pharmacologically Unrelated Treatment(s)/Intervention(s) for the
Proposed Indication(s) ................................ ................................ ................................ ...... 10
2.3 Safety and Efficacy of Pharmacologically Related Products ................................ ............ 11
2.4 Previous Human Experience with the Product (Including Foreign Experience) ............... 12
2.5 Summary of Pre- and Post -submission Regulatory Activity Related to the Submission .. 13
2.6 Other Relevant Background Information ................................ ................................ .......... 14
3. SUBMISSION QUALITY AND GOOD CLINICAL PRACTICES ................................................ 14
3.1 Submission Quality and Com pleteness ................................ ................................ ............ 14
3.2 Compliance With Good Clinical Practices And Submission Integrity ............................... 15
3.3 Financial Disclosures ................................ ................................ ................................ ........ 15
4. SIGNIFICANT EFFICACY /SAFETY ISSUES RELATED TO OTHER REVIEW DISCIPLINES ........ 16
4.1 Chemistry, Manufacturing, and Controls ................................ ................................ .......... 16
4.2 Assay Validation ................................ ................................ ................................ ................ 16
4.3 Nonclinical Pharmacology/Toxicology ................................ ................................ .............. 16
4.5 Statistical ................................ ................................ ................................ ........................... 16
4.6 Pharmacovigilance ................................ ................................ ................................ ............ 16
4.7 Risk-Benefit Assessment ................................ ................................ ................................ .. 17
5. SOURCES OF CLINICAL DATA AND OTHER INFORMATION CONSIDERED IN THE REVIEW ... 18
5.1 Review Strategy ................................ ................................ ................................ ................ 18
5.2 BLA/IND Documents That Serve as the Basis for the Clinical Review ............................. 19
5.3 Overview of Clinical Studies ................................ ................................ ............................. 20
5.4 Consultations ................................ ................................ ................................ .................... 21
5.4.1 Advisory C ommittee Meeting ................................ ................................ .................. 21
5.5 Literature Reviewed ................................ ................................ ................................ .......... 21
6. DISCUSSION OF INDIVIDUAL STUDIES /CLINICAL TRIALS .................................................. 23
6.1 Study C4591001 ................................ ................................ ................................ ............... 23
6.1.1 Objectives and Endpoints ................................ ................................ ........................ 24
6.1.2 Design Overview ................................ ................................ ................................ ..... 24
6.1.3 Population ................................ ................................ ................................ ................ 26
6.1.4 Study Treatments or Agents Mandated by the Protocol ................................ ......... 27
6.1.5 Directions for Use ................................ ................................ ................................ .... 27
6.1.6 Sites and Centers ................................ ................................ ................................ .... 27
6.1.7 Surveillance/Monitoring ................................ ................................ ........................... 27
6.1.8 Endpoints and Criteria for Study Success ................................ ............................... 29
6.1.9 Statistical Considerations & Statistical Analysis Plan ................................ ............. 30
6.1.10 Study Population and Disposition ................................ ................................ .......... 31
6.1.11 Efficacy Analyses ................................ ................................ ................................ .. 43
6.1.12 Safety Analyses ................................ ................................ ................................ ..... 56
6.1.13 Stu dy Summary and Conclusions ................................ ................................ ......... 81
Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
STN:125742
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6.2 Study BNT162 -01 .............................................................................................................. 82
7. INTEGRATED OVERVIEW OF EFFICACY ........................................................................... 83
8. INTEGRATED OVERVIEW OF SAFETY .............................................................................. 83
9. ADDITIONAL CLINICAL ISSUES ....................................................................................... 83
9.1 Special Populations ........................................................................................................... 83
9.1.1 Human Reproduction and Pregnancy Data ............................................................. 83
9.1.2 Use During Lactation ............................................................................................... 85
9.1.3 Pediatric Use and PREA Considerations ................................................................ 85
9.1.4 Immunocompromised Individuals ............................................................................ 85
9.1.5 Geriatric Use ............................................................................................................ 86
9.1.6 Patients with Human Immunodeficiency Virus (HIV) Infection ................................ 86
10. CONCLUSIONS ............................................................................................................ 92
11. RISK-BENEFIT CONSIDERATIONS AND RECOMMENDATIONS ......................................... 94
11.1 Risk -Benefit Considerations ............................................................................................ 94
11.2 Risk -Benefit Summary and Assessment ........................................................................ 98
11.3 Discussion of Regulatory Options ................................................................................. 100
11.4 Recommendations on Regulatory Actions .................................................................... 101
11.5 Labeling Review and Recommendations ..................................................................... 101
11.6 Recommendations on Postmarketing Actions .............................................................. 101
APPENDIX A CHARLSON COMORBIDITY INDEX ................................................................. 103
APPENDIX B CARDIAC DISORDERS FROM DOSE 1 TO DATE OF UNBLINDING AMONG PHASE
2/3 PARTICIPANTS 16 YEARS OF AGE AND OLDER ........................................................ 104
APPENDIX C DEATH NARRATIVES ................................................................................... 106
Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
STN:125742
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GLOSSARY
AE adverse event
AESI adverse event of special interest
BLA Biologics License Application
BNT162b2 Pfizer -BioNTech COVID -19 Vaccine
CBER Center for Biologics Evaluation and Research
CDC Centers for Disease Control and Prevention
CI confidence interval
CMC chemistry, manufacturing, and controls
COVID -19 coronavirus disease 2019
DVT deep vein thrombosis
EUA emergency use authorization
FDA Food and Drug Administrati on
FDCA Federal Food, Drug, and Cosmetic Act
HIV human immunodeficiency virus
IA interim analysis
ICU intensive care unit
IRC Internal Review Committee
IRR incidence rate ratio
LNP lipid nanoparticle
MedDRA Medical Dictionary for Regulatory Activities
MIS-A m ultisystem inflammatory syndrome in children
MIS-C m ultisystem inflammatory syndrome in adults
NAAT nucleic acid amplification -based test
PD protocol deviation
PE pulmonary embolism
PMC p ostmarketing commitment
PMR postmarketing requirement
PREA Pediatric Research Equity Act
PT Preferred Term
PVP Pharmacovigilance Plan
RT-PCR reverse transcription-polymerase chain reaction
SAE serious adverse event
SARS- CoV-2 severe acute respiratory syndrome coronavirus 2
SMQ Standardised MedDRA Query
SOC System Organ Class
Th1 T helper type 1
TTS thrombosis with thrombocytopenia syndrome
US United States
VAERS Vaccine Adverse Event Reporting System
VE vaccine efficacy
VOC variant of concern
VOI variant of interes t
VRBPAC Vaccines and Related Biological Products Advisory Committee
VSD Vaccine Safety Datalink
WHO World Health Organization
Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
STN:125742
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1. Executive Summary
BioNTech Manufacturing GmbH, Inc. submitted a Biologics License Application (BLA)
for BNT162b2 (30 μg) vaccine (COMIRNATY) and is seeking an indication for active
immunization to prevent COVID-19 caused by severe acute respiratory syndrome
coronavirus 2 (S ARS-CoV-2) in individuals 16 years of age and older. The primary
immunization series consists of 2 intramuscular doses administered 3 weeks apart.
BNT162b2 contains SARS-CoV -2 spike glycoprotein (S) antigens encoded in RNA
formulated in lipid nanoparticles (LNPs). The structural elements of BNT162b2 are
modified for translation of the antigen -encoding RNA. Encapsulation of the vaccine
mRNA into LNPs has been done to
.
Study C4591001, the main study to support the safety and efficacy of BNT162b2, is an ongoing multinational, randomized, clinical trial in a total of 44,165 participants ( 22,085
BNT162b2, 22, 080 saline placebo) 16 years of age and older. A primary objective was
to evaluate the efficacy of BNT162b2 to prevent laboratory -confirmed symptomatic
COVID -19 occurring ≥7 days after Dose 2 in participants without serological or
virological evidence of past SARS -CoV -2 infection before and during the vaccination
regimen. The central laboratory nucleic acid amplification-based test (NAA T) result is
used for the case definition, with a NAAT test that is authorized under FDA emergency
use authorization (EUA ). Vaccine efficacy (VE) against severe disease was evaluated
as a secondary endpoint. Planned safety analyses included evaluation of: 1) local
reactions, systemic events, and antipyretic/pain medication use from Day 1 through Day
7 after each dose in a subset of participants (approximately 4,900 per treatment group) ;
2) non-serious unsolicited adverse events from Dose 1 through 1 month after Dose 2 in
all participants ; 3) serious adverse events from Dose 1 through 6 months after Dose 2
in all participants ; and deaths and related serious adverse events from Dose 1 through
the end of the study in all participants .
Efficacy and safety data accumulated in the study through November 14, 2020, which
included median follow- up of 2 months after Dose 2, supported FDA’s December 11,
2020 issuance of an EUA for use of BNT162b2 in individuals 16 years of age and older.
Following issuance of the EUA, study participants 16 years of age and older were
progressively unblinded to their treatment assignment (when eligible for vaccination per
national and local public health prioritization recommendations) , and placebo recipients
could choose to receive BNT162b2 with continued active unblinded follow -up in the
study . This BLA submission included updated efficacy analyses of COVID -19 cases
accrued during blinded placebo-controlled follow -up through March 13, 2021,
representing up to 6 months of follow up after Dose 2 for participants in the efficacy
population. The median follow-up after Dose 2 of all participants in the blinded placebo-
controlled period was 4.3 months. U pdated safety analyses included in the BLA
submission evaluated data accumulated in both blinded and unblinded follow -up
through March 13, 2021. The BLA safety database included >12,000 study participants
originally randomized to BNT162b2 who completed least 6 months of total safety follow -
up after Dose 2.
As of the March 13, 2021 data cutoff, the efficacy population 16 years of age and older
who did not have evidence of SARS -CoV-2 infection through 7 days after the second
dose included N=40,111 participants (19,993 BNT162b2, 20, 118 placebo). The updated
efficacy analyses showed that VE in preventing symptomatic COVID -19 occurring ≥7
(b) (4)
Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
STN:125742
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days after Dose 2 was 91.1% [95% CI 88.8, 93.1]) in participants without evidence of
SARS- CoV-2 infection and 90.9% (95%CI 88.5, 92.8) in participants with or without
evidence of SARS -CoV-2 infection. These results were consistent with the VE in the
protocol -specified event- driven final analyses that supported issuance of the EUA (VE
95% and 94.6%, respectively). The updated analyses of VE against severe COVID -19
in preventing symptomatic COVID-19 occurring ≥7 days after Dose 2 was 95.3% (95%
CI: 71.0%, 99.9%) in participants without evidence of SARS- CoV-2 infection and 95.3%
(95% CI: 70.9 %, 99.9%) in participants with or without evidence of SARS- CoV-2
infection. SARS -CoV -2 variants of concern identified from COVID -19 cases in this study
included B.1.1.7 (Alpha) and B.1.351 (Beta).
The safety population at the March 13, 2021 data cutoff included 22,026 BNT162b2
recipients and 22,021 placebo recipients 16 years of age and older. During the placebo-
controlled phase, the most commonly reported solicited adverse reactions in the BNT162b2 group were pain, redness and swelling at the injection site, fatigue, and
headache. Adverse reactions other than solicited reactogenicity events identified from
the clinical trial data include lymphadenopathy in regional proximity to the vaccination site and potentially Bell’s Palsy (the latter from a small numerical imbalance of
temporally associated events). A slight imbalance in hypersensitivity -related events was
observed during the trial, and hypersensitivity reactions have been reported during
post-authorization use as well . There were otherwise no notable patterns between
treatment groups for specific categories of serious or non-serious adverse events
(including neurologic, neuro-inflammatory, and thrombotic events) that would suggest a causal relationship to BNT162b2. A total of 15 (0.2%) deaths in vaccine recipients and
14 (0.2%) in placebo recipients were reported during blinded, placebo-controlled follow -
up, and an additional 6 deaths were reported during unblinded follow -up following
vaccination with BNT162b2; none of these deaths were assessed to be related to
vaccination. A total of 42 pregnancies were reported by BNT162b2 recipients from
Dose 1 through the data cutoff date. The frequencies of spontaneous abortion, miscarriage, and elective abortion were similar between the vaccine and the placebo
groups.
Post-authorization safety surveillance has identified two rare but serious adverse
reactions: anaphylaxis and myocarditis/pericarditis. T he risk of anaphylaxis associated
with BNT162b2 appears to be similar in magnitude to the risk of anaphylaxis following approved preventive vaccines in general and can be managed with standard
vaccination practices . The risk of myocarditis/pericarditis appears to be greatest in
individuals under the age of 40, in particular in males following Dose 2, and increased
with decreasing age. Although some cases required intensive care support, available
data from short-term follow-up suggest that most individuals have had resolution of
symptoms with conservative management. Information is not yet available about potential long-term sequelae.
To address the identified risk of myocarditis /pericarditis, FDA conducted a quantitative,
age- and sex -stratified benefit-risk analysis , using healthcare claims and CDC
surveillance databases, to evaluate the balance of vaccine benefits (prevention of
COVID -19 hospitalizations, intensive care unit admissions and deaths) against excess
risk of myocarditis/pericarditis under various conditions of COVID -19 incidence and
vaccine effectiveness informed by real-world data. These analyses supported that
based on current understanding of vaccine-associated myocarditis/benefits of vaccination would outweigh risks of myocarditis/pericarditis for individuals 16 years of
Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
STN:125742
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age and older under all conditions examined. Mitigation of the observed risks of
myocarditis/pericarditis and associated uncertainties will be accomplished through
labeling (including warning statements about the risks of vaccine -associated
myocarditis/pericarditis) and through continued safety surveillance and postmarketing
studies to be conducted by the Applicant, US government agencies (including FDA and
CDC), and other healthcare stakeholders.
The clinical data submitted exceed FDA’s expectations for data to support licen sure of
vaccines for prevention of COVID-19, including relevant efficacy success criteria and
numbers of vaccinated study participants and follow -up time (i.e., at least 3,000
vaccinated participants in each age group with at least 6 months of total safety follow -
up) for an acceptable safety database. T he clinical data submitted in this application ,
together with the quantitative benefit -risk assessment summarized in this review,
support approval of BNT162b2 for the indication of active immunization to prev ent
symptomatic coronavirus disease 2019 (COVID 19) caused by severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2) in individuals 16 years of age and older.
Pediatric studies of BNT162b2 in children <16 years of age, as required by the Pediatric Research Equity Act, were deferred for this application and will be completed after
approval of BNT162b2 for use in individuals 16 years of age and older . The Applicant
also committed to conduct additional postmarketing safety studies, including the
assessment of pregnancy and infant outcomes following immunization with BNT162b2 during pregnancy .
1.1 Demographic Information: Subgroup Demographics and Analysis Summary
The table below summarizes demographic representation of study participants who
enrolled in t he Phase 2/3 portion of the ongoing s tudy C4591001 and were randomized
to a two-dose series of BNT162b2 or placebo.
Table 1 . Randomized Participants by Subgroup, Study C4591001
Subgroup BNT162b2 Placebo Total
Age (≥16 years) 22085 22080 44165
16-55 years 13104 13132 26236
>55 years 8981 8948 17929
16-17 years 378 377 755
Gender
Male 11357 11127 22484
Female 10728 10953 21681
Ethnicity
Hispanic/Latino 5715 5710 11425
Non- Hispanic/Non -Latino 16259 16256 32515
Not reported 111 114 225
Race
White 18106 18105 36211
Black/African American 2106 4232 4232
All others 1873 1849 3722
Source: FDA-generated table.
The demographic characteristics of the evaluable efficacy population of 42, 244
participants was 83% White, 50.9% male, and 74.7% non-Hispanic/non- Latino ethnicity.
The younger age group (16-55 years of age) represented 55.8% of the total evaluable
efficacy population, while participants >55 years of age represented 39.5% of the total.
Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
STN:125742
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Subgroup analyses of vaccine efficacy (although limited by small numbers of cases in
some subgroups) did not suggest meaningful differences in efficacy across genders, ethnic groups, geographies, or for participants with obesity or medical comorbidities associated with high risk of severe COVID -19.
The overall safety population was 49.1% female, 50.9% males, 25.6% Hispanic/Latino, 82.0% White, 9.6% African American, 4.3% Asian, <3% other racial groups. The median age was 51 years, and 20.8% were older than 65 years old. The most frequently reported comorbidities were obesity (35.1%), diabetes without chronic
complications (7.8%) and chronic pulmonary disease (7.8%). Geographically,
enrollment included individuals from the United States (US; 76.5%), Argentina (15.3%), Brazil (6.1%), South Africa (2.0%), Turkey (1.0%), and Germany (1.0%). In safety analyses, reported rates of solicited local and systemic ARs and antipyretic /pain
medication use in the 7 days after BNT162b2 vaccinations were generally lower among
older adults (>55 years of age) compared with younger adults and adolescents (16-55
years of age). Other differences between the age groups in overall rates and types of
unsolicited AEs and SAEs largely reflected differences in underlying medical conditions
between the respective age groups (as these AEs were assessed as related to the underlying medical conditions rather than to the vaccine). No clinically meaningful differences in the occurrence of solicited AEs, unsolicited AEs or SAEs were obs erved
by, ethnicity, race, or sex subgroups.
1.2 Patient Experience Data
Data Submitted in the Application
Check if
Submitted
Type of Data Section Where Discussed,
if Applicable
☐ Patient -reported outcome
☐ Observer -reported outcome
☐ Clinician -reported outcome
☐ Performance outcome
☐ Patient -focused drug development meeting
summary
☐ FDA Patient Listening Session
☐ Qualitative studies (e.g., individual
patient/caregiver interviews, focus group
interviews, expert interviews, Delphi Panel)
☐ Observational survey studies
☐ Natural history studies
☐ Patient preference studies
☐ Other: (please specify)
☒ If no patient experience data were submitted
by Applicant, indicate here. N/A
Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
STN:125742
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Check if
Considered
Type of Data Section Where Discussed,
if Applicable
☐ Perspectives shared at patient stakeholder
meeting
☐ Patient -focused drug development meeting
☐ FDA Patient Listening Session
☐ Other stakeholder meeting summary report
☐ Observational survey studies
☐ Other: (please specify)
2. Clinical and Regulatory Background
2.1 Disease or Health-Related Condition(s) Studied
COVID -19 is an infectious disease caused by SARS -CoV -2, a novel, zoonotic
coronavirus , which can cause severe respiratory symptoms, pneumonia, respiratory
failure, multi -organ failure, and death. Disease symptoms vary, with many persons
presenting with asymptomatic or mild disease and some progressing to sever e
respiratory tract disease including pneumonia and acute respiratory distress syndrome,
leading to multiorgan failure and death. Elderly individuals ( in particular men >60 years
of age) and those with several underlying medical conditions, including obesi ty,
diabetes, asthma, chronic kidney disease, hypertension, and immunosuppression, have
been reported to be at increased risk for severe illness from COVID -19. Multisystem
inflammatory syndrome in both children (MIS -C) and adults (MIS-A) is a rare but
serious COVID -19-associated condition that can present with persistent fever,
laboratory markers of inflammation and heart damage, and, in severe cases, hypotension and shock (CDC 2021a; CDC Advisory Committee on Immunization
Practices 2021a).
The first recorded COVID -19 cases were reported in December 2019 in Wuhan, China.
During January 2020 c ases were reported from several other countries, including the
United States. The first case report of novel coronavirus 2019 (2019-nCov) in the
United States was published on January 31, 2020 in the New England Journal of
Medicine (Holshue et al. 2020). On January 31, 2020, the United States Secretary of
Health and Human Services made the declaration that COVID -19 constitutes a
nationwide public health emergency . On March 11, 2020, the World Health
Organization (WHO) declared the COVID -19 outbreak a pandemic.
The severe acute respiratory syndrome coronavirus 2 (SARS -CoV -2) pandemic
continues to present a challenge to global health and, at the time of this review, has
caused approximately 20 9 million cases of COVID -19, including 4.4 million deaths
worldwide (World Health Organization 2021a). In the United States (US), more than 37
million cases have been reported to the Centers for Disease Control and Prevention
(CDC) , of which 90% have occurred in individuals 16 years of age or older . While the
pandemic has caused morbidity and mortality on an individual level, the continuing
spread of SARS -CoV -2 and variants has caused significant challenges and disruptions
worldwide to healthcare systems, economies, and many aspects of human activity
(travel , employment, education). Socioeconomic effects of the pandemic are
exacerbating health and societal disparities that disproportionately affect historically
disadvantaged groups, and appear to be leading to widening inequality (CDC 2021b).
Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
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As such, the COVID -19 pandemic has disproportionately affected individuals of racial
and ethnic minority groups, including African American and Hispanic/Latino groups
(CDC 2021c ).
The emergence of SARS -CoV -2 variants with multiple mutations in the SARS -CoV -2
spike (S) protein in India (B1.617 lineage [B1.617.2 delta variant]), the United Kingdom
(B.1.1.7 lineage [alpha variant] ), Brazil (P.1 lineage [gamma variant] ), and South Afric a
(B.1.351 lineage [beta variant] ), has raised concerns regarding increased transmission
rates; at the time of this review, these variants of concern account for 82.2%, 9.0%,
3.8% and 0. 1%, respectively, of SARS-CoV-2 lineages circulating in the US (CDC
2021d). Since December 2020, COVID -19 vaccin es have been available in the United States
under EUA. As of August 15, 2021, among more than 168 million fully vaccinated
individuals in the U.S., 6,239 hospitalizations and 1,263 deaths due to vaccine
breakthrough have been reported by passive surveillance . Of hospitalized or fatal
breakthrough cases, 74% occurred among individuals 65 years of age and older.
Despite the occurrence of breakthrough cases in vaccinated individuals, according to current data, v accination elicited protection against severe disease, hospitalization, and
death remains high. COVID -19 cases, and in particular severe cases, hospitalizations ,
and deaths, remain overwhelmingly among unvaccinated individuals . Increasing
representation of vaccinated individuals among m ild to moderate COVID -19 cases is
likely due in part to increasing uptake of the vaccine (which is not 100% protective) ,
although waning immunity and/or decreased vaccine effectiveness against the delta
variant may be contributing . Surveillance is ongoing to assess the impact of new
variants on vaccine effectiveness. Vaccine clinical research and epidemiological
surveillance are ongoing to assess durability of protection and parameters to determine
whether and when there would be a need for a booster dose.
2.2 Currently Available, Pharmacologically Unrelated Treatment(s)/Intervention(s) for
the Proposed Indication(s)
Remdesivir is the only product currently approved by the FDA for use in adults and
pediatric patients 12 years of age and older for treatment of COVID -19 requiring
hospitalization. Prior to its approval, remdesivir was authorized for emergency use in
adults and pediatric patients and remains authorized for emergency use in h ospitalized
pediatric patients who are not included in the indicated population under licensure. Emergency use authoriz ations of COVID -19 pharmacological products for post-
exposure prophylaxis and/or treatment of COVID -19 are as follows:
Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
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Table 2 . Emergency Use Authorized Pharmacological Products for Post-exposure
Prophylaxis and/or Treatment of COVID -19
Product Date of EUA Authorized Use and Population
SARS -CoV-2-targeting
Monoclonal Antibodies
• Bamlanivimab/etesevimab
• Sotrovimab
• Casirivimab/imdevimab
Reissued February
25, 2021
May 26, 2021
Reissued July 30, 2021
All three products are indicated for the treatment of mild- to-moderate COVID -
19 in adults and pediatric patients 12
years and older at high risk for
progressing to severe COVID -19
a
Casirivimab/imdevimab is also
authorized for post-exposure
prophylaxis (prevention) for COVID -19
in patients at high risk for progressing
to severe COVID -19b
Antiviral Drugs
• Remdesivir
Reissued October 22, 2020 (following
FDA approval in
adults and some pediatric patients )
Treatment of COVID -19 in
hospitalized pediatric patients
weighing at least 3.5 kg to <40 kg,
or <12 years of age weighing at least 3.5 kg, or ≥12 years and
weighing at least 40 kg
Immune Modulators
• Baricitinib
• Actemra
11/19/2020
06/24/2021
Treatment of COVID -19 in
hospitalized patientsb receiving
systemic corticosteroids and require
supplemental oxygen, non- invasive
or invasive mechanical ventilation,
or ECMO
COVID -19 Convalescent
Plasma Reissued March 9,
2021 Treatment of h ospitalized patients
with COVID -19
a Indicated for adults and pediatric patients 12 years of age and older weighing at least 40 kg
b Indicated for adults and pediatric patients 2 years and older
ECMO e xtracorporeal membrane oxygenation, EUA emergency use authorization
Source: https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and- policy -
framework/emergency-use-authorization#coviddrugs Accessed August 2, 2021.
2.3 Safety and Efficacy of Pharmacologically Related Products
At present, no vaccine is approved by the FDA for prevention of COVID -19. The FDA
has issued EUAs for three COVID -19 vaccines to mitigate the SARS -CoV-2 pandemic .
Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
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Table 3 . Emergency Use Authorized Vaccines to Prevent COVID- 19
Applicant Regimen Population Date of EUA and Amendments
Pfizer/BioNTech 2 doses 3 weeks
apart Individuals ≥1 6 years of age
Individuals ≥12 years of age Decembe r 11, 2020
EUA Amendment: May 10, 2021
Pfizer/BioNTech
3rd dose Certain
immunocompromiseda
individuals ≥12 years of age EUA Amendment: August 12,
2021
Moderna 2 doses 4 weeks
apart Adults ≥18 years of age December 18, 2020
Moderna
3rd dose Certain
immunocompromiseda
individuals ≥18 years of age EUA Amendment: August 12, 2021
Janssen Single dose Adults ≥18 years of age February 27 , 2021
a Solid organ transplantation, or who are diagnosed with conditions that are considered to have an equivalent level of
immunocompromise.
Moderna COVID -19 mRNA vaccine
In an ongoing Phase 3 study that enrolled participants ≥18 year of age (n=~14,000
vaccine, n=~14,000 placebo), VE was 94.1% to prevent PCR-confirmed COVID-19
occurring at least 14 days after completion of a 2- dose regimen. Common solicited
adverse reactions after vaccination were injection site reactions , headache, fatigue,
muscle aches , and nausea, which were generally mild to moderate and lasted 1-2 days
(FDA 2020a ). At the time of this review, more than 142 million doses of the Moderna
COVID -19 vaccine have been administered in the US (CDC 2021). Consistent with
Phase 3 trials, real -world efficacy of mRNA vaccines has been demonstrated to be
about 90% (Pawlowski et al. 2021; Thompson et al. 2021). During post-EUA
surveillance myocarditis and pericarditis, and rare cases of anaphylaxis , were reported
after vaccination (CDC 2021e).
Janssen COVID -19 repli cation-incompetent human adenovirus serotype 26 (Ad26)
vector vaccine
In an ongoing Phase 3 study that enrolled participants ≥ 18 year of age (n=~20,000
vaccine, n=~20,000 placebo), VE was 66.9% to prevent laboratory -confirmed,
moderate-severe COVID19 occurring at least 14 days after a single dose. C ommon
solicited adverse reactions were injection site pain, headache, fatigue, and myalgia,
which were mostly mild and moderate. In the post-EUA surveillance period, thrombosis
with thrombocytopenia s yndrome (TTS) and Guillain-Barré syndrome were identified as
rare, but serious adverse reactions following vaccination ( CDC Advisory Committee on
Immunization Practices 2021b).
2.4 Previous Human Experience with the Product (Including Foreign Experience)
Clinical trial experience
EUA of the Pfizer -BioNTech COVID -19 Vaccine (also referred to as BNT162b2) was
based on the following data: In individuals ≥16 years of age enrolled in a Phase 2/3
portion of an ongoing study (n= ~22,000 vaccine, n=~22,000 placebo), vaccine efficacy
(VE) was 95% to prevent PCR-confirmed COVID -19 occurring at least 7 days after
completion of a 2-dose regimen. Common solicited adverse reactions after vaccination
were injection site reactions , fatigue, headache, muscle pain , chills, and joint pain,
which were generally mild to moderate and lasted a few days. Vaccine effectiveness in
participants 12-15 years of age (n=1, 131 vaccine, n=1, 129 placebo) was inferred by
Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
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immunobridging, based on a comparison of SARS -CoV -2 50% neutralization antibody
titers (SARS-CoV -2 mNG microneutralization assay) at 1 month after Dose 2, to
participants 16-25 years of age, and supported by a supplemental efficacy analysis
showing VE after 7 days post Dose 2 was 100% (95% CI 75.3; 100.0) without prior
evidence of SARS -CoV-2 infection and 100% in participants with or without prior
infection (FDA 2020b).
Post-EUA
As discussed in more detail above, s ince the issuance of the EUA, published
observational studies have supported the effectiveness of BNT162b2 to prevent
COVID -19, including high-level protection against severe disease, hospitalization, and
death, although recent evidence suggests some decrease in vaccine effectiveness
against mild to moderate disease since emergence of the delta variant in the US (CDC
2021f).
During the post-EUA surveillance period, cases of myocarditis and pericarditis were
reported after vaccination, as well as rare cases of anaphylaxis (CDC Advisory
Committee on Immunization Practices 2021c ; CDC 2021e).
Please see CBER pharmacovigilance reviewer’s memorandum for details about the
Applicant’s ongoing post -authorization studies and results of cumulative analysis of
post-authorization AE reports received through February 28, 2021.
2.5 Summary of Pre- and Post-submission Regulatory Activity Related to the
Submission
Prior to BLA submission
EUA 27034
• November 20, 2020: Submission of EUA request for individuals ≥16 years of age
• December 11, 2020: Issuance of EUA for individuals ≥16 years
of age
• April 9, 2021: Submission of EUA request for individuals 12 -15 years of age
• May 10, 2021: Issuance of EUA for individuals 12-15 years of age
• June 25, 2021: EUA amendment to include warning statement and associated
information regarding myocarditis and pericarditis in the Fact Sheet for
Vaccination Providers and the Fact Sheet for Recipients and Caregivers
Major
pre-submission BLA-associated regulatory activity
• April 22, 2020: IND 19736 submission, first subject enrolled on April 29 , 2020
• June 11, 2020-July 6, 2020 Type C Meeting to discuss c linical development
program, including revised Phase 1/2/3 Study C4591001 intended to support
licensure
• July 7, 2020: Fast Track Designation granted for individuals ≥18 years of age
• November 18, 2020-April 2, 2021 Request for Comments and Advice re: Study
C4591001 Placebo Participants
• March 31, 2021: Pre-BLA meeting (chemistry, manufacturing, and controls
[CMC ])
• March 9, 2021: Pre-BLA meeting (clinical)
• April 16, 2021: plans for rolling BLA submis sion agreed upon between CBER and
the Applicant
Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
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Major post-submission BLA regulatory activity
• July 15, 2021: Priority review granted
2.6 Other Relevant Background Information
Relevant FDA guidance
In June 2020, FDA published guidance on the Development and Licensure of Vaccines
to Prevent COVID -19 (FDA 2020c ). In October 2020, FDA published guidance on
Emergency Use Authorization for Vaccines to Prevent COVID -19 (revised February
2021) (FDA 2021a).
Vaccines and Related Biological Products Advisory Committee (VRBPAC) meetings
On October 22, 2020, a VRBPAC meeting was held to discuss considerations for
development, EUA and licensure of vaccines to prevent COVID -19. The VRBPAC
committee endorsed the principles outlined in the June and October FDA guidance
documents regarding safety and effectiveness data to support EUA and licensure
and expectations for continued post- authorization and post-approval evaluation of
COVID -19 vaccines .
On December 10, 2020, a VRBPAC meeting was held to discuss Pfizer -BioNTech’s
EUA request for their vaccine to prevent COVID -19 in individuals 16 years of age
and older. The committee voted in favor of a determination that, based on the
totality of scientific evidence available, the benefits of the vaccine outweighed its
risks for use in individuals 16 years of age and older.
Discussion topics included : (a) Pfizer -BioNTech’s plan for an unblinded, placebo-
controlled follow-up in ongoing trials , in the event that the vaccine were made
available under EUA . Study participants 16 years of age and older were then
progressively unblinded to their treatment assignment (when eligible per local
recommendations ), and placebo recipients could choose to receive BNT162b2; (b)
scientific knowledge gaps and considerations for evaluation of vaccine safety and
effectiveness in populations who would receive the Pfizer-BioNTech COVID-19
Vaccine under an EUA: the VRBPAC committee commented on the need to further assess vaccine effect on asymptomatic infection and viral shedding, and further
evaluation of safety and effectiveness in subpopulations such as individual s with
HIV and individuals with prior exposure to SARS -CoV-2.
An emerging signal for myocarditis and pericarditis following mRNA COVID-19
vaccines was discussed at FDA VRBPAC and CDC Advisory Committee on
Immunization Practices meetings held on June 10, 2021. Based on the strength of
evidence for a causal association, the Pfizer -BioNTech COVID -19 Vaccine EUA
Fact Sheet was revised on June 25, 2021 to add a Warning for myocarditis and pericarditis , and the Pharmacovigilance Plan (PVP) was amended to include
myocarditis and pericarditis as important identified risks.
3.
SUBMISSION QUALITY AND GOOD CLINICAL PRACTICES
3.1 Submission Quality and Completeness
The submission was adequately organized and integrated to accommodate the conduct
of a complete clinical review.
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3.2 Compliance With Good Clinical Practices And Submission Integrity
Sponsor responsibilities were transferred from BioNTech SE to Pfizer Inc. for the
conduct of clinical study C4591001, including compliance with Good Clinical Practice as
per 21 CFR 312. Bioresearch Monitoring inspections of nine clinical sites in study
C4591001 did not identify deficiencies that would affect the integrity of the clinical data
submitted in this BLA.
3.3 Financial Disclosures
Studies C4591001 and BNT162 -01
Disclosure start date: April 29, 2020. Disclosure Cut -off Date: March 25, 2021
Was a list of clinical investigators provided? Yes ☐ No
Total number of investigators identified: 1834
Number of investigators who are sponsor employees (including both full -time and part -time
employees): 0
Number of investigators with disclosable financial interests/arrangements (Form FDA 3455): 7
If there are investigators with disclosable financial interests/arrangements, identify the number
of investigators with interests/arrangements in each category (as defined in 21 CFR 54.2(a), (b),
(c) and (f)):
Compensation to the investigator for conducting the study where the value could be influenced by the outcome of the study: 0
Significant payments of other sorts: 3
Proprietary interest in the product tested held by investigator: 0
Significant equity interest held by investigator in sponsor of covered study: 4
Is an attachment provided with details of the disclosable financial
interests/arrangements? Yes ☐ No
Is a description of the steps taken to minimize potential bias provided?
Yes ☐ No
Number of investigators with certification of due diligence (Form FDA 3454, box 3): 4
Is an attachment provided with the reason? Yes ☐ No
The investigators with disclosable financial interests represented 0.4 % (n=7/1, 834) of
the total investigators who participated in covered clinical studies.
Efforts reported to eliminate bias for the covered studies consisted of the following:
• Randomized, double-b lind and multicenter study design as well as pre-specified
statistical methods as per the statistical analysis plan
• Frequent monitoring of investigator trial sites and auditing of study sites
• Validity of data collected was confirmed by standard monitoring procedures
• Data processing involved cleaning checks (querying data through electronic edit
checks) to ensure that errors were identified and corrected
• Data were reviewed by clinicians and queries were generated in case of
inconsistencies during the course of the trial
• The study report underwent review by the project team and Quality Control; and
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• Study sites performing safety evaluations were determined acceptable based on
appropriate certification or historical performance and/or qualifications and
credentials.
Reviewer Comment: The Applicant satisfactorily addressed possible study
investigator financial interests that could impact clinical data quality .
4. SIGNIFICANT EFFICACY /SAFETY ISSUES RELATED TO OTHER REVIEW DISCIPLINES
4.1 Chemistry, Manufacturing, and Controls
The CBER CMC r eviewer identified no issues that would impact the conclusions of the
clinical review.
4.2 Assay Validation
Two clinical diagnostic assays were used to assess clinical endpoints in pre -licensure
clinical trials . The information provided in the BLA suppor ted the suitability of Cepheid
Xpert Xpress assay and Roche Elecsys Anti -SARS -CoV -2 assay for their intended us es
to detect SARS -CoV -2 in clinical specimens and to determine serostatus to SARS -CoV-
2, respectively.
4.3 Nonclinical Pharmacology/Toxicology
The CBER toxicology reviewer identified no issues in preclinical studies that would
affect clinical review of the submitted interim clinical study reports , and based on
current hypotheses regarding the etiology of vaccine-associated enhanced disease, the
preclinical data provided in the BLA are reassuring due to: (1) the robust induction of
functional (i.e., neutralizing) antibodies in mice and rhesus macaques; (2) the T helper type 1 (Th1) bias in T cell responses; and (3) the lack of disease in vaccinated rhesus
macaques challenged with SARS -CoV -2. The nonclinical absorption, distribution,
metabolism , and excretion studies indicate that the LNP mainly localizes to the site of
injection and, to a lesser extent, distributes to the liver. Please see CBER toxicology
review memorandum for further details.
4.5 Statistical
No major statistical issues were identified by CBER statistical reviewers in this application. The key statistical analyses for safety and efficacy were confirmed by
CBER statistical reviewers.
4.6 Pharmacovigilance
Post-EUA safety surveillance reports received by FDA and CDC identified two rare but
clinically important serious adverse reactions: anaphylaxis and myocarditis/pericarditis.
The crude reporting rate for anaphylaxis in the Vaccine Adverse Event Reporting
System (VAERS), including unconfirmed and potentially duplicate reports , has been ~ 6
cases per million doses, which is similar in magnitude to rates of anaphylaxis reported
for other preventive vaccines. Reporting rates for medical chart-confirmed myocarditis/pericarditis in VAERS have been higher among males under 40 years of
age than among females and older males and have been highest in males 12-17 years
of age (~65 cases per million doses administered as per CDC communication on
August 20, 2021). Although some cases of vaccine-associated myocarditis/pericarditis required intensive care support (with several suspected fatal cases under CDC
Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
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investigation but not confirmed at the time of this review), available data from short-term
follow -up suggest that most individuals affected by vaccine-associated
myocarditis/pericarditis have had resolution of symptoms with conservative management. Information is not yet available about potential long-term sequelae and
outcomes in affected individuals .
Anaphylaxis will be monitored through routine pharmacovigilance activities, including a
data capture aid to identify relevant clinical information, and post-licensure safety
studies. Mitigation of the observed risks of myocarditis /pericarditis and associated
uncertainties will be accomplished through labeling (including warning statements about the risks of vaccine-associated myocarditis/pericarditis) and through continued safety
surveillance and postmarketing studies conducted by the Applicant, by public health
agencies within the US government (including FDA and CDC), and by other healthcare stakeholders. Please see CBER PVP review memorandum for further details.
4.7 Risk-Benefit Assessment
FDA conducted a quantitative benefit -risk assessment to inform the review of Pfizer and
BioNTech’s Biological Licensure Application (BLA) for use of mRNA COVID -19 vaccines
in individuals 16 years of age and older. The assessment evaluated the benefits and
risks per million individuals who complete vaccination with two doses of BNT162b2. The
analysis was conducted for the groups stratified by combinations of sex and age (12-15,
16-17, 18-24, and 25-29 years). The model assessed the benefits of vaccine-
preventable COVID -19 cases, hospitalizations, ICU visits and deaths, and the risks of
vaccine -related excess myocarditis/pericarditis cases, hospitalizations, and deaths. The
major sources of data included age/sex specific COVID-19 case and hospitalization
incidences reported on COVID NET on July 10, 2021, the myocarditis/pericarditis case rate attributable to vaccine obtained from the OPTUM database, and the vaccine related
myocarditis/pericarditis deaths reported through VAERS. The assessment constructed
scenarios for both the most likely short-term moving direction of the pandemic and the worst case, which used the most conservative assumptions for all model inputs. The most likely scenario assumed vaccine protection duration of 6 months, 10x COVID -
19 case incidence and 4x COVID -19 hospitalization incidence as compared with those of
July 10 (recent nadir), 70% vaccine efficacy against COVID -19 case, 80% vaccine
efficacy against hospitalization, and no vaccine-related myocarditis death. The m odel
results indicate that, for all age/sex groups and across all model outcomes, the benefits clearly outweigh the risks. For males 16-17 years old—the group with the highest risk of
myocarditis/pericarditis —the model predicts that prevented COVID cases,
hospitalizations, ICU admissions , and deaths are 136,000, 506, 166 and 4 per million
vaccinated individuals , respectively. The excess myocarditis/pericarditis cases,
associated hospitalizations, and deaths attributable to vaccine are 196, 196, and 0 per
million vaccinated individuals, respectively.
The worst-case scenario used the most conservative assumptions for all the model
inputs and assumed protection against COVID -19 over 6 months post-vaccination , the
COVID -19 case and hospitalization incidences a s of July 10, 2021, 70% vaccine efficacy
against COVID -19 case, 80% vaccine efficacy against COVID -19 hospitalization, and
0.002% myocarditis/pericarditis death rate. For males 16-17 years old, the model predicted that prevented COVID cases, hospitalizations, ICU admissions , and deaths
are 14,000, 127, 41, and 1 per million vaccinated individuals in this age group,
Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
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respectively. The excess myocarditis/pericarditis cases and associated hospitalizations
and deaths attributable to the vaccine are 196, 196, and 0 per million vaccinated
individuals in this age group, respectively. Even with the conservative assumption on the myocarditis/pericarditis death rate, the model predicted 0 deaths associated with
myocarditis/pericarditis. The model predicts a higher number of myocarditis/pericarditis -
related hospitalizations compared to prevented COVID -19 hospitalizations. However,
considering the differential clinical outcomes of the hospitalization from two difference
causes, FDA considers the benefits of the vaccine still outweigh the risks for the highest
risk group, males 16-17 years old, under this worst-case scenario.
The benefit- risk estimates are limited by uncertainties associated with the dynamics of
pandemics. The major uncertainties in benefits are related to potential changes in
COVID -19 incidence over time and vaccine efficacy and duration of protection in the
face of emerging virus variants. The major risk uncertainty is the data on vaccine-related myocarditis cases and deaths.
For further details, please refer to the review memorandum from the Analytics and
Benefit-Risk Assessment Team, Office of Biostatistics and Epidemiology, CBER .
5.
SOURCES OF CLINICAL DATA AND OTHER INFORMATION CONSIDERED IN THE REVIEW
5.1 Review Strategy
Clinical data that were available as of November 14, 2020 from Phase 1 study BNT162-01 and Phase 1/2/3 study C4591001 participants ≥ 16 years of age enrolled by October
9, 2020 were submitted and reviewed by FDA. See the
EUA Memorandum for the
Pfizer COVID -19 Vaccine .
This BLA contains new clinical data, as follows:
Study C4591001
Phase 1
For BNT162b2 (30 μg), for participants ages 18-55 years (inclusive) and 65-85
years (inclusive) :
• Safety to approximately 6 months after Dose 2 (cutoff date: March 13, 2021)
• Immunogenicity at 6 months after Dose 2 (adults 18-55 years of age only)
Phase 2/3 For participants 16-55 years and > 55 years of age:
• Safety to ≥6 months after Dose 2, comprised of participants in the blinded
placebo-controlled and/or open-label follow -up period
• Efficacy for all participants in the efficacy analysis populations ( i.e., ≥12 years of
age) with confirmed COVID-19 cases up to March 13, 2021.
Study BNT162-01
BNT162b2 by dose level (1 to 30 μg) for participants 18-85 years of age:
• Safety to 1 month after Dose 2
• Immunogenicity: neutralizing antibody titers up to 42 days after Dose 2 , T-cell
responses up to ~6 months after Dose 2 (18-55 years of age: all dose levels ; 56-
85 years of age: 20-µg dose level only)
Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
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Only safety and efficacy data in individuals 16 years of age and older, the population for
intended use, who received the final vaccine formulation (BNT162b2 30 µg ) are
presented in this clinical memorandum .
Because the primary source of pre-licensure study data to support vaccine safety and
effectiveness is a single study, C4591001, FDA agreed with the Applicant’s proposal
not to include integrated summaries of efficacy or safety in the BLA submission. Consequently, the sections of the clinical memo usually reserved for review of these integrated summaries (Sections 7 and 8) are not applicable.
Post-authorization effectiveness data from observational studies referenced in
Section
2 and Section 11 are limited to published literature and were not submitted as part of
the licensure application. Therefore, FDA has not independently reviewed and
confirmed the data or assessed the study designs for potential sources of bias.
5.2 BLA/IND Documents That Serve as the Basis for the Clinical Review
The primary source of data considered for review of this investigational vaccine were
documents submitted to STN 125742/0. The following sections were reviewed in
support of this application: Module 1, all sections: Administrative Information and Prescribing Information Section 2.2 Introduction
Section 2.5 Clinical Overview Section 2.7.3 Summary of Clinical Efficacy
Section 2.7.4 Summary of Clinical Safety
Section 2.7.6 Synopses of Individual Studies Section 5.2 Tabular Listing of All Clinical Studies
Section 5.3.5.1 Clinical Study Reports
During the BLA review period, the Applicant submitted a total of 35 amendments in
response to CBER’s requests for clinical information.
Table 4. Amendments to the Original BLA 12 5742/0 (submitted May 6, 2021)
Amendment
Numb er Date Submitted Description
1 May 18, 2021 Second roll of the BLA
2 May 19, 2021 Request for proprietary name review
3 May 19, 2021 Response to May 18, 2021 comments re: datasets
5 June 7, 2021 COVID -19 cases: strain sequencing data
6 June 16, 2021 Response to June 8, 2021 comments re: datasets, label
7 June 17, 2021 Response to June 9, 2021 comments re: PREA deferred
studies
8 July 2, 2021 Response to June 29, 2021 comments re: latest date of
randomization for study C4591001 participants in the
reactogenicity subset
9 July 2, 2021 Response to June 25, 2021 comments re: solicited local
reactions frequencies, by severity, in study BNT162 -01
participants
12 July 16, 2021 Response to July 6, 2021 comments re: HIV cohort: severe
AEs and AEs leading to study withdrawal
15 July 23, 2021 Response to July 15 and 20, 2021 comments re: study
C4591007 goal dates and revised pediatric plan
Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
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Amendment
Numb er Date Submitted Description
17,18, 28 July 26, 2021
July 28, 2021
August 2, 2021 Responses to Q1 -2, 3-5 of July 22, 2021 comments re: shell
tables and other clinical comments
22 July 30, 2021 Response to July 27, 2021 comments re : vaccine
effectiveness
23 July 30, 2021 Response to July 26, 2021 comments re: disposition of
pregnant participants
26 August 2, 2021 Response to July 29, 2021 comments re: safety analysis by
age
27 August 2, 2021 Response to July 28, 2021 comments for package insert
30 August 3, 2021 Response to July 28, 2021 comments re : post marketing
observational safety studies to assess
myocarditis/pericarditis
32 August 5, 2021
Response to August 3, 2021 comment regarding excluding a
case from the efficacy analyses
37 August 9, 2021 Response to comment 6 of July 22, 2021 request re: shell
tables (efficacy)
38 August 9, 2021 Response to August 5, 2021 comments for package inser t
45 August 12, 2021 Response to August 9 , 2021 comments re: sequencing data
49 August 16, 2021 Response to August 13, 2021 comments for package insert
51 August 16, 2021 Response to August 13, 2021 comments re: safety -related
PMR/PMC studies
52 August 16, 2021 Response to August 13, 2021 comments re: duration of
follow up for the efficacy population
58 August 18, 2021 Response to August 17, 2021 comments for package insert
59, 67, 69 August 18, 2021
August 19, 2021
August 20, 2021 Response to August 17 and 19, 2021 comments re:
PMC/PMR commitments received in Amendment 51
66 August 19, 2021 Response to August 18, 2021 comments for package insert
68 August 20, 2021 Response to August 19, 2021 comments for package insert
71 August 2 0, 2021 Response to August 20, 2021 comments re: package insert
72 August 20, 2021 Response to August 20, 2021 comments re: shell table for
unsolicited AEs
74 August 21, 2021 Response to August 21, 2021 comments for package insert
75 August 21, 2021 Response to August 21, 2021 comments re: PMR/PMC
studies and final study protocol date for study C4591007
Source: FDA -generated table.
The amendments satisfactorily addressed all clinical requests sent during the review
period, and salient responses from the amendments were incorporated into this
memorandum.
Supportive information from EUA 27034/0 and clinical study protocols reviewed under
IND 19736 were also referenced during the review cycle.
5.3 Overview of Clinical Studies
Interim reports from two ongoing clinical studies were submitted to support approval
and licensure of Pfizer -BioNTech COVID -19 Vaccine (BNT162b2). Study C4591001 is
a multicenter, multinational Phase 1/2/ 3 randomized, blinded, placebo-controlled safety,
immunogenicity, and efficacy study . Study BNT162-01 is a Phase 1 study that
Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
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evaluated various vaccine candidates and dose levels for differing formulations of the
vaccine .
Table 5. Overview of Clinical Studies
Study
Number Description BNT162b2 (30 µg)* Group
Phase, Number of
Participants,
Country Placebo Group
Phase, Number
of Participants,
Country Study
Status
C4591001
Phase 1,2,3
randomized, placebo-
controlled, observer -
blind; to evaluate
safety,
immunogenicity and
efficacy of COVID -19
vaccine Phase 1a: 24 (USA)
Phase 2/3b: 220 85
Argentina: 2887
Brazil: 1452
Germany: 250
South Africa: 401
Turkey: 251
USA: 1 6844 Phase 1a: 6 (USA)
Phase 2/3b: 22080
Argentina: 2889
Brazil: 1448
Germany: 250
South Africa: 399
Turkey: 249
USA: 1 6845 Ongoing
BNT162 -01
Phase 1/2 randomized,
open -label; to evaluate
safety and
immunogenicity, dose
escalation Phase 1: 24 (Germany) 0 Ongoing
Source: STN 125742.037 c4591001-508-safety tables
N = total number of randomized participants 16 years of age and older, as of March 13, 2021 Placebo: saline.
Studies C4591001 and BNT162-01 started in April 2020 (first participant, first visit). * Phase 1 studies included additional participants vaccinated with other dose levels and other mRNA vaccine candidates.
a Phase 1: enrolled individuals 18-85 years of age.
b Phase 2/3: Phase 2: enrolled individuals ≥18 years of age (stratified as 18-55 years and 56-85 years); Phase 3:
enrolled individuals ≥16 years of age (stratified as 16-55 years and >55 years).
5.4 Consultations
For the purpose of informing the design of required postmarketing safety studies and
pediatric clinical trials as required by PREA , FDA cardiologists from the Center for Drug
Evaluation and Research were asked to provide recommendations for diagnostic
evaluations and monitoring for myocarditis/pericarditis (including feasibility of routine
screening tests for subclinical myocarditis ), interpretation of cardiac testing, and follow -
up of identified clinical and subclinical cases. FDA incorporated these recommendations
into negotiations with the Applicant on postmarketing studies .
5.4.1 Advisory Committee Meeting
The most critical issues involving data to support safety and effectiveness of this
vaccine were covered in the October 2020, December 2020, and June 2021 VRBPAC
meetings. More complete information concerning the risk of myocarditis/pericarditis
became available during the BLA review as post- EUA surveillance and observational
studies . FDA’s assessment of this information did not impact the overall benefit/risk
considerations to an extent that VRBPAC input was needed to guide a licensure decision for use in individuals ages 16 years and older .
5.5 Literature Reviewed
CDC, 2021, COVID -19 Vaccinations in the United States. https://covid.cdc.gov/covid -data-
tracker/#vaccinations vacc -total-admin -rate-total. Accessed August 20, 2021.
CDC, 2021a, Information for Healthcare Providers about Multisystem Inflammatory Syndrome in
Children (MIS -C). February 17, 2021. https://www.cdc.gov/mis -c/hcp/ .
Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
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CDC, 2021b, Health Equity Considerations and Racial and Ethnic Minority Groups. Updated
April 19, 2021. https://www.cdc.gov/coronavirus/2019 -ncov/community/health -equity/race-
ethnicity.html . Accessed August 20, 2021. .
CDC, 2021c, COVID Data Tracker. Demographic trends of COVID -19 cases and deaths in the
US reported to the CDC. www.cdc.gov/covid -data-tracker/index.html#demographics . Accessed
August 2, 2021.
CDC, 2021d, COVID Data Tracker. Variant Proportions. https://covid.cdc.gov/covid -data-
tracker/#variant -proportions . Accessed August 20, 2021.
CDC, 2021e, COVID -19 Vaccine Safety Update (slide presentation).
https://www.cdc.gov/vaccines/acip/meetings/downloads/slides- 2021 -02/28- 03-01/05- covid -
Shimabukuro.pdf Accessed August 20, 2021.
CDC, 2021f, Update on Emerging SARS -CoV-2 Variants and COVID- 19 vaccines (slide
presentation). https://www.cdc.gov/vaccines/acip/meetings/downloads/slides- 2021 -08-13/04-
COVID -Scobie- 508.pdf . Accessed August 20, 2021.
CDC, 2021g, SARS- CoV-2 Variant Classifications and Definitions.
https://www.cdc.gov/coronavirus/2019 -ncov/variants/variant -info.html . Accessed August 20,
2021.
CDC Advisory Committee on Immunization Practices, 2021a, COVID -19 VaST Work Group
Report – May 17, 2021. https://www.cdc.gov/vaccines/acip/work -groups -vast/report -2021 -05-
17.html?CDC AA refVal=https%3A%2F%2Fwww.cdc.gov%2Fvaccines%2Facip%2Fwork -
groups -vast%2Ftechnical -report -2021- 05-17.html . Accessed August 20, 2021.
CDC Advisory Committee on Immunization Practices, 2021b, COVID -19 Vaccine Safety
Technical (VaST) Work Group (slide presentation). April 23, 2021.
https://www.cdc.gov/vaccines/acip/meetings/downloads/slides- 2021 -04-23/05- COVID -Lee-
508.pdf Accessed August 20, 2021.
CDC Advisory Committee on Immunization Practices, 2021c, COVID -19 Vaccine Safety
Technical (VaST) Work Group (slide presentation). June 23, 2021.
https://www.cdc.gov/vaccines/acip/meetings/downloads/slides- 2021 -06/04- COVID -Lee-508.pdf .
Accessed August 20, 2021.
FDA, 2020a, Emergency Use Authorization Review Memorandum for the Moderna COVID -19
Vaccine/mRNA -1273. December 18, 2020. https://www.fda.gov/media/144673/download .
FDA, 2020b, Emergency Use Authorization Review Memorandum for the Pfizer -BioNTech
COVID -19 Vaccine/ BNT162b2. December 11, 2020.
https://www.fda.gov/media/144416/download .
FDA, 2020c, Guidance for Industry: Development and Licensure of Vaccines to Prevent COVID -
19. June 2020. https://www.fda.gov/media/139638/download .
FDA, 2021a, Guidance for Industry: Emergency Use Authorization for Vaccines to Prevent COVID -19. February 2021. https://www.fda.gov/media/142749/download
.
FDA, 2021b, Emergency Use Authorization Amendment Review Memorandum (for use of the
Pfizer CO VID-19 Vaccine in adolescents).
https://fda.report/media/149528/nr EUA+27034.132+Review+Memo+Pfizer -BioNTech+COVID -
19+Vacci ne REVISED24May final.pdf .
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Holshue, ML, C DeBolt, S Lindquist, KH Lofy, J Wiesman, H Bruce, C Spitters, K Ericson, S
Wilkerson, A Tural, G Diaz, A Cohn, L Fox, A Patel, SI Gerber, L Kim, S Tong, X Lu, S
Lindstrom, MA Pallansch, WC Weldon, HM Biggs, TM Uyeki, and SK Pillai, 2020, First Case of
2019 Novel Coronavirus in the United States, New England Journal of Medicine, 382(10):929 -
936.
Pawlowski, C, P Lenehan, A Puranik, V Agarwal, A Venkatakrishnan, MJM Niesen, JC O’Horo, A Virk, MD Swift, AD Badley, J Halamka, and V Soundararajan, 2021, FDA -authorized COVID -
19 vaccines are effective per real -world evidence synthesized across a multi -state health
system, medRxiv:2021.2002.2015.21251623.
Thompson, MG, JL Burgess, AL Naleway, HL Tyner, SK Yoon, J Meece, LEW O lsho, AJ Caban-
Martinez, A Fowlkes, K Lutrick, JL Kuntz, K Dunnigan, MJ Odean, KT Hegmann, E Stefanski, LJ Edwards, N Schaefer -Solle, L Grant, K Ellingson, HC Groom, T Zunie, MS Thiese, L Ivacic, MG
Wesley, JM Lamberte, X Sun, ME Smith, AL Phillips, KD Gro over, YM Yoo, J Gerald, RT Brown,
MK Herring, G Joseph, S Beitel, TC Morrill, J Mak, P Rivers, KM Harris, DR Hunt, ML Arvay, P Kutty, AM Fry, and M Gaglani, 2021, Interim Estimates of Vaccine Effectiveness of BNT162b2 and mRNA -1273 COVID -19 Vaccines in Pre venting SARS- CoV-2 Infection Among Health Care
Personnel, First Responders, and Other Essential and Frontline Workers - Eight U.S. Locations,
December 2020 -March 2021, MMWR Morb Mortal Wkly Rep, 70(13):495 -500.
World Health Organization, 2021a, WHO Coronavirus (COVID -19) Dashboard.
https://covid19.who.int
. Accessed August 20, 2021.
World Health Organization, 2021b, Weekly epidemiological update on COVID -19 - 1 June 2021.
https://www.who.int/publications/m/item/weekly -epidemiological -update- on-covid -19---1-june-
2021 . Accessed August 20, 2021.
6. DISCUSSION OF INDIVIDUAL STUDIES /CLINICAL TRIALS
6.1 Study C4591001
NCT04368728
Title: Phase 1/2/3, Placebo-Controlled, Randomized, Observer -Blind, Dose-Finding
Study to Evaluate the Safety, Tolerability, Immunogenicity, and Efficacy of SARS-COV -
2 RNA Vaccine Candidates Against COVID-19 in Healthy Individuals
Reviewer Comment: The protocol for this ongoing study has been amended over
time to add study populations, interventions, and analyses not included in the original design and not pertinent to this BLA. The study design as described
herein reflects objectives, endpoints , and monitoring pertaining to safety,
immunogenicity, and efficacy evaluations following a 2-dose BNT162b2 primary
series, according to protocol amendment 14, which was the active version at the
time of the March 13, 2021 data cutoff. Secondary/exploratory objectives
pertaining to immu nobridging evaluations in individuals 12-15 years of age, re-
vaccination ( e.g., 3
rd BNT162b2 dose) , and evaluation of modified BNT162b2
vaccine formulations were beyond the scope of this BLA, and therefore not
presented in this clinical review . Secondary objectives and associated efficacy
analyses starting from 14 days after Dose 2, based on CDC definitions , were
reviewed but not considered by the clinical reviewers as critical ly important to the
interpretation of the primary endpoint . Lastly, the BLA submission did not include
data to address asymptomatic COVID -19 infection, based on seroconversion or
surveillance PCR testing or immunogenicity data from Phase 2/3; thus, study
Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
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objectives pertaining to asymptomatic infection and Phase 2/3 immunogenicity
evaluations are not presented.
6.1.1 Objectives and Endpoints
The objectives and endpoints are presented below are for the Phase 2/3 portion of the
study. The objectives for the Phase 1 portion are described in Section 6.1.2 Design
Overview.
Primary efficacy objectives
1. To evaluate the efficacy of BNT162b2 against confirmed COVID-19 occurring from
7 days after Dose 2 in participants without evidence of SARS-CoV-2 infection
before vaccination.
Endpoint: COVID -19 incidence per 1000 person-years of follow -up based on
laboratory -confirmed NAAT in participants with no serological or virological
evidence (up to 7 days after Dose 2) of past SARS -CoV -2 infection.
2. To evaluate the efficacy of BNT162b2 against confirmed COVID-19 occurring from
7 days after Dose 2 in participants with and without evidence of SARS- CoV-2
infection before vaccination.
Endpoint: COVID- 19 incidence per 1000 person-years of follow -up based on
laboratory -confirmed NAAT
Primary safety objective: To characterize the safety of BNT162b2.
Endpoints : solicited local adverse reactions (injection site pain, redness, swelling) ,
solicited systemic adverse events (AE) (fever, fatigue, headache, chills, vomiting,
diarrhea, new or worsened muscle pain, and new or worsened joint pain ), AEs,
serious adverse events (SAEs)
Solicited AEs were assessed for the first 360 participants (Phase 2) and then a
subset of at least 6, 000 participants in Phase 2/3.
Pertinent secondary efficacy objectives
• To evaluate the efficacy of BNT162b2 against severe COVID -19 occurring from
7 days after Dose 2 in
o participants without evidence of SARS-CoV -2 infection before vaccination
o participants with and without evidence of SARS- CoV-2 infection before
vaccination
Endpoint for both populations: Severe COVID -19 incidence per 1000 person-
years of follow -up
For all of the study objectives described above, NAAT could be confirmed in a central or
local laboratory, unless otherwise specified. Evidence of past SARS-CoV -2 infection
(before Dose 1) was documented serologically or virologically.
6.1.2 Design Overview
Study C4591001 is an ongoing, randomized Phase 1/2/3 study being conducted in the
US, Argentina, Brazil, Germany, South Africa and Turkey. Initially , the study was
Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
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designed as a placebo-con trolled Phase 1 study in healthy US adults to assess the
safety and immunogenicity of several vaccine candidates and dose levels . In Phase 1,
to facilitate review of phase 1 data in real time, the Applicant was not blinded to the
vaccine assignment. The protocol was amended to include observer-blinded, placebo-
controlled Phase 2 (US) and Phase 3 (international) portions to evaluate safety and
clinical disease efficacy endpoints , initially in adults 18 years of age and older but later
amended to include adolescents 16-17 years of age and then adolescents 12-15 years
of age. Following FDA issuance of an EUA for BNT162b2, progressive unblinding to the
randomized assignment began for all participants . This review focus es on the
population of participants 16 years of age and older, the population proposed for initial
licensure.
In Phase 1, two vaccine candidates were evaluated in adults who were not at high risk
of SARS-CoV-2 exposure, without medical conditions that represented risk factors for
more severe COVID -19, and without serologic/virologic evidence of SARS -CoV -2
infection. For each vaccine candidate, several dose levels were evaluated in adults 18
through 55 years of age, with progression to the next higher dose level and to adults 65
through 85 years of age based on recommendation from an Internal Review Committee
(IRC). For each vaccine candidate and dose 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 6.2
of this review) , supported selection of the
final vaccine candidate and dose level (BNT162b2 30 μg) to proceed into Phase 2/3. Immune responses in P hase 1 (SARS -CoV -2 neutralizing titer, S1- and receptor binding
domain- IgG) were assessed pre-Dose 1, after Dose 1 (at Days 7 and 21) and after
Dose 2 (at 7 and 14 days and 1 and 6 months).
In Phase 2/3, enrolled participants were initially stratified by age (18-55 years and >55
years ), with a goal of 40% enrollment in the older adults (>55 years of age) . The
protocol was later amended to include a dolescents 16-17 years of age (and
subsequently 12 to 15 years of age) , following IRC review of safety data in adults ;
hence, the age strata for the initial EUA submission and for this BLA submission were
revised as follows: 16-55 years of age, and > 55 years of age . The study population for
Phase 2/3 included 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, 3 weeks apart. The Phase 2 portion of the study evaluated reactogenicity
and immunogenicity for 360 participants, and these participants also contribute to the
overall efficacy and safety data in the Phase 3 portion.
Changes in the conduct of the study or planned analyses relevant to the proposed
indication and use:
• Participants 18-55 years of age and >55 years of age began enrollment into Phase
2/3 from July 27, 2020 and participants 16-17 years of age began enrollment from
September 16, 2020.
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Other protocol amendments :
• Amendment 6, dated September 8, 2020: Added an exploratory objective to
describe safety, immunogenicity, and efficacy in participants with stable HIV disease; increased the sample size for Phase 2/3 to ~44,000.
• Amendment 8, dated October 15, 2020: Clarified that for participants who are not in the reactogenicity subset, local reactions and systemic events following vaccination should be detected and reported as AEs.
• Amendment 12, dated January 14, 2021: participants ≥16 years of age who
originally received placebo would be eligible for receipt of BNT162b2, in a phased
manner.
Per protocol, since December 14, 2020, following issuance of the Emergency Use
Authorization for the Pfizer-BioNTech COVID -19 Vaccine, Phase 2/3 participants ≥16
years of age in the vaccine and placebo groups were progressively unblinded to their
treatment assignment (when eligible per local recommendations). Participants initially randomized to the placebo group were offered BNT162b2 vaccination at a time no later
than the 6-month follow -up visit after the second placebo vaccination. For participants
unblinded to his/her vaccine assignment, follow -up evaluations thereafter were
conducted in an open-label manner.
Reviewer Comment: During the blinded placebo -controlled time period in Phases 2
and 3, study staff who prepared and administered the study interventions were
unblinded to the treat ment assignment, due to differences in appearance of
BNT162b2 and saline placebo, and s tudy investigators /personnel collecting and
evaluating safety and efficacy information were blinded to the participants’ treatment
assignment (observer -blinded). In the package insert, double-blind refers only to the
study investigators/personnel collecting and evaluating safety and efficacy
information and the parti cipant.
After BNT162b2 became available for emergency use, participants who elected to receive BNT162b2 were unblinded to their initial study intervention assignment. The Applicant and site personnel who are responsible for the ongoing conduct of
the study remain blinded to the data from participants whose treatment assignment
has not been disclosed.
6.1.3 Population
Phase 1: key eligi bility criteria described in Section 6.1.2
Design Overview .
Phase 2/3
Key i nclusion criteria
• Healthy or had pre-existing stable chronic medical conditions
• ≥12 years of age. Individuals <18 years of age were not enrolled in the EU.
• At higher risk for acquiring COVID-19 (including, but not limited to, use of mass
transportation, relevant demographics, frontline essential workers).
Key e xclusion criteria
Phase 2 only: Known infection with HIV, hepatitis C virus, or hepatitis B virus
• Previous clinical (based on COVID -19 symptoms/signs alone, if a SARS -CoV -2
NAAT result was not available) or microbiological (based on COVID -19
symptoms/signs and a positive SARS -CoV -2 NAAT result) diagnosis of COVID -19
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• Known or suspected immunodeficiency, or received/planning treatment with
immunosuppressive therapy, including cytotoxic agents or systemic corticosteroids,
or planned receipt throughout the study
• Women who are pregnant or breastfeeding
• Receipt of blood/plasma products or immunoglobulin, from 60 days before study intervention administration or planned receipt throughout the study.
Criteria for temporarily delaying enrollment/randomization/study intervention administration
• Current febrile illness (T ≥38°C) or other acute illness within 48 hours before study
intervention administration, including symptoms that could represent a potential
COVID -19 illness: n ew or increased cough; n ew or increased shortness of breath,
chills, new or increased muscle pain, new loss of taste/smell , sore throat, d iarrhea,
vomiting.
• Receipt or planning to receive a seasonal or pandemic influenza vaccine within 14
days, or any other n on-study vaccine within 28 days, before study vaccination.
6.1.4 Study Treatments or Agents Mandated by the Protocol
The BNT162b2 ( 30 μg) vaccine candidate was selected for further evaluation in Phase
2/3. BNT162b2 contains a nucleoside-modified messenger RNA that encodes the viral
spike (S) glycoprotein of SARS -CoV-2 encapsulated in a lipid nanoparticle. Each dose
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.
6.1.5 Directions for Use
Two doses of BNT162b2 (0.3 mL per dose) were administered 3 weeks apart. Each
dose was injected intramuscularly into the deltoid muscle.
See the full prescribing information for further information regarding preparation of
BNT162b2.
6.1.6 Sites and Centers
A total of 153 clinical sites enrolled participants for Study C4591001 [US (131), Turkey
(9), Germany (6), South Africa, (4), Brazil (2) and Argentina (1)].
6.1.7 Surveillance/Monitoring Efficacy
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 in clude 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 tes t (NAAT),
to detect SARS -CoV -2. Case ascertainment is based on central laboratory NAAT
results , unless it is not possible to test the sample at the central laboratory. In that case,
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the following NAAT results are acceptable: Cepheid Xpert Xpress SARS -CoV-2, Roche
cobas SARS-CoV -2 real -time RT-PCR test (EUA200009/A001), and Abbott
Molecular/RealTime SARS -CoV -2 assay (EUA200023/A001). The primary and
secondary efficacy endpoints were analyzed in the protocol -specified event-driven final
efficacy analysis after at least 164 COVID -19 cases were accrued (see Section 6.1.9 ).
Participants are expected to participate for a maximum of approximately 26 months.
Safety
Solicited AEs (local and systemic reactions, and antipyretic/pain medication usage from
Day 1 through Day 7 after each dose) were assessed for the first 360 P hase 2
participants and then a subset of at least 6, 000 participants in Phase 2/3 .
Reviewer Comment: The total number of participants enrolled in the reactogenicity
subset was 9,839.
The subset of Phase 2/3 participants ≥16 years of age with stable HIV were analyzed separately per protocol. For all participants, all unsolicited adverse events (AEs) were
collected from Dose 1 to 1 month after the l ast dose and all serious AEs (SAEs) from
Dose 1 to 6 months after the last dose. The planned safety follow -up for currently
enrolled adolescents and adults is a maximum of 26 months (i.e., through 24 months after vaccination #2) and will include collection of deaths and related SAEs reported
after 6 months post-Dose 2. Figure 1
below shows the study safety monitoring plan.
Figure 1. Safety Monitoring Plan, Study C4591001
Reactogeni
city 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. For 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.
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Clinical laboratory tests were assessed routinely in Phase 1 only, at 1-week post-
vaccination.
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 for the theoretical
concern of vaccine-enhanced disease 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%. Participants who
discontinued study intervention continued the protocol -specified follow-up procedures.
After BNT162b2 was granted emergency use authorization ( December 11, 2020),
unblinding procedures were initiated to vaccinate the placebo group. Please see
Section 6.1.10.1
(Population enrolled/analyzed) for additional details.
6.1.8 Endpoints and Criteria for Study Success
Efficacy Evaluation The case definition for a confirmed case of COVID-19 for the primary efficacy endpoint, 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
The case definition for severe COVID-19 case included a confirmed COVID -19 c ase
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, SpO
2≤93% on room air at sea level, or
PaO2/FiO 2<300 mm Hg)
• Respiratory failure (defined as needing high-flow oxygen, noninvasive ventilation, mechanical ventilation, or extracorporeal membrane oxygenation)
• Evidence of shock ( systolic blood pressure <90 mm Hg, diastolic blood pressure
<60 mm Hg, or requiring vasopr essors)
• Significant acute renal, hepatic, or neurologic dysfunction
• Admission to an ICU
• Death
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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
Study success criteria: In Phase 2/3, the assessment of VE was based on posterior
probability of VE 1>30% and VE 2>30%, where VE 1 represented VE for prophylactic
BNT162b2 against confirmed COVID -19 in participants without evidence of infection
before vaccination, and VE 2 represented VE for prophylactic BNT162b2 against
confirmed COVID -19 in all participants after vaccination. Only the first primary endpoint
was analyzed at interim analyses. The criteria for success at an interim analysis were
based on the posterior probability, i.e. Pr(VE >30%|data) at the current number of
cases. Efficacy w as declared if the posterior probability was higher than the success
threshold, where the success threshold for each interim analysis was calibrated to maintain a familywise type I error rate of 2.5%. If the first primary objective was met, the
second primary objective was evaluated at the final analysis.
Pertinent secondary efficacy endpoint
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 ≥7 days after Dose 2
6.1.9 Statistical Considerations & Statistical Analysis Plan
The statistical analyses for the Phase 1 portion were descriptive. For Phase 2/3, the evaluable efficacy population, which included all randomized
participants who received all study interventions as randomized within the predefined
window and had no other important protocol deviations as determined by the c linicians,
was the primary analysis population for all efficacy analyses. Additional analyses based
on the all -available efficacy population, which included all randomized participants who
received either at least 1 dose of vaccine or placebo (Dose 1 all -available set) or 2
doses (Dose 2 all -available set), were also performed.
The VE is defined as VE = 100 × (1 – IRR), where IRR is calculated as the ratio of the
confirmed COVID -19 illness rate in the vaccine group to the corresponding illness rate
in the placebo group. Assuming a true VE of 60%, 164 COVID -19 cases would provide
90% power to conclude true VE >30%. Because the analyses are based on the number
of cases rather than the number of participants, the total number of participants enrolled
in Phase 2/3 would vary depending on the incidence of COVID -19 at the time of
enrollment, the true underlying VE, and a potential early stop for efficacy or futility. Four
interim analyses (IAs) were planned to be performed after accrual of at least 32, 62, 92,
and 120 cases. However, for operational reasons, the first IA was not performed until
94 cases were accrued, followed by the final analysis with 170 cases.
VE was evaluated using a beta-b inomial model and the posterior probability of VE being
>30% was assessed. A minimally informative beta prior, beta (0.700102, 1), was proposed for θ = r(1-VE)/(1+r(1-VE)), where r is the ratio of surveillance time in the
Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
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BNT162b2 group over that in the pl acebo group. For participants with multiple
confirmed cases, only the first case contributed to the VE calculation. The two primary
efficacy endpoints were evaluated sequentially to control the familywise type I error at
2.5% (one-sided). For the primary endpoint analysis, missing efficacy data w ere not
imputed; only participants with known disease status were included. A sensitivity
analysis was performed by imputing missing values with the assumption of missing at
random. Secondary endpoints were evaluated similarly to the primary endpoints.
After the protocol -specified event-driven final efficacy analyses at 170 cases, updated
efficacy analyses on primary and s econdary efficacy endpoints were performed with
additional data accrued during the blinded placebo-controlled follow -up time period. The
point estimate of VE in the blinded follow -up period and associated 2-sided 95% CI
were derived using the Clopper Pearson method adjusting for surveillance time. The
posterior probability, r(VE >30%|data), was also provided.
Reviewer Comment: Although the total planned follow -up for study participants
is 2 years, due to complexities introduced by unblinding and placebo cross -over
following emergency use authorization of the vaccine l onger term vaccine
effectiveness (beyond the evaluable period from placebo-controlled follow -up in
the clinical trial) will be best evaluated in observational studies.
Solicited safety analyses were based on participants in the reactogenicity subset who
received at least one dose of the vaccine and responded yes or no to any reaction
within 7 days of each dose. Unsolicited safety analyses were based on the safety
population, which consisted of participants randomized in the Phase 2/3 study who
received at least one dose of the vaccine, analyzed according to the vaccine received. Safety endpoints were summarized descriptively for the number of participants within
the analysis set reporting at least one event in each categor y.
6.1.10 Study Population and Disposition
6.1.10.1 Populations Enrolled/Analyzed
The study protocol was revised to allow participants ≥16 years of age who originally
received placebo the opportunity to receive BNT162b2 following local or national
recommendations or following completion of the active safety surveillance period,
following issuance of the EUA (protocol am endment 10) . On December 14, 2020, the
process of disclosing vaccine assignments for all trial participants ≥16 years of age
began (following issuance of the EUA for use of the Pfizer -BioNTech COVID -19 vaccine
in individuals 16 years of age and older) . Hence, for each trial participant, there are 2
periods in the study: enrollment into the observer -blind phase until the date of vaccine
disclosure and the time in the study after disclosure. Participants who originally were randomized to BNT162b2 are continui ng to be followed for safety as specified in the
protocol. The safety data for participants who originally were randomized to and received placebo prior to disclosure of vaccine assignment include blinded data that
contribute to controlled assessment of safety compared to individuals who randomly
assigned to BNT162b2. After vaccine treatment disclosure and the administration of BNT162b2, the placebo participants can no longer be used for direct comparison with
those who originally were randomized to BNT162b2. Even though individuals were
unblinded on different days after December 14, 2020, the difference in the total blinded
follow -up duration is minor between the treatment arms. Thus , the analysis of the
observer -blinded, placebo-controlled portion of the study as well as the open-label
Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
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portion is reported in frequencies, such that the number of participants within the
analysis set reporting at least one event in each category is disp layed.
Safety data presented for Phase 3 of Study C4591001, based on the data cutoff date of
March 13, 2021, include:
1. Blinded placebo-controlled period: Dose 1 to 1 month after Dose 2 and to unblinding date:
• Participants with up to ~6 months after Dose 2 (N=43,847; BNT162b2 group
N=21,926 and placebo group N=21,921).
• Solicited local ARs and systemic AEs were assessed during this time period from
a subset of participants.
2. Open-label observational period: from time of unblinding to data cutoff date:
• Participants originally randomized to BNT162b2 (N=20,309)
• Participants originally randomized to placebo who then received BNT162b2
(N=19,525)
• Participants originally randomized to placebo who had confirmed COVID -19
then received BNT162b2 (N=852)
• Only unsolicited AEs (AEs, SAEs and adverse events of special interest [AESIs ]) were assessed during this time period.
3. Cumulative follow -up from Dose 1 to at least 6 months after Dose 2:
• Participants originally randomized to BNT162b2 (inclusive of blinded data and
open-label data through the March 13, 2021 data cutoff). (Total N=12,006: 16-55
years of age/younger age group [N =6,666] and >55 years of age/older age
group [N =5,340]).
Revie wer Comment: The BLA safety database exceeded FDA expectations for at
least 3, 000 vaccine recipients in each age group with at least 6 months of total
safety follow -up.
A graphic of these three different time periods taken into consideration for the
evaluation of the safety data is displayed in Figure 2
, below.
Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
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Figure 2 . Phase 2/3 Safety Analyses: Time Period and Analysis Groups
Source: STN 125742.0 c4591001-interim-mth6- report -body.pdf. Figure 11 (p 140).
1 Will vary by participant. Adverse event data analyzed from Dose 1 to unblinding date, or from unblinding date to data
cutoff date.
2 Up to ~6 months after Dose 2.
3 Cumulative BNT162b2 follow-up to at least 6 months after Dose 2.
Analysis populations
Population Description
Evaluable efficacy All eligible randomized participants who receive all vaccination(s) as
randomized within the predefined window and have no other impor tant
protocol deviations as determined by the clinician.
All-available efficacy 1. All randomized participants who receive at least 1 dose of vaccine .
2. All randomized participants who complete 2 vaccination doses.
Safety All randomized participants who receive at least 1 dose of the study
intervention.
Reactogenicity subset Subset of pa rticipants in the safety population who had e -diary data
reported afte r vaccination.
Data analysis cutoff dates:
• August 24, 2020 (Phase 1 safety and immunogenicity data through 1 month after
Dose 2)
• September 2, 2020 (Phase 2 safety data through 7 days after Dose 2)
• November 4, 2020 (Phase 2/3 first interim analysis for efficacy)
Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
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• November 14, 2020 (Phase 2/3 final analysis for efficacy, safety data for 37,586
participants with a median follow -up of at least 2 months, and available safety data
for all 43,252 participants)
• March 13, 2021 (Phase 2/3 updated vaccine efficacy analysis and safety follow -up)
6.1.10.2 Demographics
A total of 42,436 randomized participants 16 years of age and older (21, 136 in the
BNT162b2 group and 21, 300 in the placebo group) comprise the evaluable efficac y
population from the March 13, 2021 data cutoff. Overall, the evaluable efficacy
population included 49.2 % females ; 82.0% White, 9.5% African American, 4.4% Asian,
and <4 % from other racial groups; 25. 5% of participants were Hispanic/Latino; 20.8 % of
participants were ≥65 years of age. The median age was 51 years. One or more
comorbidities that increase the risk of severe COVID -19 disease were present among
45.8% of participants . The most frequently reported comorbidity was obesity (34.5%).
Only 3 .1% of participants had evidence of prior SARS -CoV-2 infection. Geographically,
76.4% of participants lived in the US, 12.7% lived in Argentina, 6.8% lived in Brazil, and
<2% of participants lived in each of the following countries: Germany, Turkey and South
Africa. The demographics were balanced between the treatment groups. The
demographics of the evaluable efficacy population used for the updated vaccine
efficacy analysis of the second primary endpoint ( participants with or without evidence
of SARS-CoV-2 infection prior to 7 days post-Dose 2) is displayed in Table 6 .
Table 6 . Demographics and Other Baseline Characteristics, Participants 16 Years of Age
and Older With or Without Evidence of Infection Prior to 7 Days After Dose 2, Evaluable
Efficacy Population
Vaccine Group (as Randomized)
Characteristic BNT162b2
(Na =21136)
nb (%) Placebo
(Na =21300)
nb (%) Total
(Na =42436)
nb (%)
Sex: Female 10280 (48.6) 10579 (49.7) 20859 (49.2)
Sex: Male 10856 (51.4) 10721 (50.3) 21577 (50.8)
Age at Vaccination: Mean years (SD) 49.8 (15.99) 49.7 (16.03) 49.7 (16.01)
Age at Vaccination: Median (years) 51.0 51.0 51.0
Age at Vaccination: Min, max (years) (16, 89) (16, 91) (16, 91)
Age Group: 16 -18 years 370 (1.8) 362 (1.7) 732 (1.7)
Age Group: 18 -55 years 12120 (57.3) 12252 (57.5) 24372 (57.4)
Age Group: >55 years 8646 (40.9) 8686 (40.8) 17332 (40.8)
Age Group: ≥65 years 4407 (20.9) 4429 (20.8) 8836 (20.8)
Race: American Indian or Alaska Native 204 (1.0) 190 (0.9) 394 (0.9)
Race: Asian 929 (4.4) 924 (4.3) 1853 (4.4)
Race: Black or African American 2009 (9.5) 2036 (9.6) 4045 (9.5)
Race: Native Hawaiian or Other Pacific
Islander 56 (0.3) 32 (0.2) 88 (0.2)
Race: White 17304 (81.9) 17487 (82.1) 34791 (82.0)
Race: Multiracial 545 (2.6) 519 (2.4) 1064 (2.5)
Race: Not reported 89 (0.4) 112 (0.5) 201 (0.5)
Ethnicity: Hispanic or Latino 5403 (25.6) 5409 (25.4) 10812 (25.5)
Ethnicity: Not Hispanic or Latino 15628 (73.9) 15778 (74.1) 31406 (74.0)
Ethnicity: Not reported 105 (0.5) 113 (0.5) 218 (0.5)
Obesity: Yesc 7239 (34.2) 7386 (34.7) 14625 (34.5)
Obesity: No 13897 (65.8) 13914 (65.3) 27811 (65.5)
Comorbidities: Yesd 9712 (46.0) 9736 (45.7) 19448 (45.8)
Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
STN:125742
35
Vaccine Group (as Randomized)
Characteristic BNT162b2
(Na =21136)
nb (%) Placebo
(Na =21300)
nb (%) Total
(Na =42436)
nb (%)
Comorbidities: No 11424 (54.0) 11564 (54.3) 22988 (54.2)
Baseline evidence of prior SARS -CoV-2
infection: Negativef 20365 (96.4) 20511 (96.3) 40876 (96.3)
Baseline evidence of prior SARS -CoV-2
infection: Positivee 627 (3.0) 669 (3.1) 1296 (3.1)
Baseline evidence of prior SARS -CoV-2
infection: Missing 144 (0.7) 120 (0.6) 264 (0.6)
Country: Argentina 2686 (12.7) 2710 (12.7) 5396 (12.7)
Country: Brazil 1437 (6.8) 1432 (6.7) 2869 (6.8)
Country: Germany 240 (1.1) 243 (1.1) 483 (1.1)
Country: South Africa 391 (1.8) 392 (1.8) 783 (1.8)
Country: Turkey 241 (1.1) 238 (1.1) 479 (1.1)
Country: United States 16141 (76.4) 16285 (76.5) 32426 (76.4)
Source: STN 125742.032 c4591001- 508-efficacy tables , Table F, Page 9
Abbreviation: SARS -CoV-2 = severe acute respiratory syndrome coronavirus 2.
Note: HIV -positive participants are included in this summary but not included in the analyses of the overall study
objectives.
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. Participants who had BMI ≥30 kg/m2.
d. Number of participants who have 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 category or BMI ≥30 kg/m2.
e. Positive N- binding antibody result at Visit 1, positive NAAT result at Visit 1, or medical history of COVID- 19.
f. Negative N- binding antibody result and negative NAAT result at Visit 1 and no medical history of COVID- 19.
The population for the updated vaccine efficacy analysis of the first primary endpoint
included 40,111 participants 16 years of age and older (19,993 in the BNT162b2 group
and 20,118 in the placebo group) who did not have evidence of prior infection with
SARS- CoV-2 through 7 days after the second dose and who were HIV negative.
Demographics for this analysis population were not meaningfully different from those in
the table above, with the exception of being limited to participants without evidence of
SARS- CoV-2 infection prior to 7 days post-Dose 2.
The safety population included 44,047 participants 16 years of age and older ( 22,02 6 in
the BNT162b2 group and 22,021 in the placebo group). Overall, the safety population
included 49.1 % females ; 82.0% White, 9.6 % African American, 4.3 % Asian, and <2%
from other racial groups; 25.9 % of participants were Hispanic/Latino; 20.7% of
participants were ≥65 years of age. The median age was 51 years. One or more
comorbidities that increase the risk of severe COVID -19 disease were present among
45.8% of participants . Only 3 .2% of participants had evidence of prior SARS -CoV -2
infection. Geographically, 76.3% of participants lived in the U S, 13.1% lived in
Argentina, 6.6% lived in Brazil and, <2% of participants lived in each of the following
countries: Germany, Turkey and South Africa. The demographics were balanced
between the treatment groups. Table 7 presents the specific demographic
characteristics in the studied population.
Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
STN:125742
36
Table 7 . Demographics and Other Baseline Characteristics, Participants 16 Years of Age
and Older, Safety Population
Vaccine Group (as Administered)
Characteristic BNT162b2
(Na =22026)
nb (%) Placebo
(Na =22021)
nb (%) Total
(Na =44047)
nb (%)
Sex: Female 10704 (48.6) 10923 (49.6) 21627 (49.1)
Sex: Male 11322 (51.4) 11098 (50.4) 22420 (50.9)
Age at Vaccination: Mean years (SD) 49.7 (15.99) 49.6 (16.05) 49.7 (16.02)
Age at Vaccination: Median (years) 51.0 51.0 51.0
Age at Vaccination: Min, max (years) (16, 89) (16, 91) (16, 91)
Age Group: 16 -17 years 378 (1.7) 376 (1.7) 754 (1.7)
Age Group: 18 -55 years 12691 (57.6) 12719 (57.8) 25410 (57.7)
Age Group: >55 years 8957 (40.7) 8926 (40.5) 17883 (40.6)
Age Group: ≥65 years 4552 (20.7) 4545 (20.6) 9097 (20.7)
Race: American Indian or Alaska Native 221 (1.0) 217 (1.0) 438 (1.0)
Race: Asian 952 (4.3) 942 (4.3) 1894 (4.3)
Race: Black or African American 2098 (9.5) 2118 (9.6) 4216 (9.6)
Race: Native Hawaiian or Other Pacific
Islander 58 (0.3) 32 (0.1) 90 (0.2)
Race: White 18056 (82.0) 18064 (82.0) 36120 (82.0)
Race: Multiracial 550 (2.5) 533 (2.4) 1083 (2.5)
Race: Not reported 91 (0.4) 115 (0.5) 206 (0.5)
Ethnicity: Hispanic or Latino 5704 (25.9) 5695 (25.9) 11399 (25.9)
Ethnicity: Not Hispanic or Latino 16211 (73.6) 16212 (73.6) 32423 (73.6)
Ethnicity: Not reported 111 (0.5) 114 (0.5) 225 (0.5)
Obesity: Yesc 7543 (34.2) 7629 (34.6) 15172 (34.4)
Obesity: No 14483 (65.8) 14392 (65.4) 28875 (65.6)
Comorbidities: Yesd 10119 (45.9) 10071 (45.7) 20190 (45.8)
Comorbidities: No 11907 (54.1) 11950 (54.3) 23857 (54.2)
Baseline evidence of prior SARS -CoV-2
infection: Negativef 21185 (96.2) 21180 (96.2) 42365 (96.2)
Baseline evidence of prior SARS -CoV-2
infection: Positivee 689 (3.1) 716 (3.3) 1405 (3.2)
Baseline evidence of prior SARS -CoV-2
infection: Missing 152 (0.7) 125 (0.6) 277 (0.6)
Country: Argentina 2883 (13.1) 2881 (13.1) 5764 (13.1)
Country: Brazil 1452 (6.6) 1448 (6.6) 2900 (6.6)
Country: Germany 249 (1.1) 250 (1.1) 499 (1.1)
Country: South Africa 401 (1.8) 399 (1.8) 800 (1.8)
Country: Turkey 249 (1.1) 249 (1.1) 498 (1.1)
Country: United States 16792 (76.2) 16794 (76.3) 33586 (76.3)
Source: STN 125742.037 c4591001-508-safety tables, Table E, Page 9
Abbreviation: SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2.
Note: HIV-positive participants are included in this summary but not included in the analyses of the overall study
objectives.
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. Participants who had BMI ≥30 kg/m2.
d. Number of participants who have 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 category (see Appendix A ) or BMI ≥30 kg/m2.
e. Positive N-binding ant body result at Visit 1, positive NAAT result at Visit 1, or medical history of COVID-19.
f. Negative N-binding antibody result and negative NAAT result at Visit 1 and no medical history of COVID-19.
The demographics tables above include participants with chronic, stable HIV infection,
but they are ex cluded from the analysis populations for the efficacy and safety results in
Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
STN:125742
37
Sections 6.1.11 and 6.1.12 . Efficacy was not evaluated in participants with chronic,
stable HIV infection. The safety analyses for this population are discussed in Section
9.1.6 .
6.1.10.3 Subject Disposition
The overall study disposition tables are presented below in Table 8 (Blinded Follow -up
Time Period) and Table 9 (Open-label Unblinded Follow -up Time Period). Overall, few
participants were discontinued or lost to follow -up and these discontinuations were
generally balanced between treatment groups.
A total of 87 (0.4%) Phase 2/3 original BNT162b2 participants received Dose 1 of
BNT162b2 during the blinded placebo-controlled follow -up period and then received
Dose 2 of BNT162b2 during the open-label follow -up period (when they were
unblinded).
During the open-label follow -up period, most participants originally randomized to the
placebo group for Doses 1 and 2 of study vaccine received BNT162b2 as Doses 3 and
4 (88.8% and 72.4%, respectively) of study vaccine. Most participants who received
Dose 3 but not Dose 4 were within the 3-week window between the two doses as of the
data cutoff date. There were few participants in this group (0.1%) who were withdrawn
from the study, and most were due to withdrawals by the participant. The number of
participants originally randomized to the placebo group who were unblinded and
received BNT162b2 was 19,525. Additionally, 839 of the initial randomized placebo
recipients (610 in the younger age group and 229 in the older age group) either opted
not to receive vaccine after unblinding or had not had the opportunity to receive
BNT162b2 at the time of the March 13, 2021 data cutoff.
Table 8. Study Disposition, Phase 2/3 Participants 16 Years of Age and Older, Blinded
Follow- up Period
Vaccine Group (as Randomized)
Disposition BNT162b2
(Na=22085)
nb (%) Placebo
(Na=22080)
nb (%) Total
(Na=44165)
nb (%)
Randomized 22085 (100.0) 22080 (100.0) 44165 (100.0)
Not vaccinated 55 (0.2) 50 (0.2) 105 (0.2)
Original blinded placebo -controlled follow -up
period
Vaccinated 22030 (99.8) 22030 (99.8) 44060 (99.8)
Dose 1 22030 (99.8) 22030 (99.8) 44060 (99.8)
Dose 2 21675 (98.1) 21650 (98.1) 43325 (98.1)
Discontinued from original blinded placebo -
controlled vaccination periodc 352 (1.6) 528 (2.4) 880 (2.0)
Reason for discontinuation
Lost to follow -up 151 (0.7) 153 (0.7) 304 (0.7)
Withdrawal by subject 109 (0.5) 181 (0.8) 290 (0.7)
No longer meets eligibility criteria 26 (0.1) 120 (0.5) 146 (0.3)
Adverse event 27 (0.1) 26 (0.1) 53 (0.1)
Physician decision 5 (0.0) 8 (0.0) 13 (0.0)
Pregnancy 6 (0.0) 6 (0.0) 12 (0.0)
Protocol deviation 3 (0.0) 8 (0.0) 11 (0.0)
Death 3 (0.0) 4 (0.0) 7 (0.0)
Medication error without associated AE 3 (0.0) 2 (0.0) 5 (0.0)
Withdrawal by parent/guardian 1 (0.0) 0 1 (0.0)
Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
STN:125742
38
Vaccine Group (as Randomized)
Disposition BNT162b2
(Na=22085)
nb (%) Placebo
(Na=22080)
nb (%) Total
(Na=44165)
nb (%)
Other 18 (0.1) 20 (0.1) 38 (0.1)
Unblinded before 1 -month post–Dose 2 visit 253 (1.1) 240 (1.1) 493 (1.1)
Completed 1 -month post –Dose 2 visit 21382 (96.8) 21293 (96.4) 42675 (96.6)
Withdrawn from the study 343 (1.6) 484 (2.2) 827 (1.9)
Withdrawn after Dose 1 and before Dose 2 176 (0.8) 211 (1.0) 387 (0.9)
Withdrawn after Dose 2 and before 1 -month
post–Dose 2 visit 100 (0.5) 139 (0.6) 239 (0.5)
Withdrawn after 1 -month post –Dose 2 visit 67 (0.3) 134 (0.6) 201 (0.5)
Reason for withdrawal from the study
Lost to follow -up 174 (0.8) 191 (0.9) 365 (0.8)
Withdrawal by subject 122 (0.6) 226 (1.0) 348 (0.8)
Protocol deviation 11 (0.0) 24 (0.1) 35 (0.1)
Death 16 (0.1) 15 (0.1) 31 (0.1)
Adverse event 9 (0.0) 8 (0.0) 17 (0.0)
Physician decision 3 (0.0) 6 (0.0) 9 (0.0)
No longer meets eligibility criteria 1 (0.0) 4 (0.0) 5 (0.0)
Pregnancy 0 1 (0.0) 1 (0.0)
Medication error without associated AE 1 (0.0) 0 1 (0.0)
Withdrawal by parent/guardian 1 (0.0) 0 1 (0.0)
Other 5 (0.0) 9 (0.0) 14 (0.0)
Source: STN 125742.037 c4591001- 508-safety tables , Table B, Page 1
Note: Human immunodeficiency virus (HIV) -positive participants are included in this summary but analyzed
and reported separately.
Note: Participants randomized but did not sign informed consent or had a signifi cant quality event due to lack
of PI oversight are not included in any analysis population. Note: Because of a dosing error, 4 participants received an additional dose of BNT162b2 at an unscheduled
visit after receiving 1 dose of BNT162b2 and 1 dose of pl acebo.
a. N = number of randomized 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 spec ified characteristic.
c. Original blinded placebo- controlled vaccination period is defined as the time period from Dose 1 to 1 month
post–Dose 2.
Table 9. Study Disposition, Phase 2/3 Participants 16 Years of Age and Older, Open -label
(Unblinded) Follow- up Period
Vaccine Group (as Randomized)
Disposition BNT162b2
(Na =22085)
nb (%) Placebo
(Na =22080)
nb (%)
Randomized 22085 (100.0) 22080 (100.0)
Not vaccinated 55 (0.2) 50 (0.2)
Originally randomized to BNT162b2 20404 (92.4)
Received Dose 2/unplanned dose 87 (0.4)
Completed 6 -month post –Dose 2 visit 6414 (29.0)
Withdrawn from the study 105 (0.5)
Withdrawn before 6 -month post –Dose 2 visit 103 (0.5)
Withdrawn after 6 -month post –Dose 2 visit 2 (0.0)
Reason for withdrawal from the study
Withdrawal by subject 56 (0.3)
Protocol deviation 35 (0.2)
Lost to follow -up 4 (0.0)
Death 3 (0.0)
Physician decision 2 (0.0)
Adverse event 1 (0.0)
Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
STN:125742
39
Vaccine Group (as Randomized)
Disposition BNT162b2
(Na =22085)
nb (%) Placebo
(Na =22080)
nb (%)
No longer meets eligibility criteria 1 (0.0)
Other 3 (0.0)
Originally randomized to placebo 20948 (94.9)
Completed 6 -month post -Dose 2 visit 153 (0.7)
Withdrawn from the study after unblinding and before
Dose 3 497 (2.3)
Received Dose 3 (first dose of BNT162b2) 19612 (88.8)
Received Dose 4 (second dose of BNT162b2) 15986 (72.4)
Discontinued from open -label vaccination perio d 24 (0.1)
Reason for discontinuation from open -label vaccination
period
Protocol deviation 6 (0.0)
Adverse event 5 (0.0)
Withdrawal by subject 5 (0.0)
Pregnancy 4 (0.0)
Death 2 (0.0)
Lost to follow -up 2 (0.0)
Completed 1 -month post -Dose 4 visit 7209 (32.6)
Withdrawn from the study 14 (0.1)
Withdrawn after Dose 3 and before Dose 4 11 (0.0)
Withdrawn after Dose 4 and before 1 -month post-
Dose 4 visit 2 (0.0)
Withdrawn after 1 -month post -Dose 4 visit 1 (0.0)
Reason for withdrawal from the study
Withdrawal by subject 7 (0.0)
Protocol deviation 3 (0.0)
Death 2 (0.0)
Adverse event 1 (0.0)
Lost to follow -up 1 (0.0)
Source: STN 125742.037 c4591001- 508-safety tables Table B, Page 1
Note: Open- label (unblinded) vaccination period is defined as the time period from Dose 3 (first dose of BNT162b2) to 1
month post–Dose 4 (second dose of BNT162b2).
Note: Human immunodeficiency virus (HIV) -positive participants are included in this summary but analyzed and reported
separately.
Note: Participants randomized but did not sign informed consent or had a significant quality event due to lack of PI
oversight are not included in any analysis population.
a. N = number of randomized 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 character istic.
The duration of blinded follow -up after completion of the 2-dose vaccine series in the
safety and evaluable efficacy populations are displayed in Table 10 and Table 11 ,
respectively. Because this study is ongoing, and participants were unblinded to their
study intervention following issuance of the EUA in December 2020 or at their 6-month
follow -up visit, the number of participants with blinded follow -up decreases beyond 6
months, as expected.
Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
STN:125742
40
Table 10. Blinded Follow -up Duration After Dose 2, Participants 16 Years of Age and
Older, Safety Population
Vaccine Group (as Administered)
Length of Follow -upc BNT162b2
Na =22026
nb (%) Placebo
Na =22021
nb (%) Total
Na =44047
nb (%)
<2 Month s 1251 (5.7) 1331 (6.0) 2582 (5.9)
≥2 Month to < 4 months 7744 (35.2) 8070 (36.6) 15814 (35.9)
≥4 Months to < 6 months 11253 (51.1) 11316 (51.4) 22569 (51.2)
≥6 Months 1778 (8.1) 1304 (5.9) 3082 (7.0)
Source: STN 125742.0 c4591001 -interim -mth6- report -body.pdf , Table 9, page 84
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 Length of follow -up is the total exposure from Dose 2 to cutoff date or the date of unblinding, whichever date was
earlier.
Table 11. Blinded Follow -up Duration after Dose 2, Phase 2/3 Participants 16 Years of Age
and Older, Evalua ble Efficacy Population
Vaccine Group (as Randomized)
Duration of Follow -up BNT162b2
Na =21047
nb (%) Placebo
Na =21210
nb (%) Total
Na =42257
nb (%)
<2 Months 840 (4.0) 910 (4.3) 1750 (4.1)
≥2 Months to <4 Months 7411 (35.2) 7851 (37.0) 15262 (36.1)
≥4 Months to <6 Months 11031 (52.4) 11158 (52.6) 22189 (52.5)
≥6 Months 1765 (8.4) 1291 (6.1) 3056 (7.2)
Source: Source: STN 125742.0.52 Table 1, page 4
Note: HIV -positive participants are not included in this summary because they are not included in the efficacy analyses.
a. N = number of participants in the analysis population for the primary efficacy endpoints (evaluable participants with and
without evidence of prior infection). This value is the denominator for the percentage calculations
b. n = Number of participants with the specified characteristic.
The number of participants originally randomized to the BNT162b2 group who received
both doses, were included in the evaluable efficacy population and had at least 6
months of blinded follow -up after Dose 2 is 1765 (8.4%).
Disposition tables are presented below in Table 12 (efficacy analysis populations) and
Table 13 (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 gr oups.
For the evaluable efficacy population, m ost participants who were excluded from the
analysis had not received all vaccinations as randomized or did not receive Dose 2
within the predefined window (i .e., 19 to 42 days after Dose 1). A total of 240
participants in the BNT162b2 group and 60 participants in the placebo group were
excluded for having important protocol deviation s (PDs) on or prior to 7 days after Dose
2. In the BNT162b2 group, most of these deviations wer e related to improper
administration of the investigational product (203 participants, as compared with 23
participants in the placebo group). Specifically, in the BNT162b2 group most PDs were
due to dosing/administration errors (errors in dilution of the vaccine, 76 participants) or
administration of investigational product that was deemed not suitable for use
(temperature excursions in shipment or storage at the distributor, 110 participants) that
would have not applied to placebo.
Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
STN:125742
41
Table 12. Disposition, Participan ts 16 Years of Age and Older, Efficacy Population
Vaccine Group (as Randomized)
Disposition BNT162b2
na (%) Placebo
na (%) Total
na (%)
Randomizedb 22085 (100.0) 22080 (100.0) 44165 (100.0)
Dose 1 all -available efficacy population 22009 (99.7) 22008 (99.7) 44017 (99.7)
Participants without evidence of infection
before Dose 1 21172 (95.9) 21168 (95.9) 42340 (95.9)
Participants excluded from Dose 1 all -available
efficacy population 76 (0.3) 72 (0.3) 148 (0.3)
Reason for exclusionc
Did not receive at least 1 vaccination 55 (0.2) 50 (0.2) 105 (0.2)
Data considered potentially unreliable due to
lack of PI oversight identified as significant
quality event 21 (0.1) 22 (0.1) 43 (0.1)
Dose 2 all -available efficacy population 21648 (98.0) 21624 (97.9) 43272 (98.0)
Participants without evidence of infection
prior to 7 days after Dose 2 20536 (93.0) 20487 (92.8) 41023 (92.9)
Participants excluded from Dose 2 all -available
efficacy population 437 (2.0) 456 (2.1) 893 (2.0)
Reason for exclusionc
Did not receive 2 vaccinations 374 (1.7) 430 (1.9) 804 (1.8)
Data considered potentially unreliable due to
lack of PI oversight identified as significant
quality event 21 (0.1) 22 (0.1) 43 (0.1)
Unblinded prior to 7 days after Dose 2 44 (0.2) 11 (0.0) 55 (0.1)
Evaluable efficacy (7 days) population 21136 (95.7) 21300 (96.5) 42436 (96.1)
Participants without evidence of infection
prior to 7 days after Dose 2 20064 (90.8) 20197 (91.5) 40261 (91.2)
Participants excluded from evaluable efficacy
(7 days) population 949 (4.3) 780 (3.5) 1729 (3.9)
Reason for exclusionc
Randomized but did not meet all eligibility
criteria 32 (0.1) 30 (0.1) 62 (0.1)
Data considered potentially unreliable due to
lack of PI oversight identified as significant
quality event 21 (0.1) 22 (0.1) 43 (0.1)
Did not receive all vaccinations as
randomized or did not receive Dose 2 within
the predefined window (19 -42 days after
Dose 1) 718 (3.3) 729 (3.3) 1447 (3.3)
Unblinded prior to 7 days after Dose 2 44 (0.2) 11 (0.0) 55 (0.1)
Had other important protocol deviations on or
prior to 7 days after Dose 2 240 (1.1) 58 (0.3) 298 (0.7)
Source: STN 125742.032 c4591001- 508-efficacy tables , Table D, Page 7
Note: HIV -positive participants are included in this summary but not included in the analyses of the overall study
objectives.
a. n = Number of participants with the specified characteristic.
b. These values are the denominators for the percentage calculations.
c. Participants may have been excluded for more than 1 reason.
The safety population included a total of 44,050 participants: 22,026 participants in the
BNT162b2 group and 22,021 participants in the placebo group. Most of the 115
participants excluded from the safety population were excluded because they did not
receive study vaccine.
Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
STN:125742
42
Table 13. Disposition, Participants 16 Years of Age and Older, Safety Population
Vaccine Group (as Administered)
Disposition BNT162b2
(Na =22026)
nb (%) Placebo
(Na =22021)
nb (%) Total
(Na =44050)
nb (%)
Randomized
44165
Not vaccinated
105
Vaccinated 22026 (100.0) 22021 (100.0) 44050 (100.0)
Completed 1 dose 22026 (100.0) 22021 (100.0) 44050 (100.0)
Completed 2 doses 21674 (98.4) 21645 (98.3) 43319 (98.3)
Safety population 22026 (100.0) 22021 (100.0) 44050 (100.0)
Reactogenicity subset 5033 (22.9) 5032 (22.9) 10068 (22.9)
HIV-positive 100 (0.5) 100 (0.5) 200 (0.5)
Indeterminate vaccine
3 (0.0)
Participants excluded from safety population
115 (0.3)
Reason for exclusion
Participant did not receive study vaccine
105 (0.2)
Unreliable data due to lack of PI oversight
10 (0.0)
Completed at least 6 months follow -up after
Dose 2 in blinded placebo -controlled follow -
up period 1778 (8.1) 1304 (5.9) 3082 (7.0)
Completed at least 6 months follow -up after
Dose 2 in blinded and open -label follow -up
period 12006 (54.5)
Completed 1 -month post –Dose 2 visit
(vaccination period) 21378 (97.1) 21291 (96.7) 42669 (96.9)
Discontinued from vaccination period but
continued in the study up to 1- month post –
Dose 2 visit 350 (1.6) 520 (2.4) 873 (2.0)
Discontinued after Dose 1 and before Dose
2 233 (1.1) 359 (1.6) 595 (1.4)
Discontinued after Dose 2 and before 1 -
month post –Dose 2 visit 117 (0.5) 161 (0.7) 278 (0.6)
Reason for discontinuation from
vaccination period
Lost to follow -up 151 (0.7) 149 (0.7) 300 (0.7)
Withdrawal by subject 108 (0.5) 181 (0.8) 289 (0.7)
No longer meets eligibility criteria 25 (0.1) 120 (0.5) 145 (0.3)
Adverse event 27 (0.1) 26 (0.1) 53 (0.1)
Physician decision 5 (0.0) 7 (0.0) 12 (0.0)
Pregnancy 6 (0.0) 6 (0.0) 12 (0.0)
Protocol deviation 3 (0.0) 8 (0.0) 11 (0.0)
Death 3 (0.0) 4 (0.0) 7 (0.0)
Medication error without associated
adverse event 2 (0.0) 0 5 (0.0)
Withdrawal by parent/guardian 1 (0.0) 0 1 (0.0)
Other 19 (0.1) 19 (0.1) 38 (0.1)
Withdrawn from study before 1 -month post –
Dose 2 visit 273 (1.2) 344 (1.6) 617 (1.4)
Withdrawn after Dose 1 and before Dose 2 173 (0.8) 205 (0.9) 378 (0.9)
Withdrawn after Dose 2 and before 1 -
month post –Dose 2 visit 100 (0.5) 139 (0.6) 239 (0.5)
Reason for withdrawal
Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
STN:125742
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Vaccine Group (as Administered)
Disposition BNT162b2
(Na =22026)
nb (%) Placebo
(Na =22021)
nb (%) Total
(Na =44050)
nb (%)
Lost to follow -up 151 (0.7) 153 (0.7) 304 (0.7)
Withdrawal by subject 101 (0.5) 168 (0.8) 269 (0.6)
Adverse event 9 (0.0) 7 (0.0) 16 (0.0)
Physician decision 3 (0.0) 5 (0.0) 8 (0.0)
Death 3 (0.0) 4 (0.0) 7 (0.0)
Protocol deviation 0 1 (0.0) 1 (0.0)
Medication error without associated
adverse event 1 (0.0) 0 1 (0.0)
No longer meets eligibility criteria 0 1 (0.0) 1 (0.0)
Withdrawal by parent/guardian 1 (0.0) 0 1 (0.0)
Other 4 (0.0) 5 (0.0) 9 (0.0)
Source: STN 125742.037 c4591001-508-safety tables, Table C, Page 6
Note: Human immunodeficiency virus (HIV)-positive participants are included in this summary but not included in the
analyses of the overall study objectives. Note: Participants randomized but did not sign informed consent or had a significant quality event due to lack of PI
oversight are not included in any analysis population.
Note: Because of a dosing error, Participants C4591001 , C4591001 , C4591001
and C4591001 received an additional dose of BNT162b2 (30 µg) at an unscheduled visit after
receiving 1 dose of BNT162b2 (30 µg) and 1 dose of placebo. Note: "Indeterminate vaccine" refers to participants whose vaccine group (as administered) could not be determined. These participants were included in the number of participants for "Total" column. These participants were not included
in the safety analysis but their safety data are listed separately.
a. N = number of randomized 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
The disposition tables above include participants with chronic, stable HIV infection, but
they are ex cluded from the analysis populations for the efficacy and safety results in
Sections 6.1.11 and 6.1.12 . Efficacy was not evaluated in participants with chronic,
stable HIV infection. The safety analyses for this population are discussed in Section
9.1.6 .
6.1.11 Efficacy Analyses
6.1.11.1 Analyses of Primary Endpoint(s)
Vaccine Efficacy (Evaluable Efficacy Population)
Protocol-s pecified, e vent-d riven final primary efficacy analysis
For the 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. Cases were counted from 7 days after
Dose 2. The population in the protocol -specified, event-driven final primary efficacy
analysis included all participants 12 years of age and older who had been enrolled from
July 27, 2020 and followed for the development of COVID -19 through November 14,
2020.
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%
(95% credible interval: 90.0, 97.9), which met the pre-specified success criterion. The case split was 8 COVID -19 cases in the BNT162b2 group compared to 162 COVID -19
cases in the placebo group. This protocol -specified, event-driven final primary efficacy
(b) (6)
(b) (6)
(b) (6)
(b) (6)
Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
STN:125742
44
analysis was the basis for issuance of the emergency use authorization for the Pfizer -
BioNTech COVID -19 Vaccine on December 11 , 2020. Please refer to the EUA Review
Memo for the Pfizer COVID -19 Vaccine for additional details from that analysis time
point.
Updated efficacy analyses
Updated efficacy analyses were performed with additional confirmed COVID -19 cases
accrued during blinded placebo-controlled follow -up through March 13, 2021,
representing up to 6 months of follow -up after Dose 2 for participants in the efficacy
population. All of the following updated primary and secondary VE analyses are from
this blinded placebo-controlled follow -up period through the March 13, 2021 data cutoff.
For the first updated 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 updated efficacy endpoint,
VE for BNT162b2 against confirmed COVID -19 was evaluated in participants with and
without evidenc e 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 .
For participants without evidence of SARS -CoV-2 infection prior to 7 days after Dose 2,
the updated VE against confirmed COVID -19 occurring at least 7 days after Dose 2 was
91.1% . The case split was 77 COVID -19 cases in the BNT162b2 group compared to
833 COVID -19 cases in the placebo group (Table 14
).
Table 14. Updated Vaccine Efficacy Against Confirmed COVID -19 in Participants Without
Evidence of Prior SARS- CoV-2 Infection, Evaluable Efficacy Population (Data Cutoff
March 13, 2021)
Pre-specified Age Group BNT162b2
(Na =19993)
Cases
n1b
Surveillance Timec
(n2d) Placebo
(Na =20118)
Cases
n1b
Surveillance Timec
(n2d) Vaccine Efficacy %
(95% CI)e
All participants 77
6.092 (19711) 833
5.857 (19741) 91.1
(88.8, 93.1)
16-55 years of age 52
3.593 (11517) 568
3.439 (11533) 91.2
(88.3, 93.5)
>55 years of age 25
2.499 (8194) 265
2.417 (8208) 90.9
(86.2, 94.2)
Source: STN 125742.032 c4591001- 508-efficacy tables , Table H, Page 13
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 (pr ior to 7 days after receipt of the last dose) of past
SARS- CoV-2 infection (ie, 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.
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 for surveillance time.
For participants with and without evidence of SARS -CoV -2 infection before and during
vaccination regimen, the updated VE against confirmed COVID -19 occurring at least 7
Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
STN:125742
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days after Dose 2 was 90.9%, with 81 and 854 cases in the BNT162b2 and placebo
groups , respectively (Table 15 ).
Table 15. Updated Vaccine Efficacy Against Confirmed COVID -19 in Participants With or
Without Evidence of Prior SARS- CoV-2 Infection, Evaluable Efficacy Population
Pre-specified Age
Group BNT162b2
(Na =21047)
Cases
n1b
Surveillance Timec
(n2d) Placebo
(Na =21210)
Cases
n1b
Surveillance Timec
(n2d) Vaccine Efficacy %
(95% CI)e
All participants 81
6.340 (20533) 854
6.110 (20595) 90.9
(88.5, 92.8)
16-55 years of age 56
3.766 (12088) 584
3.619 (12142) 90.8
(87.9, 93.1)
>55 years of age 25
2.573 (8445) 270
2.492 (8453) 91.0
(86.5, 94.3)
Source: STN 125742.032 c4591001- 508-efficacy tables , Table I, Page 14
Abbreviations: SARS -CoV-2 = severe acute respiratory syndrome coronavirus 2; VE = vaccine efficacy.
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 V E is derived based on the Clopper and Pearson method adjusted for surveillance time.
Multiple Cases of COVID -19
Five placebo recipients developed 2 separate and clinically symptomatic instances of
COVID -19 which were confirmed by NAAT at the central laboratory. Only the first
occurrence of the confirmed COVID -19 illness w as counted towards the updated VE
analyses. All of the second confirmed COVID -19 cases occurred during the period
before their first dose of BNT162b2 except for 1 participant developed their second
COVID -19 diagnosis 4 days after his second dose of BNT162b2. All participants were
N-binding antibody negative prior to their first instance of COVID -19. The time interval
between the COVID -19 episodes varied from 1 to 5 months. Multiple cas es of COVID -
19 did not occur in vaccine recipients during the blinded portion of the study follow -up.
Subgroup Analyses
Subgroup analyses of the updated second vaccine 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 prior infection status
may not be known by vaccine recipients . The results are displayed below in Table 16 .
The VE point estimates for the subgroup analyses were comparable to results for the first primary efficacy endpoint.
VE point estimates were consistent 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 partici pants 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.
Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
STN:125742
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Table 16. Subgroup Analyses of Second Primary Endpoint, by Demographic and Baseline
Characteristics: Updated Vaccine Efficacy Against Confirmed COVID -19 in Participants
With or Without Evidence of Prior SARS -CoV-2 Infection, Evaluable Efficacy Population
Vaccin e Group (as Randomized)
Subgroup BNT162b2
(Na =21047)
Cases n1b
Surveillance
Timec (n2d) Placebo
(Na =21210)
Cases n1b
Surveillance
Timec (n2d) Vaccine
Efficacy (%)
(95% CIe)
Overall 81
6.340 (20533) 854
6.110 (20595) 90.9
(88.5, 92.8)
Age group: 16 -17 years 0
0.065 (365) 11
0.061 (355) 100.0
(62.4, 100.0)
Age group: 18 -64 years 74
5.008 (15853) 715
4.817 (15914) 90.0
(87.3, 92.3)
Age group: ≥65 years 7
1.267 (4315) 128
1.232 (4326) 94.7
(88.7, 97.9)
Age group: 65 -74 years 6
1.021 (3450) 102
0.992 (3468) 94.3
(87.1, 98.0)
Age group: ≥75 years 1
0.246 (865) 26
0.240 (858) 96.2
(77.2, 99.9)
Sex: Female 37
3.051 (9985) 455
3.013 (10241) 92.0
(88.8, 94.4)
Sex: Male 44
3.289 (10548) 399
3.097 (10354) 89.6
(85.8, 92.6)
Ethnicity: Hispanic or Latino 32
1.841 (5280) 240
1.777 (5266) 87.1
(81.3, 91.4)
Ethnicity: Not Hispanic or Latino 48
4.466 (15149) 614
4.300 (15220) 92.5
(89.9, 94.5)
Ethnicity: Not reported 1
0.032 (104) 0
0.034 (109) -∞
(NA, NA)
Race: American Indian or Alaska
native 0
0.043 (196) 3
0.038 (180) 100.0
(-116.0, 100.0)
Race: Asian 3
0.258 (907) 24
0.247 (896) 88.0
(60.6, 97.7)
Race: Black or African American 4
0.602 (1909) 49
0.591 (1928) 92.0
(78.1, 97.9)
Race: Native Hawaiian or other
Pacific Islander 0
0.016 (54) 1
0.008 (31) 100.0
(-1947.9, 100.0)
Race: White 69
5.234 (16846) 749
5.054 (16952) 91.1
(88.6, 93.2)
Race: Multiracial 5
0.160 (538) 22
0.140 (503) 80.1
(46.1, 94.1)
Race: Not reported 0
0.027 (83) 6
0.031 (105) 100.0
(1.4, 100.0)
Baseline SARS -CoV-2
Status:Positiveh 3
0.183 (593) 6
0.195 (643) 46.7
(-149.5, 91.4)
Baseline SARS -CoV-2
Status:Negativei 77
6.119 (19805) 846
5.883 (19838) 91.2
(88.9, 93.2)
Baseline SARS -CoV-2
Status:Unknown 1
0.038 (135) 2
0.033 (114) 56.9
(-728.5, 99.3)
Country: Argentina 16
1.033 (2655) 110
1.017 (2670) 85.7
(75.7, 92.1)
Country: Brazil 14
0.441 (1419) 82
0.408 (1401) 84.2
(71.9, 91.7)
Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
STN:125742
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Vaccin e Group (as Randomized)
Subgroup BNT162b2
(Na =21047)
Cases n1b
Surveillance
Timec (n2d) Placebo
(Na =21210)
Cases n1b
Surveillance
Timec (n2d) Vaccine
Efficacy (%)
(95% CIe)
Country: Germany 0
0.047 (237) 1
0.048 (243) 100.0
(-3868.6, 100.0)
Country: South Africa 0
0.099 (358) 10
0.096 (358) 100.0
(56.6, 100.0)
Country: Turkey 0
0.029 (238) 6
0.026 (232) 100.0
(22.2, 100.0)
Country: United States 51
4.692 (15626) 645
4.515 (15691) 92.4
(89.9, 94.4)
Source: STN 125742.032 c4591001-508-efficacy tables, Table J, Page 15
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.
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 for surveillance time.
f. Includes participants who had at least one of the Charlson Comorbidity Index category (see Appendix A ) or obesity
(BMI ≥30 kg/m2).
g. Participants (≥16 y ears of age) who had BMI ≥30 kg/m2.
h. Positive N-binding ant body result at Visit 1, positive NAAT result at Visit 1, or medical history of COVID-19.
i. Negative N-binding ant body result and negative NAAT result at Visit 1 and no medical history of COVID-19.
The subgroup analyses of updated vaccine efficacy by risk status in participants are
presented in Table 17 .
Table 17. Subgroup Analyses of Second Primary Endpoint, by Risk Status: Updated
Vaccine Efficacy Against Confirmed COVID -19 in Participants With or Without Evidence
of Prior SARS -CoV- 2 Infection, Evaluable Efficacy Population
Vaccine Group (as Randomized)
Subgroup BNT162b2
(Na =21047)
Cases n1b
Surveillance
Timec
(n2d) Placebo
(Na =21210)
Cases n1b
Surveillance
Timec
(n2d) Vaccine
Efficacy (%)
(95% CIe)
Overall 81
6.340 (20533) 854
6.110 (20595) 90.9
(88.5, 92.8)
At risk: Yesf 36
2.887 (9359) 402
2.772 (9340) 91.4
(87.9, 94.1)
At risk: No 45
3.453 (11174) 452
3.338 (11255) 90.4
(86.9, 93.1)
Age group and Risk: 16 -64 and not
at risk 44
2.887 (9254) 397
2.779 (9289) 89.3
(85.4, 92.4)
Age group and Risk: 16 -64 and at
risk 30
2.186 (6964) 329
2.100 (6980) 91.2
(87.3, 94.2)
Age group and Risk: ≥65 and not at
risk 1
0.566 (1920) 55
0.559 (1966) 98.2
(89.6, 100.0)
Age group and Risk: ≥65 and at risk 6
0.701 (2395) 73
0.672 (2360) 92.1
(82.0, 97.2)
Obese: Yesg 28
2.185 (6999) 314
2.139 (7111) 91.3
(87.1, 94.3)
Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
STN:125742
48
Vaccine Group (as Randomized)
Subgroup BNT162b2
(Na =21047)
Cases n1b
Surveillance
Timec
(n2d) Placebo
(Na =21210)
Cases n1b
Surveillance
Timec
(n2d) Vaccine
Efficacy (%)
(95% CIe)
Obese: No 53
4.153 (13528) 540
3.970 (13478) 90.6
(87.5, 93.1)
Age group and obese:16 -64 and
not obese 49
3.303 (10629) 458
3.158 (10614) 89.8
(86.2, 92.5)
Age group and obese:16 -64 and
obese 25
1.768 (5584) 268
1.719 (5649) 90.9
(86.3, 94.2)
Age group and obese: ≥65 and not
obese 4
0.850 (2899) 82
0.811 (2864) 95.3
(87.6, 98.8)
Age group and obese: ≥65 and
obese 3
0.417 (1415) 46
0.420 (1462) 93.4
(79.5, 98.7)
Source: STN 125742.032 c4591001-508-efficacy tables, Table J, Page 15
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.
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 for surveillance time.
f. Includes participants who had at least one of the Charlson Comorbidity Index category (see Appendix A ) or obesity
(BMI ≥30 kg/m2).
g. Participants (≥16 y ears of age) who had BMI ≥30 kg/m2.
h. Positive N-binding ant body result at Visit 1, positive NAAT result at Visit 1, or medical history of COVID-19.
i. Negative N-binding ant body result and negative NAAT result at Visit 1 and no medical history of COVID-19.
Participants with positive prior SARS -CoV -2 status at baseline were defined as those
with positive N -binding antibody or NAAT results at Visit 1 or a medical history of
COVID -19. In the evaluable efficacy analysis for this subgroup, the estimated VE
against cases occurring ≥7 days after Dose 2 was 46.9% (3 cases BNT162b2; 6 cases
placebo), and in the all-available efficacy analysis the estimated VE against cases
occurring at any time after Dose 1 was 19.2% (13 cases BNT162b2, 17 cases placebo) .
The low baseline seropositivity rate and small number of cases that occurred in these
participants limits the interpretation of these data but indicate that symptomatic re-
infection s did occur among participants who were previously infected.
Additional analyses of the updated vaccine efficacy endpoint were conducted to evaluate the vaccine efficacy, by demographic characteristics, geographic area, and
comorbidity status, as displayed above in Section 6.1.11.1
. VE point estimates were
uniformly high across the comorbidities examined, though interpretation of some of the results is limited by small numbers of participants and/or cases.
The demographics of the participants with confirmed COVID -19 cases contributing to
the updated vaccine efficacy analysis are displayed below in Table 18
.
Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
STN:125742
49
Table 18. Demographic Characteristics of Participants With Protocol -Defined COVID -19,
Participants Without Evidence of Prio r SARS -CoV-2 Infection
Vaccine Group (as Randomized)
Characteristic BNT162b2
(Na =77)
nb (%) Placebo
(Na =833)
nb (%) Total
(Na =910)
nb (%)
Age at Vaccination: Mean years (SD) 46.9 (14.79) 47.1 (15.58) 47.1 (15.51)
Age at Vaccination: Median (years) 50.0 47.0 48.0
Age at Vaccination: Min, max (years) (19, 77) (16, 88) (16, 88)
Age Group: 16 -17 years 0 10 (1.2) 10 (1.1)
Age Group: 18 -64 years 70 (90.9) 699 (83.9) 769 (84.5)
Age Group: ≥65 years 7 (9.1) 124 (14.9) 131 (14.4)
Age Group: 65 -74 years 6 (7.8) 98 (11.8) 104 (11.4)
Age Group: ≥75 years 1 (1.3) 26 (3.1) 27 (3.0)
Race: American Indian or Alaska Native 0 3 (0.4) 3 (0.3)
Race: Asian 3 (3.9) 23 (2.8) 26 (2.9)
Race: Black or African American 4 (5.2) 48 (5.8) 52 (5.7)
Race: Native Hawaiian or Other Pacific
Islander 0 1 (0.1) 1 (0.1)
Race: White 67 (87.0) 730 (87.6) 797 (87.6)
Race: Multiracial 3 (3.9) 22 (2.6) 25 (2.7)
Race: Not reported 0 6 (0.7) 6 (0.7)
Sex: Female 35 (45.5) 444 (53.3) 479 (52.6)
Sex: Male 42 (54.5) 389 (46.7) 431 (47.4)
Ethnicity: Hispanic or Latino 29 (37.7) 236 (28.3) 265 (29.1)
Ethnicity: Not Hispanic or Latino 47 (61.0) 597 (71.7) 644 (70.8)
Ethnicity: Not reported 1 (1.3) 0 1 (0.1)
Comorbidities: Yesc 35 (45.5) 395 (47.4) 430 (47.3)
Comorbidities: No 42 (54.5) 438 (52.6) 480 (52.7)
Obesity: Yesd 27 (35.1) 310 (37.2) 337 (37.0)
Obesity: No 50 (64.9) 523 (62.8) 573 (63.0)
Country: Argentina 15 (19.5) 108 (13.0) 123 (13.5)
Country: Brazil 12 (15.6) 80 (9.6) 92 (10.1)
Country: Germany 0 1 (0.1) 1 (0.1)
Country: South Africa 0 9 (1.1) 9 (1.0)
Country: Turkey 0 5 (0.6) 5 (0.5)
Country: United States 50 (64.9) 630 (75.6) 680 (74.7)
Source: STN 125742.032 c4591001- 508-efficacy tables , Table K, Page 22
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 participants who had at least one of the Charlson comorbidity index category (see Appendix A ) or BMI ≥30 kg/m2.
d. Participants who had BMI ≥30 kg/m2.
Additional analyses of the updated vaccine efficacy endpoint were conducted to
evaluate the vaccine efficacy by comorbidity status. VE point estimates were uniformly
high across the comorbidities examined, though interpretation of some of the results is
limited by small numbers of participants and/or cases Table 19 .
Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
STN:125742
50
Table 19. Updated Vaccine Efficacy by Comorbidity Status, Participants Without Evidence
of Prior SARS -CoV-2 Infection, Evaluable Efficacy Population
Vaccine Group (as Randomized)
Subgroup BNT162b2
(Na =19993)
Cases n1b
Surveillance Timec
(n2d) Placebo
(Na =20118)
Cases n1b
Surveillance Timec
(n2d) Vaccine
Efficacy (%)
(95% CIe)
Overall 77
6.092 (19711 ) 833
5.857 (19741 ) 91.1
(88.8, 93.1)
Comorbidity
No comorbidity 42
3.329 (10757 ) 438
3.207 (10808 ) 90.8
(87.3, 93.4)
Any comorbidityf 35
2.763 (8954 ) 395
2.65 (8933 ) 91.5
(88.0, 94.2)
Cardiovascular 3
0.172 (584) 22
0.159 (555) 87.4
(58.1, 97.6)
Chronic pulmonary disease 8
0.474 (1582 ) 66
0.443 (1562 ) 88.7
(76.3, 95.3)
Diabetes 9
0.465 (1528 ) 60
0.444 (1513 ) 85.7
(70.9, 93.7)
Obese (≥30.0 kg/m2) 27
2.083 (6673 ) 310
2.034 (6770 ) 91.5
(87.4, 94.5)
Hypertension 15
1.481 (4900 ) 190
1.427 (4895 ) 92.4
(87.1, 95.8)
Diabetes (including gestational
diabetes) 9
0.468 (1537 ) 62
0.447 (1527 ) 86.1
(71.9, 93.9)
Source: STN 125742.032 c4591001- 508-efficacy tables , Table L, Page 25
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 (ie, 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.
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 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 category (see Appendix A ) or BMI ≥30 kg/m2.
Cumulative incidence curves
Based on the cumulative incidence curve for the all -available effi cacy population after
Dose 1, ( Figure 3 ), 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 .
Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
STN:125742
51
Figure 3 . Updated Cumulative Incidence Curves for the First COVID -19 Occurrence After
Dose 1, All-Available Efficacy Population (data cutoff March 13, 2021)
Source: Adapted from STN 125742.0 c4591001-interim-mth6- report -body.pdf. Figure 2. page 104.
An updated analysis of the number of confirmed COVID -19 cases following Dose 1 was
conducted with the all -available efficacy population, for all participants regardless of
evidence of prior infection through 7 days after Dose 2, and at time intervals following
completion of the vaccine series (Table 20 ).
Table 20. Update d Vaccine Efficacy after Dose 1, Dose 1 All -Available Efficacy Population
Efficacy Endpoint Subgroup BNT162b2
(Na =21909)
Cases
n1b
Surveillance
Timec
(n2d) Placebo
(Na =21908)
Cases
n1b
Surveillance
Timec
(n2d) Vaccine
Efficacy %
(95% CI)e
First COVID -19 occurrence after Dose 1 128
8.155 (21385) 998
7.874 (21315) 87.6
(85.1, 89.8)
After Dose 1 to before Dose 2 43
1.273 (21385) 98
1.266 (21315) 56.4
(37.0, 70.3)
Dose 2 to 7 days after Dose 2 3
0.403 (21049) 30
0.401 (20952) 90
(68.0, 98.1)
≥7 Days after Dose 2 82
6.479 (21019) 870
6.207 (20901) 91
(88.7, 92.9)
≥7 Days after Dose 2 to <2 Months after
Dose 2 12
2.786 (21019) 296
2.750 (20901) 96.0
(92.9, 98)
Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
STN:125742
52
Efficacy Endpoint Subgroup BNT162b2
(Na =21909)
Cases
n1b
Surveillance
Timec
(n2d) Placebo
(Na =21908)
Cases
n1b
Surveillance
Timec
(n2d) Vaccine
Efficacy %
(95% CI)e
≥2 Months after Dose 2 to 4 Months after
Dose 2 46
2.665 (20160) 446
2.564 (19720) 90.1
(86.5, 92.8)
≥4 Months after Dose 2 24
1.028 (12624) 128
0.893 (11760) 83.7
(74.7, 89.9)
Source: STN 125742.032 c4591001-508-efficacy tables, Table O, Page 30
Abbreviation: VE = vaccine efficacy.
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 Dose 1 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.
The VE estimate for the prevention of COVID -19 disease after Dose 1 in the all -
available efficacy population is 8 7.6%. Additionally, VE at ≥4 Months after Dose 2 is
83.7% in the all -available efficacy population, suggesting some modest attenuation in
efficacy over time. However, this attenuation was limited to efficacy against non-severe
COVID -19, as the only protocol -confirmed severe case reported during blinded,
placebo-controlled follow -up among BNT162b2 recipients in the all -available efficacy
population occurred with onset at 35 days after Dose 2 and did not result in
hospitalization (see Section 6.1.11.2 for further details). 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 3 weeks after a single dose. VE
estimates over these time intervals in the all -available efficacy population w ere similar
to estimates in the evaluable efficacy population.
Additional analyses assessed vaccine efficacy in two successive periods of follow -up,
from days 35-90 and 91-224, to explore whether changes in COVID -19 epidemiology or
potential waning of immunity during the blinded follow -up period may have impacted
vaccine efficacy over time. V accine efficacy for days 35-90 and days 91- 224 were
93.7% [90.6;96.0] and 88.3% [84.6;91.2], respectively. The risk ratio of the incidence rates between vaccine and placebo in the period from Dose 1 to Day 57 and from Dose 1 to Day 224 were 0.173 [95% CI 0.128;0.232] and 0.122 [95% CI 0.101;0.147], suggesting a small, non - significant change in vaccine efficacy over time.
Reviewer Comment: Updated efficacy analyses were conducted in March 2021,
prior to the emergence of the B.1.617.2 (D elta) variant in the US.
6.1.11.2 Analyses of Secondary Endpoints
In the protocol -specified event-driven final analysis of the evaluable efficacy population,
vaccine efficacy against severe COVID -19 for participants without prior SARS -CoV -2
infection occurring at least 7 days after Dose 2 was 66.4% (95% Credible Interval: -
124.8%, 96.3 %). In this analysis, only four participants had severe COVID -19 disease
at least 7 days after Dose 2 (1 BNT162b2 group; 3 placebo group). Please refer to the
EUA Review Memo
for additional details from that analysis time point.
Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
STN:125742
53
Updated efficacy analyses of the secondary efficacy endpoint for prevention of severe
COVID -19 were also evaluated with additional confirmed COVID -19 cases accrued
during blinded placebo- controlled follow -up through March 13, 2021. Vaccine efficacy
against severe COVID -19 is presented in Table 21 for participants without prior SARS -
CoV-2 infection. In the updated analysis, among participants without evidence of prior
infection, the estimated VE against severe COVID -19 disease occurring at least 7 days
after Dose 2 was 95.3% (71.0%, 99.9%) with severe COVID -19 cases in one participant
who received BNT162b2 and 21 participants who rec eived placebo. The same number
of severe cases were reported among participa nts with or without evidence of prior
infection, and the estimated VE was the same (95.3%). These updated analyses of the
secondary vaccine efficacy based on a larger number of severe cases now show more
compelling protection against severe COVID -19 disease offered by BNT162b2. 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. COVID -
19 symptoms began 35 days after Dose 2. The participant was <55 years of age, not
hospitalized, did not seek further medical care, and did not have risk fact ors for severe
disease. Additional details about the severe cases in placebo recipient s are discussed
below, with the all -available efficacy population.
Table 21. Updated Vaccine Efficacy Against Severe COVID -19, Participants Without
Evidence of Prior SARS- CoV-2 Infection, Evaluable Efficacy Population
Secondary Efficacy Endpoint BNT162b2
(Na =19993)
Cases
n1b
Surveillance
Timec
(n2d) Placebo
(Na =20118)
Cases
n1b
Surveillance
Timec
(n2d) Vaccine Efficacy %
(95% CI)e
First severe COVID -19 occurrence
from 7 days after Dose 2 in
participants without evidence of
prior SARS -CoV-2 infection 1
6.103
(19711) 21
5.971
(19741) 95.3
(71.0, 99.9)
Source: STN 125742.032 c4591001- 508-efficacy tables , Table M, Page 28
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 (ie, 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.
b n1 = Number of participants meeting the endpoint definition.
c Total surveill ance 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.
In the all -available efficacy population, 31 participants had severe COVID -19 disease
after Dose 1 (one subject who received BNT162b2 and 30 participants who received
placebo) (Table 22 ).
Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
STN:125742
54
Table 22. Updated Vaccine Eff icacy Against First Occurrence of Severe COVID -19 After
Dose 1, Dose 1 All -Available Efficacy Population
Secondary Efficacy Endpoint BNT162b2
(Na =21909)
Cases
n1b
Surveillance
Timec
(n2d) Placebo
(Na =21908)
Cases
n1b
Surveillance
Timec
(n2d) Vaccine Efficacy %
(95% CI)e
First severe case occurrence after
Dose 1 1
8.181 (21385 ) 30
8.032 (21316 ) 96.7
(80.3, 99.9)
After Dose 1 to before Dose 2 0
1.285 (21385 ) 6
1.293 (21316 ) 100
(14.6, 100.0)
Dose 2 to 7 days after Dose 2 0
0.403 (21056 ) 1
0.402 (20962 ) 100
(-3783.8, 100.0)
≥7 days after Dose 2 1
6.493 (21029 ) 23
6.337 (20940 ) 95.8
(73.9, 99.9)
Source: STN 125742.032 c4591001- 508-efficacy tables , Table N, Page 29
Abbreviation: VE = vaccine efficacy.
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 Dose 1 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.
The 30 placebo recipi ents who had severe COVID -19 had a mean age of 51 years, with
a range of 19 to 71 years of age. The demographics of these 30 participants are as
follows: 17 (56.7% ) participants were in the younger age group, 20 (66.7%) were male,
11 (36.7%) identified as Hispanic or Latinx, 15 (50%) were obese, and 9 (30%) had
other comorbidities that increased the risk for severe disease. Ten (33.3%) participants
were on high flow oxygen, 8 (26.7%) were admitted to the ICU , 2 (6.7%) were on a
ventilator, and 1 participant died with septic shock while hospitalized for severe
COVID 19.
6.1.11.4 Dropouts and/or Discontinuations
The number of participants who dropped out and/or discontinued from the study did not
affect the interpretation of the vaccine efficacy outcomes. Refer to Section 6.1.12.7 for
details regarding dropouts and/or discontinuations.
6.1.11.5 Exploratory and Post Hoc Analyses
Sequencing Data from Centrally Confirmed COVID -19 Cases
During the Phase 2/3 portion of Study C4591001 ( July 27, 202 0, through the data cutoff
date of March 13, 2021), new SARS -CoV-2 vari ants emerged in geogr aphical regions
where the study was conducted. In a post hoc analysis , whole genome sequencing was
performed for confirmed cases of COVID -19 evaluated for efficacy during the blinded
placebo-controlled follow -up period up to the data cutoff date of March 13, 2021. SARS-
CoV-2 variants of concern identified from COVID -19 cases in this study include B.1.1.7
(Alpha) and B.1.351 (Beta). Representation of identified variants among cases in
vaccine versus placebo recipients did not suggest decreased vaccine effectiveness
against these variants.
Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
STN:125742
55
Table 23 below displays the sequence analysis summary for all SARS-CoV -2 lineages
associated with confirmed COVID -19 cases in the BNT162b2 and placebo groups,
including any designated as variants of concern (VOCs) or variants of interest (VOIs) ,
based on WHO and CDC SARS CoV -2 variant classifications and definitions (World
Health Organization 2021b; CDC 2021g ). The designation as “Other ” indicates that the
sequenced SARS CoV- 2 lineages were not considered VOCs or VOIs .
Table 23. SARS -CoV-2 Variants of Concern or Variants of Interest for the First COVID -19
Occurrence From 7 Days After Dose 2, Blinded Placebo -Controlled Follow- up Period,
Subjects With or Without Evidence of Infection Prior to 7 Days After Dose 2 , Evaluable
Efficacy (7 Days) Population
Vaccine Group (as Randomized)
SARS -CoV-2 Lineageb
(Location First Identified) BNT162b2 (30 μg)
(Na =81)
nc(%) Placebo
(Na =873)
nc(%) Total
(Na =954)
nc(%)
B.1.1.7 (United Kingdom) 0 3 (0.3) 3 (0.3)
B.1.351 (South Africa) 0 9 (1.0) 9 (0.9)
B.1.427/B.1.429 (USA) 1 (1.2) 23 (2.6) 24 (2.5)
B.1.525 (UK and Nigeria) 0 1 (0.1) 1 (0.1)
B.1.526 (USA) 0 1 (0.1) 1 (0.1)
B.1.616 (France) 0 0 0
B.1.617 (India) 0 0 0
B.1.618 (India) 0 0 0
P.1 (Brazil/Japan) 1 (1.2) 1 (0.1) 2 (0.2)
P.2 (Brazil) 6 (7.4) 40 (4.6) 46 (4.8)
P.3 (Philippines) 0 0 0
Other 66 (81.5) 755 (86.5) 821 (86.1)
Unknownd 7 (8.6) 33 (3.8) 40 (4.2)
Not sequenced 0 8 (0.9) 8 (0.8)
Source: STN 125742.6 c4591001 -sequencing- report.pdf, Table 1, page 11.
Abbreviation: SARS -CoV-2 = severe acute respiratory syndrome coronavirus 2.
a. N = number of subjects with first COVID -19 occurrence. This value is the denominator for the percentage calculations.
b. Based on PANGO lineages (cov -lineages.org).
c. n = Number of subjects with the specified characteristic.
d. Include indeterminate result and not quantifiable samples.
Reviewer Co mment: The updated efficacy analyses were done prior to the
emergence of the B.1.617.2 (D elta) variant in the US.
Updated Vaccine Efficacy Against Severe COVID -19, CDC definition
The Applicant conducted an additional updated analysis of vaccine efficacy against
severe cases of COVID -19 using the CDC definition of severe COVID -19
(hospitalization, admission to the ICU, intubation or mechanical ventilation, or death) ,
based on confirmed COVID -19 cases accrued during blinded placebo-controlled follow -
up through March 13, 2021. Among participants without evidence of SARS -CoV -2
infection prior to 7 days after Dose 2, the estimated VE against CDC -defined severe
COVID -19 occurring at least 7 days after Dose 2 was 100.0% (2 -sided 95% CI: 88.1%,
100.0%), with 0 and 31 cases in the BNT162b2 and placebo groups, respectively . This
additional analysis further supports the conclusion that BNT162b2 offers protection
against severe COVID -19 disease.
Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
STN:125742
56
6.1.12 Safety Analyses
The Phase 2/3 safety data presented in this section are categorized in following time
periods:
1. Blinded placebo-controlled period: Dose 1 to 1 month after Dose 2 and to unblinding
date:
• Participants with up to ~ 6 months after Dose 2 (N=43,847; BNT162b2 group
N=21,926 and placebo group N=21,921) .
• Solicited local ARs and systemic AEs were assessed during this time period from
a subset of participants.
2. Open-label observational period: from time of unblinding to data cutoff date:
• Participants originally randomized to BNT162b2 (N=20,309)
• Participants originally randomized to placebo who then received BNT162b2
(N=19,525)
• Participants originally randomized to placebo who had confirmed COVID -19
then received BNT162b2 (N=852)
• Only unsolicited AEs (AEs, SAEs and adverse events of special interest [AESIs]) were assessed during this time period.
3. Cumulative follow -up from Dose 1 to at least 6 months after Dose 2:
• Participants originally randomized to BNT162b2 (inclusive of blinded data and open-label data through the March 13, 2021 data cutoff). (Total N=12,006: 16-55
years of age/younger age group [N =6,666] and >55 years of age/older age
group [N =5,340]).
Reviewer Comment: Interpretation of safety data from the open-label observational
period are limited because there was no longer a study group for safety comparisons in the unblinded portion of the study. Additionally, 839 of the initial
randomized placebo recipients (610 in the younger age group and 229 in the older
age group) either opted not to receive vaccine after unblinding or had not had the
opportunity to receive BNT162b2 at the time of the March 13, 2021 data cutoff.
Participants with chronic, stable HIV infection were excluded from the general safety
population analyses and are summarized in a separate analysis (see Section 9.1.6
of
this memo).
6.1.12.1 Methods
Please see Section 6.1.7 .
6.1.12.2 Overview of Adverse Events
Overview of adverse events
Table 24 below presents an overview of immediate unsolicited adverse events and
solicited local reactions and systemic adverse events in the safety population. Table 25
below presents an overview of participants reporting at least 1 unsolicited adverse
event during the blinded placebo-controlled time period.
In the blinded placebo-controlled time period, the most f requently reported solicited
adverse reactions in all age groups included injection site pain, fatigue, headache,
muscle pain, and chills . Additionally, unsolicited ARs reported at higher frequency by
Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
STN:125742
57
the BNT162b2 group than the placebo group among participants not included in the
reactogenicity subset were consistent with local and systemic adverse reactions
adverse reactions solicited among participants in the reactogenicity subset.
Table 24. Immediate and Solicited Local Reactions and Systemic Adverse Events,
Participants 16 Years of Age and Older, Safety Population
Event BNT162b2
na/Nb (%) Placebo
na/Nb (%)
Immediate unsolicited AE within 30 minutes
after vaccination
Dose 1 105/21926 (0.5) 81/219 1 (0.4)
Dose 2 71/21571 (0.3) 54/21549 ( 0.3)
Solicited local reaction within 7 days
Dose 1 3877/4907 (79.0) 639/4897 (13.0)
Dose 2 3351/4542 (73.8) 483/4517 (10.7)
Solicited systemic AE within 7 days
Dose 1 2963/4907 (60.4) 2308/4897 (47.1)
Dose 2 3237/4542 (71.3) 1542/4517 (34.1)
Source: STN 125742.0.37 c4591001- 508-safety -tables .pdf, Table P , page 12.
Note: MedDRA (v23.1) coding dictionary applied.
Note: Immediate AE refers to an AE reported in the 30- minute observation period after vaccination.
an = Number of subjects reporting at least 1 occurrence of the specified event category .
b N: number of participants in the specified age group in the reactogenicity subset of the safety population with data
available for the adverse event. .
Table 25. Unsolicited Adverse Events, Blinded Placebo -controlled Follow- up Period,
Participants 16 Years of Age and Older , Safety Population
Adverse Event BNT162b2
16-55 Years
(Na =12995)
nb (%) BNT162b2
>55 Years
(Na =8931)
nb (%) BNT162b2
Total
(Na =21926)
nb (%) Placebo
16-55 Years
(Na =13026)
nb (%) Placebo
>55 Years
(Na =8895)
nb (%) Placebo
Total
(Na =21921)
nb (%)
Dose 1 through 1 Month
after Dose 2
Any unsolicited AE 4233
(32.6) 2384
(26.7) 6617
(30.2) 1871
(14.4) 1177
(13.2) 3048
(13.9)
Unsolicited non -serious AE 4207
(32.4) 2350
(26.3) 6557
(29.9) 1855
(14.2) 1141
(12.8) 2996
(13.7)
SAEs 52
(0.4) 75
(0.8) 127
(0.6) 49
(0.4) 67
(0.8) 116
(0.5)
Withdrawal due to
unsolicited AE 19
(0.1) 13
(0.1) 32
(0.1) 20
(0.2) 16
(0.2) 36
(0.2)
Death 0
(0.0) 3
(0.0) 3
(0.0) 2
(0.0) 3
(0.0) 5
(0.0)
Dose 1 to cutoff date or
participant unblinding
(whichever is earlier)
Any unsolicited AE 4396
(33.8) 2551
(28.6) 6947
(31.7) 2136
(16.4) 1432
(16.1) 3568
(16.3)
Unsolicited non -serious AE 4347
(33.5) 2471
(27.7) 6818
(31.1) 2086
(16.0) 1347
(15.1) 3433
(15.7)
SAE 103 (0.8) 165
(1.8) 268
(1.2) 117
(0.9) 151
(1.7) 268
(1.2)
Withdrawal due to
unsolicited AE 22 (0.2) 23
(0.3) 45
(0.21) 28
(0.2) 23
(0.3) 51
(0.2)
Death 3
(0.0) 12
(0.1) 15
(0.1) 4
(0.0) 10
(0.1) 14
(0.1)
Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
STN:125742
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Source: STN 125742.0, amendment 66. Response to IR.
N = number of subjects in the specified group. This value is the denominator for the percentage calculations.
n = Number of subjects reporting at least 1 occurrence of the specified event category. For "any event," n = number of
subjec ts reporting at least 1 occurrence of any event.
Cutoff date: March 13, 2021; unblinding date varied depending on subject contact date for unblinding.
Immediate AEs
The frequency of i mmediate AEs (defined as events occurring within the first 30
minutes following any dose) reported in the vaccine group was 0.5 % 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%). For both study groups, no participant
reported an immediate allergic reaction that was considered by the study investigator to
be related to vaccination or to the saline placebo.
Reviewer Comment: FDA agrees with the study investigators’ assessment.
Anaphylaxis
No anaphylactic reactions to BNT162b2 were reported through the cutoff date of March
13, 2021. During the open-label observational follow -up period for study C4591001,
among participants ≥16 years of age, 1 participant who received BNT162b2 as Dose 3
(crossover vaccination as subject was originally randomized to placebo) experienced an SAE of anaphylactoid reaction, which was assessed as related to study vaccine. The
subject, a female adolescent with a medical history significant for multiple allergies since infancy reported that 2 days after receiving BNT162b2, the appearance of hives
on her left arm (deltoid). Approximately 24 minutes after the appearance of the hives
she self-administered an epinephrine pen (personal medication given the history of
anaphylaxis to multiple allergens). Six minutes after injection, the subject experienced
shortness of breath. Hives and shortness of breath resolved within 10 and 30 minutes,
respectively, of epinephrine treatment. The subject did not seek additiona l medical
attention. As a result of the anaphylactoid reaction, the subject was permanently
withdrawn from the study (FDA 2021b).
During the blinded placebo-controlled follow -up period, three SAEs involving allergic
reactions were reported among three participants ≥16 years of age (previously reported
at November 14, 2020 cutoff date). A review of the temporal relationship to vaccination
and alternate inciting etiology does not support the administration of BNT162b as the
causative agent:
• Anaphylactic reaction following a bee sting in a BNT162b2 recipient (8 days after
Dose 2)
• Drug hypersensitivity to an antibiotic in a BNT162b2 recipient (9 days after Dose 2)
• Anaphylactic shock due to an ant bite in a placebo recipient (18 days after Dose 2) .
Solicited local reactions and s ystemic adverse events
Solicited Local Reactions
For each age group in the reactogenicity subset (younger: 16 -55 years, older: >55
years) and overall (16 years and older) , the median onset of solicited local reactions in
the vaccine group was 0 (day of vaccination) to 2 days after either dose and solicited
reactions 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 D ose 2, the younger age group reported any pain more frequently than
Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
STN:125742
59
the older age group ( 78.3% vs 66.1 %) and also pain characterized as moderate ( 29.4%
vs. 18.7 %); a similar pattern was observed after Dose 1. Injection site redness and
swelling after each dose were generally similar for both age groups.
Table 26 and Table 27 present the frequency and severity of reported solicited local
reactions within 7 days following each dose of BNT162b2 and placebo in the subset of
participants 16 55 years of age, and older than 55 years of age, respectively, included
in the safety population who were monitored for reactogenicity with an electronic diary.
Subgroup analyses by age
Table 26. Frequency of Solicited Local Reactions, by Maximum Severity, Within 7 Days
After Each Dose, Participants 16 Through 55 Years of Age, Reactogenicity Subset of the
Safety Population*
BNT162b2
Dose 1
Na =2899
nb (%) Placebo
Dose 1
Na =2908
nb (%) BNT162b2
Dose 2
Na =2682
nb (%) Placebo
Dose 2
Na =2684
nb (%)
Rednessc
Any (>2.0 cm) 156 (5.4) 28 (1.0) 151 (5.6) 18 (0.7)
Mild 113 (3.9) 19 (0.7) 90 (3.4) 12 (0.4)
Moderate 36 (1.2) 6 (0.2) 50 (1.9) 6 (0.2)
Severe 7 (0.2) 3 (0.1) 11 (0.4) 0
Swellingc
Any (>2.0 cm) 184 (6.3) 16 (0.6) 183 (6.8) 5 (0.2)
Mild 124 (4.3) 6 (0.2) 110 (4.1) 3 (0.1)
Moderate 54 (1.9) 8 (0.3) 66 (2.5) 2 (0.1)
Severe 6 (0.2) 2 (0.1) 7 (0.3) 0
Pain at the injection sited
Any 2426 (83.7) 414 (14.2) 2101 (78.3) 312 (11.6)
Mild 1464 (50.5) 391 (13.4) 1274 (47.5) 284 (10.6)
Moderate 923 (31.8) 20 (0.7) 788 (29.4) 28 (1.0)
Severe 39 (1.3) 3 (0.1) 39 (1.5) 0
Source: STN 125742.0 c4591001 -interim -mth6- report -body .pdf, Table 14.68, pages 531- 532.
Reactions were collected in the electronic diary (e- diary) from Day 1 to Day 7 after vaccination.
No Grade 4 solicited local reactions were reported in participants 16 through 55 years of age.
* Randomized participants in the safety analysis population who received at least 1 dose of the study intervention.
a. N = Number of participants reporting at least 1 yes or no response for the specified reaction after the specified dose.
b.n = Number of participants with the specified reaction.
c. Mild: 2.0 to ≤5.0 cm; Moderate: 5.0 to ≤10.0 cm; Severe: >10.0 cm.
d. Mild: does not interfere with activity; Moderate: interferes with activity; Severe: prevents daily activity.
Table 27. Frequency of Local Reactions, by Maximum Severity, Within 7 Days After Each
Dose , Participants Older Than 55 Years of Age , Reactogenicity Subset of the Safety
Population*
BNT162b2
Dose 1
Na =2008
nb (%) Placebo
Dose 1
Na =1989
nb (%) BNT162b2
Dose 2
Na =1860
nb (%) Placebo
Dose 2
Na =1833
nb (%)
Rednessc
Any (>2.0 cm) 106 (5.3) 20 (1.0) 133 (7.2) 14 (0.8)
Mild 71 (3.5) 13 (0.7) 65 (3.5) 10 (0.5)
Moderate 30 (1.5) 5 (0.3) 58 (3.1) 3 (0.2)
Severe 5 (0.2) 2 (0.1) 10 (0.5) 1 (0.1)
Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
STN:125742
60
BNT162b2
Dose 1
Na =2008
nb (%) Placebo
Dose 1
Na =1989
nb (%) BNT162b2
Dose 2
Na =1860
nb (%) Placebo
Dose 2
Na =1833
nb (%)
Swellingc
Any (>2.0 cm) 141 (7.0) 23 (1.2) 145 (7.8) 13 (0.7)
Mild 87 (4.3) 11 (0.6) 80 (4.3) 5 (0.3)
Moderate 52 (2.6) 12 (0.6) 61 (3.3) 7 (0.4)
Severe 2 (0.1) 0 (0.0) 4 (0.2) 1 (0.1)
Pain at the injection sited
Any (>2.0 cm) 1408 (70.1) 185 (9.3) 1230 (66.1) 143 (7.8)
Mild 1108 (55.2) 177 (8.9) 873 (46.9) 138 (7.5)
Moderate 296 (14.7) 8 (0.4) 347 (18.7) 5 (0.3)
Severe 4 (0.2) 0 (0.0) 10 (0.5) 0 (0.0)
Source: STN 125742.0 c4591001 -interim -mth6- report -body .pdf, Table 14.68, pages 532- 534.
Reactions were collected in the electronic diary (e- diary) from Day 1 to Day 7 after vaccination.
No Grade 4 solicited local reactions were reported in participants 16 through 55 years of age.
* Randomized participants in the safety analysis population who received at least 1 dose of the study intervention.
a. N = Number of participants reporting at least 1 yes or no response for the specified reaction after the specified dose.
b.n = Number of participants with the specified reaction.
c. Mild: 2.0 to ≤5.0 cm; Moderate: 5.0 to ≤10.0 c m; Severe: >10.0 cm.
d. Mild: does not interfere with activity; Moderate: interferes with activity; Severe: prevents daily activity.
Solicited Systemic Reactions
For each age group in the reactogenicity subset (younger: 16 -55 years, older: >55
years) and o verall (1 6 years and older) , the median onset of solicited systemic AEs in
the vaccine group in general was 1 to 2 days after either dose, and solicited systemic
AEs lasted a median duration of 1 day.
The frequenc ies of any and sever e solicited systemic AEs were higher in the younger
than the older age groups . Within each age group, the frequenc ies of any and sever e
systemic AEs w ere higher after Dose 2 than Dose 1, except for 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 28 and Table 29
present the frequenc ies and severities of reported solicited
systemic reactions within 7 days following each dose of BNT162b2 and placebo in the
subset of participants 16 -55 years of age, and > 55 years of age, respectively , included
in the safety population who were monitored for reactogenicity with an electronic diary.
Table 28. Frequency of Solicited Systemic Reactions, by Maximum Severity, Within
7 Days After Each Dose, Participants 16 Through 55 Years of Age, Reactogenicity Subset
of the Safety Population*
BNT162b2
Dose 1
Na =2899
nb (%) Placebo
Dose 1
Na =2908
nb (%) BNT162b2
Dose 2
Na =2682
nb (%) Placebo
Dose 2
Na =2684
nb (%)
Fever
≥38.0℃ 119 (4.1) 25 (0.9) 440 (16.4) 11 (0.4)
≥38.0℃ to 38.4℃ 86 (3.0) 16 (0.6) 254 (9.5) 5 (0.2)
>38.4℃ to 38.9℃ 25 (0.9) 5 (0.2) 146 (5.4) 4 (0.1)
>38.9℃ to 40.0℃ 8 (0.3) 4 (0.1) 39 (1.5) 2 (0.1)
>40.0℃ 0 (0.0) 0 (0.0) 1 (0.0) 0 (0.0)
Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
STN:125742
61
BNT162b2
Dose 1
Na =2899
nb (%) Placebo
Dose 1
Na =2908
nb (%) BNT162b2
Dose 2
Na =2682
nb (%) Placebo
Dose 2
Na =2684
nb (%)
Fatiguec
Any 1431 (49.4) 960 (33.0) 1649 (61.5) 614 (22.9)
Mild 760 (26.2) 570 (19.6) 558 (20.8) 317 (11.8)
Moderate 630 (21.7) 372 (12.8) 949 (35.4) 283 (10.5)
Severe 41 (1.4) 18 (0.6) 142 (5.3) 14 (0.5)
Headachec
Any 1262 (43.5) 975 (33.5) 1448 (54.0) 652 (24.3)
Mild 785 (27.1) 633 (21.8) 699 (26.1) 404 (15.1)
Moderate 444 (15.3) 318 (10.9) 658 (24.5) 230 (8.6)
Severe 33 (1.1) 24 (0.8) 91 (3.4) 18 (0.7)
Chillsc
Any 479 (16.5) 199 (6.8) 1015 (37.8) 114 (4.2)
Mild 338 (11.7) 148 (5.1) 477 (17.8) 89 (3.3)
Moderate 126 (4.3) 49 (1.7) 469 (17.5) 23 (0.9)
Severe 15 (0.5) 2 (0.1) 69 (2.6) 2 (0.1)
Vomitingd
Any 34 (1.2) 36 (1.2) 58 (2.2) 30 (1.1)
Mild 29 (1.0) 30 (1.0) 42 (1.6) 20 (0.7)
Moderate 5 (0.2) 5 (0.2) 12 (0.4) 10 (0.4)
Severe 0 (0.0) 1 (0.0) 4 (0.1) 0 (0.0)
Diarrheae
Any 309 (10.7) 323 (11.1) 269 (10.0) 205 (7.6)
Mild 251 (8.7) 264 (9.1) 219 (8.2) 169 (6.3)
Moderate 55 (1.9) 58 (2.0) 44 (1.6) 35 (1.3)
Severe 3 (0.1) 1 (0.0) 6 (0.2) 1 (0.0)
New or worsened muscle painc
Any 664 (22.9) 329 (11.3) 1055 (39.3) 237 (8.8)
Mild 353 (12.2) 231 (7.9) 441 (16.4) 150 (5.6)
Moderate 296 (10.2) 96 (3.3) 552 (20.6) 84 (3.1)
Severe 15 (0.5) 2 (0.1) 62 (2.3) 3 (0.1)
New or worsened joint painc
Any 342 (11.8) 168 (5.8) 638 (23.8) 147 (5.5)
Mild 200 (6.9) 112 (3.9) 291 (10.9) 82 (3.1)
Moderate 137 (4.7) 55 (1.9) 320 (11.9) 61 (2.3)
Severe 5 (0.2) 1 (0.0) 27 (1.0) 4 (0.1)
Use of antipyretic or pain
medicationf 805 (27.8) 398 (13.7) 1213 (45.2) 320 (11.9)
Source: STN 125742.0 c4591001 -interim -mth6- report -body .pdf, Table 14.75, pages 553- 557.
Reactions and use of antipyretic or pain medication were collected in the electronic diary (e- diary) from Day 1 to Day 7
after each dose.
No Grade 4 solicited systemic reactions were reported in participants 16 through 55 years of age.
* Randomized participants in the safety analysis population who received at least 1 dose of the study intervention.
a. N = Number of participants reporting at l east 1 yes or no response for the specified reaction after the specified dose.
b. n = Number of participants with the specified reaction.
c. Mild: does not interfere with activity; Moderate: some interference with activity; Severe: prevents daily activity.
d. Mild: 1 to 2 times in 24 hours; Moderate: >2 times in 24 hours; Severe: requires intravenous hydration.
e. 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.
f. Severity was not collected for use of antipyretic or pain medication.
Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
STN:125742
62
Table 29. Frequency of Solicited Systemic Reactions, by Maximum Severity, Within 7
Days After Each Dose, Participants Older than 55 Years of Age , Reactogenicity Subset of
the Safety Population*
BNT162b2
Dose 1
Na =2008
nb (%) Placebo
Dose 1
Na =1989
nb (%) BNT162b2
Dose 2
Na =1860
nb (%) Placebo
Dose 2
Na =1833
nb (%)
Fever
≥38.0℃ 26 (1.3) 8 (0.4) 219 (11.8) 4 (0.2)
≥38.0℃ to 38.4℃ 23 (1.1) 3 (0.2) 158 (8.5) 2 (0.1)
>38.4℃ to 38.9℃ 2 (0.1) 3 (0.2) 54 (2.9) 1 (0.1)
>38.9℃ to 40.0℃ 1 (0.0) 2 (0.1) 7 (0.4) 1 (0.1)
>40.0℃ 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
Fatiguec
Any 677 (33.7) 447 (22.5) 949 (51.0) 306 (16.7)
Mild 415 (20.7) 281 (14.1) 391 (21.0) 183 (10.0)
Moderate 259 (12.9) 163 (8.2) 497 (26.7) 121 (6.6)
Severe 3 (0.1) 3 (0.2) 60 (3.2) 2 (0.1)
Grade 4 0 0 1 (0.1) 0
Headachec
Any 503 (25.0) 363 (18.3) 733 (39.4) 259 (14.1)
Mild 381 (19.0) 267 (13.4) 464 (24.9) 189 (10.3)
Moderate 120 (6.0) 93 (4.7) 256 (13.8) 65 (3.5)
Severe 2 (0.1) 3 (0.2) 13 (0.7) 5 (0.3)
Chillsc
Any 130 (6.5) 69 (3.5) 435 (23.4) 57 (3.1)
Mild 102 (5.1) 49 (2.5) 229 (12.3) 45 (2.5)
Moderate 28 (1.4) 19 (1.0) 185 (9.9) 12 (0.7)
Severe 0 1 (0.1) 21 (1.1) 0
Vomitingd
Any 10 (0.5) 9 (0.5) 13 (0.7) 5 (0.3)
Mild 9 (0.4) 9 (0.5) 10 (0.5) 5 (0.3)
Moderate 1 (0.0) 0 1 (0.1) 0
Severe 0 0 2 (0.1) 0
Diarrheae
Any 168 (8.4) 130 (6.5) 152 (8.2) 102 (5.6)
Mild 137 (6.8) 109 (5.5) 125 (6.7) 76 (4.1)
Moderate 27 (1.3) 20 (1.0) 25 (1.3) 22 (1.2)
Severe 4 (0.2) 1 (0.1) 2 (0.1) 4 (0.2)
New or worsened muscle painc
Any 274 (13.6) 165 (8.3) 537 (28.9) 99 (5.4)
Mild 183 (9.1) 111 (5.6) 229 (12.3) 65 (3.5)
Moderate 90 (4.5) 51 (2.6) 288 (15.5) 33 (1.8)
Severe 1 (0.0) 3 (0.2) 20 (1.1) 1 (0.1)
New or worsened joint painc
Any 175 (8.7) 124 (6.2) 353 (19.0) 72 (3.9)
Mild 119 (5.9) 78 (3.9) 183 (9.8) 44 (2.4)
Moderate 53 (2.6) 45 (2.3) 161 (8.7) 27 (1.5)
Severe 3 (0.1) 1 (0.1) 9 (0.5) 1 (0.1)
Use of antipyretic or
pain medicationf 382 (19.0) 224 (11.3) 688 (37.0) 170 (9.3)
Source: STN 125742.0 c4591001 -interim -mth6- report -body .pdf, Table 14.75, pages 557- 562.
Reactions and use of antipyretic or pain medication were collected in the electronic diary (e- diary) from Day 1 to Day 7
after each dose.
The only Grade 4 solicited systemic reaction reported in participants > 55 years of age was fatigue.
Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
STN:125742
63
* Randomized participants in the safety analysis population who received at least 1 dose of the study intervention.
a. N = Number of participants reporting at least 1 yes or no response for the specified reaction after the specified dose.
b. n = Number of participants with the specified reaction.
c. Mild: does not interfere with activity ; Moderate: some interference with activity; Severe: prevents daily activity.
d. Mild: 1 to 2 times in 24 hours; Moderate: >2 times in 24 hours; Severe: requires intravenous hydration.
e. 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.
f. Severity was not collected for use of antipyretic or pain medication.
Unsolicited (non-serious and serious) AEs
Non-serious unsolicited AEs
Dose 1 through 1 month after Dose 2
A higher frequency of unsolicited, non-serious adverse events was reported in the
vaccine group (29.9%) compared to placebo group (13.7 %). These excess AEs in the
vaccine group were primarily attributed to local reactions and systemic adverse events
reported during the first 7 days following vaccination in participants not enrolled in the
reactogenicity subset and are consistent with solicited reactions/events reported by
reactogenicity subset participants. Table 30 below presents unsolicited adverse events
reported by at least 1% of participants in any treatment group for the s afety population,
with the total number of events reported, in addition to the number of events that were
graded as severe.
Table 30. Frequency of Any and Severe Unsolicited Adverse Events Occurring in ≥1% of
Participants in Any Treatment Group From Dose 1 to 1 Month After Dose 2, Safety
Population
System Organ Class
Preferred Term BNT162b2
(N=21926)
Any n (%)
Severe n (%) Placebo
(N=21921)
Any n (%)
Severe n (%)
Gastrointestinal disorders
Diarrhea 248 (1.1)
4 (<0.1) 188 (0.9)
5 (<0.1)
Nausea 274 (1.2)
1 (<0.1) 87 (0.4)
2 (<0.1)
General disorders and administration site conditions
Chills 1365 (6.2)
18 (0.1) 120 (0.5)
0
Fatigue 1463 (6.7)
24 (0.1) 379 (1.7)
2 (<0.1)
Injection site pain 2915 (13.3)
19 (0.1) 397 (1.8)
0 (<0.1)
Pain 628 (2.9)
9 (<0.1) 61 (0.3)
0
Pyrexia 1517 (6.9)
38 (0.2) 77 (0.4)
1 (<0.1)
Musculoskeletal and connective tissue disorders
Arthralgia 268 (1.2)
4 (<0.1) 102 (0.5)
6 (<0.1)
Myalgia 1239 (5.7)
21 (0.1) 168 (0.8)
3 (<0.1)
Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
STN:125742
64
System Organ Class
Preferred Term BNT162b2
(N=21926)
Any n (%)
Severe n (%) Placebo
(N=21921)
Any n (%)
Severe n (%)
Nervous system disorders
Headache 1339 (6.1)
25 (0.1) 424 (1.9)
10 (<0.1)
Source: STN 125742.037 c4591001- 508-safety tables , Table R, Page 18
MedDRA v23.1 coding dictionary applied.
Adverse events in any PT = at least one adverse event experienced (regardless of the MedDRA Preferred Term)
%: n/N. n = n umber 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.
Data analysis c utoff date: March 13, 2021
Unsolicited AEs of clinical interest (serious and non-serious)
FDA independently conducted Standardi sed MedDRA Queries (SMQs) using FDA -
developed software 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 were queried to evaluate
the occurrence of unsolicited events in the vaccine and placebo groups during the
various follow -up periods ( blinded, placebo-controlled and open label).
Dose 1 to 1 month after Dose 2
The SMQs conducted on the Phase 2/3 safety population from Dose 1 to 1 month after
Dose 2 revealed a slight numerical imbalance of adverse events potentially
representing allergic reactions, with more participants reporting hypersensitivity -related
adverse events in the vaccine group ( 272 participants [1.1%] reporting 234 events )
compared with the placebo group ( 225 participants [0.9%] reporting 190 events ).
Review of the hypersensitivity -related events indicates that most events were classified
as skin or subcutaneous disorders with a slightly increased incidence in the vaccine
group when compared to the placebo group of 152 and 123 events , respectively. Rash
was the most commonly noted skin finding with 60 events in the vaccine group and 46
events in the placebo group. No imbalances between treatment groups were evident for any of the other SMQs evaluated.
Reports of lymphadenopathy were imbalanced with notably more cases in the vaccine
group ( 83, one of which was serious) vs. the placebo group ( 7). The majority of events
were mild or moderate, with 3 severe events reported, all in the BNT162b2 group. The median onset of lymphadenopathy following BNT162b2 was 5.5 days for Dose 1, with a shorter median onset of 2 days following Dose 2 of BNT162b2. Median duration of
lymphadenopathy was 5.5 days in the BNT162b2 group.
Dose 1 to data cutoff date or participant’s unblinding date (whichever was earlier)
The previously noted imbalances between the vaccine and the placebo group for
hypersensitivity -related adverse events and lymphadenopathy remained evident, as
described above. Notable findings regarding other AEs of clinical interest reported
during blinded, placebo- controlled follow -up are summarized below. Very small
numerical imbalances between the vaccine and placebo groups for Optic neuritis (2 vaccine vs. 0 placebo) and Encephalopathy (2 vaccine vs. 0 placebo) involved adverse
events that were not assessed as related to BNT162b2 by the investigator, and FDA review of the detail s of these adverse events did not identify a basis to conclude a
Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
STN:125742
65
causal relationship. Otherwise, no imbalances in non-serious unsolicited AEs between
treatment groups were evident for any of the other SMQs evaluated.
AEs of clinical interest
Cardiac Disorders
The overall occurrence of cardiac disorders was numerically greater in the BNT162b2 vaccine group when compared to the placebo group (87 to 78,
respectively ), but for both groups the numbers represented an occurrence rate of
0.4%, with more participants in the older age groups (>55 years of age) reporting cardiac disorders compared with the younger age groups. Within each age group,
rates of cardiac disorders were similar between the BNT162b2 vaccine group and
placebo group, with the exception of tachycardia, which occurred more frequently in
the younger age group subjects who received BNT162b2. See Appendix B
for a list
of cardiac disorders that occurred from Dose 1 to date of unblinding among Phase
2/3 partic ipants 16 years of age and older .
Bell’s Palsy
Bell’s palsy (facial paralysis) was reported by 4 participants in the BNT162b2 group
and 2 participants in the placebo group. Onset of facial paralysis was Day 37 after
Dose 1 (participant did not receive Dose 2) and Days 3, 9, and 48 after Dose 2. In
the placebo group, the onset of facial paralysis was Day 32 and Day 102.
Deafnes s
A total of 11 cases (6 in the BNT162b2 group and 5 in the placebo group) were
reported that included the following preferred terms associated with deafness:
deafness, deafness unilateral, deafness neurosensory, hypoacusis and sudden
hearing loss. The tox icity grades were mostly mild (4 in the BNT162b2 group and 2
in placebo) or moderate (1 in the BNT162b2 group and 3 in placebo), with one
being severe (BNT162b2 group). For BNT162b2 recipients, the age range was 43-
65 years of age, with one event occurring 19 days after Dose 1 and onset ranging
from 1-55 days after Dose 2. Two of the reported events were considered by
investigators as possibly related to BNT162b2:
• One female participant >55 years of age reported unilateral deafness which
occurred 19 days after Dose 1 and resolved 9 days later. The participant
was discontinued from study intervention and remained in the study for
safety evaluation.
• One female participant 16-55 years of age reported unilateral deafness and
dizziness which occurred 1 day after Dose 2, which was ongoing at the time of the data cutoff.
One report of sudden unilateral neurosensory deafness was still ongoing at the time
of the data cutoff and occurred in a BNT162b2 recipient 55 days after Dose 2. The event was considered u nlikely to be related to the study intervention by the
investigator, and FDA agrees with this assessment.
Deep Vein Thrombosis (DVT) and Other Venous Thromboembolic Events
One BNT162b2 recipient and one placebo recipient reported DVT characterized as
non-serious AEs. The BNT162b2 recipient developed a DVT in the leg 14 days after
Dose 2, which resolved after 6 days and was assessed by the study investigator as
unrelated to vaccination; no hematologic res ults or medical intervention details were
provided. The placebo recipient developed a DVT in the leg 85 days after placebo
Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
STN:125742
66
Dose 2 that resolved after 1 day and was attributed by the study investigator to
metabolic causes. No further information was provided.
During the blinded placebo-controlled follow -up period, two subjects who received
BNT162b2 experienced venous thromboembolic events following Dose 2
(coagulopathy at 150 days and ophthalmic vein thrombosis at 70 days after the last
vaccination). No sim ilar events were observed in the placebo cohort. Neither event
was temporally related to vaccination; both events were considered not related to
vaccination by FDA.
None of the above events were associated with thrombocytopenia per the
Applicant.
Guillain -Barre syndrome
One male placebo recipient (baseline SARS -CoV-2 negative) ≤ 55 years of age
reported the occurrence of Guillain -Barre syndrome, which was considered a SAE
and ongoing at the data cutoff. No vaccine recipients reported AEs consistent with
Guillain -Barre syndrome.
Open-label observational follow -up: from participant unblinding to the March 13, 2021
data cutoff
In independent FDA analys es of SMQs of non- serious AEs occurrin g in the unblinded
follow -up period, there were no notable patterns of specific categories of AEs that would
suggest a causal relationship to BNT162b2.
Original BNT162b2 recipients
Overall, 20,309 original BNT162b2 recipients were followed after unblinding. Of these,
243 (1.2%) participants reported any adverse event; 20 (0.1%) participants had at least
1 occurrence of an event that was considered related to the vaccine, and 43 (0.2% )
participants had at least 1 occurrence of an event that was graded as severe.
Overall, the rates of AEs in all System Organ Classes ( SOCs ) after the unblinding date
decreased or remained similar to those in the blinded placebo-controlled period. The
most commonly reported events occurred in the SOC of I njury, poisoning and
procedural complications with 40 (0.2%) participants reporting at least 1 event, and the Preferred Term (PT) Fall had the highest number of participants (n=10). The SOC of
Vascular disorders was reported by 23 (0.1%) participants, with the PT H ypertension
having the highest number of participants (n=17).
Of the 20 participants who reported at least 1 event considered related to the vaccine,
the events were similar to reactogenicity events, reflecting AEs within 7 days of
vaccination (n=3 participants) or events reported more than 7 days from vaccination
indicating either recurrent or prolonged reactogenicity symptoms. Note that one
participant can report multiple events.
The most common SOCs and PTs are listed below:
• 13 participants reported at least 1 event in the SOC General disorders and
administration site conditions: I njection site pain (7), F atigue (6), Chills (3), Pain,
and Pyrexia ( 2 each) and 1 reported I njection site swelling.
• 6 participants reported at least 1 event in the SOC N ervous system disorders:
Headache (5), D izziness (2) and 1 reported D ysgeusia (altered/impaired taste).
Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
STN:125742
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• 4 participants reported at least 1 event in the SOC M usculoskeletal and connective
tissue disorders : Myalgia (2) and 1 participant each reported Back pain and Pain in
extremity.
Placebo recipients who were unblinded and received BNT162b2
Overall, 19,525 original placebo participants were unblinded and received BNT162b2.
The number of participants reporting any AE and at least 1 related AE were
4,885/19, 525 ( 2.5%) and 4,508/19, 525 ( 2.3%), respectively. The number of participan
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