Document text
Stati stical Review
STN: 125742/0
Page i Application Type BLA, Original Application
STN 125742/0
CBER Received Date May 18, 2021
PDUFA Goal Date January 16, 2022
Division / Office DVRPA /OVRR
Committee Chair Ramachandra Naik
Clinical Reviewer(s) Ann Schwartz; Susan Wollersheim
Project Mana ger Mike Smith ; Laura Gottsch alk
Priority Review Yes
Reviewer Name(s) Lei Huang
Review Completion Date /
Stamped Date
Supervisory Concur rence Tsai-Lien Lin, Bra nch Chief, VEB, DB,
OBE
John A. Scott, Director, DB, OBE
Applicant BioNTech Manufacturi ng GmbH (in
partners hip with Pfizer, Inc. )
Established Name COVID -19 Vaccine , mRNA
(Proposed) Trade Name COMIRNATY
Pharmacologic Class Vaccine
Formulation(s), including
Adjuvants, etc After preparation, each 0.3 mL dose
contains 30ug modified mRNA encoding
SARS -CoV -2 spike glycoprotei n
Dosage Form(s) and Route(s) of
Administration Injectable Suspension, Intramuscular
Dosing Regimen Two 0.3 mL doses , 3 weeks ap art
Indication(s) and Intended
Population(s) Active immunization to prevent
coronavirus disease 2019 (C OVID- 19)
caused by severe acute respiratory
syndrome coronavirus 2 (SARS- CoV -2) in
individuals 16 years of age and older.
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Page ii Table of Contents
Glossary ............................................................................................................................. 3
1. Executive Summary ...................................................................................................... 3
2. Clinical and Regulatory Background ......................................................................... 4
3. Submission Qualit y and Good Clinic al Practices ...................................................... 4
3.1 Submission Quality and Completeness ................................ ................................ .......................... 4
3.2 Compliance With Good Clinical Practices And Data Integrity ................................ ................... 4
4. Significant Efficacy/Safety Issues Related to Other Review Disciplines.................. 5
5. Sources of Clinical Data and Other Information Considered in th e Review .......... 5
5.1 Review Strategy ................................ ................................ ................................ ............................... 5
5.2 BLA/IND Documents That Serve as the Basis for the Statistical Review ................................ ... 5
5.3 Table of Studies/Clinical Trials ................................ ................................ ................................ ...... 6
6. Discussion of Individual Studies/Clinical Tri als ........................................................ 7
6.1 Study C4591001 ................................ ................................ ................................ ............................... 7
6.1.1 Objectives ................................ ................................ ................................ ................................ 7
6.1.2 Design Overview ................................ ................................ ................................ ..................... 8
6.1.3 P opulation ................................ ................................ ................................ ............................. 10
6.1.4 Study Treatments or Agents Mandated by the Protocol ................................ ........................ 10
6.1.6 Sites and Centers ................................ ................................ ................................ ................... 10
6.1.7 Surveillance/Monitoring ................................ ................................ ................................ ........ 10
6.1.8 Endpoints and Cr iteria for Study Success ................................ ................................ ............. 11
6.1.9 Statistical Considerations & Statistical Analysis Plan ................................ .......................... 11
6.1.10 Study Population and Disposition ................................ ................................ ....................... 12
6.1.11 Efficacy Analyses ................................ ................................ ................................ ................ 16
6.1.12 Safety Analyses ................................ ................................ ................................ ................... 25
7. Integrated Overview of Efficacy ................................................................................ 25
8. Integr ated Overvie w of Safety ................................................................................... 25
9. Additional Statistical Issues ....................................................................................... 25
10. Conclusions ................................................................................................................ 25
10.1 Statistical Issues and Collective Evidence ................................ ................................ ................. 25
10.2 Conclusions and Recommendations ................................ ................................ ........................... 26
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Page 3 GLOSSARY
BIMO Bioresearch Monitoring
BNT162b 2 Pfize rBioNTech COVID -19 Vaccin e
CDC Centers for Disease Control an d Preventio n
CI Confidence interval
COVID -19 coronavirus disease 201 9
EUA Emergency Use Authorizatio n
HHS Health and Human Serv ices
HIV human immunodeficiency viru s
IM intramuscula r
IR Information request
LNP lipid nanoparticl e
modRN A nucleoside -modified messenger RNA
NAA T nucleic acid amplification -based tes t
PY person -years
RT-PCR reverse transcription -polymerase c hain reactio n
SAR S-CoV -2 severe acute respiratory syndrome coronavirus 2
VE vaccine efficac y
VRBPAC Vaccines and Related Biological Products Advisory Committe e
WHO World Health Organization
1. EXECUTIVE SUMMARY
Pfizer submitted a Biologics Licen se Application ( BLA 125742/0) on May 18, 2021 to
seek licensure of the Pfizer -BioNTech COVID-19 Vaccine (BNT162b2) for active
immunization to prevent Coronavirus Disease 2019 (COVID -19) caused by Severe Acute
Respiratory Syndrome C oronavirus 2 ( SARS -CoV-2) in individual s 16 years of age and
older. The BLA is supported by safety, efficacy, and immunogenicity data from two ongoing studies (C4591001 and BNT-162- 01). This statistical review focuses on the
analyses of efficacy data collect ed during the blinded, placebo -contro lled follow-up in the
Phase 2/3 portion of Study C4591001. Study C4591001 is an ongoing, randomized, placebo-controlled, observer-blinded Phase
1/2/3 study being conducted in the United States, Argentina, Brazil, Germany, South Africa, and T urkey. In the Phase 2/3 portion of the study, 44,165 subjects aged 16 and
above were randomized 1:1 to receive two doses of BNT162b2 or placebo 21 days apart .
Randomization was stratified by age group. Starting December 14, 2020, following
issuance of an Emergency Use Authorization (EUA) , participants 16 years of age and
older were systematically unblinded when e ligible per local recommendations and
offered BNT162b2 vaccination if they had been randomized to placebo.
In the updated effic acy analysis f or cases accrued during blinded placebo -controlled
follow-up (cut off date: March 13, 2021) of Study C4591001 in parti cipants 16 years of
age and ol der, the estimated vaccine efficacy ( VE) against confirmed COVID -19
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Page 4 occurring at least 7 days after Dose 2 was 91. 1% (95% CI: 88.8%, 93.1%), with 77
COVID- 19 cases in the B NT162b2 group comp ared to 833 cases in the placebo gro up
among participants without evidence of SARS-CoV-2 infection before and during the
vaccination regimen; the estimated vaccine efficacy ( VE) against confirmed COVID-19
occurring at least 7 days after D ose 2 was 9 0.9% (95% CI: 88. 5%, 92.8%), with 81
COVID- 19 cases in the BNT162b2 group compared to 854 cases in the placebo group
among participants with or without evidence of SARS- CoV-2 infection before and during
the vaccination regimen .
With respect to efficacy against severe COVID- 19 cases occurring at least 7 days after
Dose 2, the estimated V E was 95.3% (95% CI: 71.0%, 99.9%), with 1 and 21 cases in the
BNT162b2 and placebo groups, respectively, among participants without evide nce of
SARS -CoV-2 infec tion; the VE r esult was the same among participants with or without
evidence of SARS -CoV- 2 infection .
Overall, the updated efficacy analysis results show that BNT162b2 provided high VE in
preventing sympt omatic COVID-19 and severe COVID -19 cases.
2. CLINICAL AND REGULATORY BACKGROUND
Coronavirus disease 2019 (COVID-19) is an infectious disease caused by SARS -CoV-
2, a novel coronavirus that emerged in late 2019 in patients with pneumoni a of unknown
cause. On January 31, 2020, the United States Secretary of Health and Human
Services ( HHS ) made the declarati on that COVID-19 constitutes a nationwide public
health emergency. On March 11, 2020, the World Health Organization (WHO) declar ed
the C OVID-19 outbreak a pandemic.
The BNT162b2 vaccine, developed by BioNTech Manufacturing GmbH in partners hip
with Pfizer, Inc. , was granted Fast Track Designa tion on July 7, 2020 for individuals ≥ 18
years of age. An Emergency Use Authorization ( EUA) was granted in the U.S. on
December 11, 2020 for individuals ≥ 16 years of age (EUA 27034). An amendment to the
EUA was submitted on May 10, 2021 to support emergency use in participants 12 to 15
years of age.
3. SUBMISSION QUALITY AND GOOD CLINICAL PRACTICES
3.1 Subm ission Quality and Completeness
The submission was adequately organized and integrated to accommodate the conduct of a complete statistical review .
3.2 Compliance With Good Clinical Pract ices And Data Integrity
Please refer to Haecin Chun’s Bior esearch Monitoring ( BIMO ) review memo.
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DISCIPLINES
Please refer to other review disci plines ’ memo s.
5. SOURCES OF CLINICAL DATA AND OTHER INFORMATION CONSIDERE D IN THE
REVIEW
5.1 Review Strat egy
This me mo fo cuses on the statistical review of clinical efficacy data. Plea se refer to Dr.
Ye Yang ’s memo for the statistical review of clinical safety data, and to Dr. Xinyu
Tang ’s memo for the statistical review of non -clinical data.
To demonstrate e fficacy of BN T162b2, the applicant provided the efficacy results from
the interim analys is (cutoff date: November 4, 2020) , the final analysis ( cutoff date:
November 14, 2020), and an updated anal ysis for cases accrued during blinded placebo -
controlled f ollow-up (cutoff date: March 13, 2021) for Study C4591001. As the efficacy
results from th e interim and final analyses supported the issuance of an EUA and have
been r eviewed under EUA 27034, this statistical review primarily focuses on the updated
efficacy results .
5.2 BLA/IND Documents That Serve as the Basis f or the Statistical Review
The f ollowing documents submitted to the BLA are reviewed:
125742/0 (submitted on 5/6/2021) Module 2. Common Te chnical Document Summaries
• Clinical O verview
• Summary of Clinical Efficacy
Module 5. Clinical Study Reports
• C4591001 Statistical Analysis Plan
• C4591001 Interim 6- Month Report
125742/0.3 (submitted on 5/19/2021) Module 1.11. 3 Clinical Information Amendmen t
• Response to FDA 18 Ma y 2021 IR
125742/0.17 (submitted on 7/26/2021) Module 1.11.3 Clinical Information Amendment
• Response to CBER Clinical 22 July 2021 Info Request
125742/0.18 (submitted on 7/28/2021)
Module 1.11.3 Cli nical Information Amendment
• Response to CBER 22 July 2021 Info Request
125742/0.27 (subm itted on 8/2/2021)
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Page 6 Module 1.14.1 Draft L abeling
125742/0.28 (submitted on 8/02/2021)
Module 1.11.3 Clinical Information Amendment
• Response to CBER Clinical 22 J uly 202 1 Information Request
125742/0.32 (submitted on 8/05/2021)
Module 1.11.3 Clinical Info rmation Amendment
• Response 22 Jul 2021 – Follow-up #3
Module 5 Clinical Study Reports
• C4591001 – 508 Efficacy Tables
125742/0.38 (submitted on 8/09/2021)
Module 1.14.1 Draft Lab eling
Module 5 C linical Study Reports
• C4591001 – Source Vaccine Efficacy Tables
125742/0.49 (submitted on 8/16/2021)
Module 1.14.1 Draft Lab eling
Module 5 C linical Study Reports
• C4591001 – Follow Up Table (with and without evidence of infection )
5.3 Table of Studies/Clinical Trials
Data from two o ngoing clinical stu dies were submitted to support the licensing
application for BNT162b2 and are summarized in Table 1 below. The pivotal d ata are
derived from a single s tudy, C4591001, which is a mu lti-center, Phase 1/2/3, randomized,
double-blinded, placebo- controlled safety, immuno genicity, and efficacy study; the
second study, BNT162-01, is a Phase 1 safety and immunog enicity study evalua ting
various vaccine candidates and dose levels.
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Page 7 Table 1. Clinical Trials Support ing Licensure of the Pfizer -BioNTe ch COVID -19 Vaccine
Study Num ber/
Country Description BNT162b2 (30 µg)*
participants
(N) Placebo
participant s
(N) Study
Status
C4591001
Argentina, Brazil,
Germany, S.
Africa, Turkey,
U.S.A. Phase 1/2/3 randomized, placebo -
controlled, observer -blind; to
evaluate safety, immunogenicity
and efficacy of COVID- 19
vaccine Phase 1a: 24
Phase 2/3b: 22085 Phase 1a: 6
Phase 2/3b: 22080 Ongoing
BNT16 2-01
Germany Phase 1/2 randomized, open -label;
to evaluate safety and
immunogenicity, dose escalation 24 0 Ongoing
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 vaccin ated with other dose levels a nd 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 to 55 years and 56 to 85
years); Phase 3: enrolled individual s ≥16 years of age (stratifie d as 16-55 years and >55 years of age).
Source: Summarized by reviewer based o n information provided in Modul e 2 - Clinical Overvi ew.
6. DISCUSSION OF INDIVIDUAL STUDIES /CLINICAL TRIALS
6.1 Study C4591001
Title : Phase 1/2 /3, Placebo -Controlled, Randomized, Observer-Blind, Dose-Finding
Study to Evaluate the Safety, Tolerability, Immunogenicity, and Efficacy of S ARS -CoV-
2 RNA Vaccin e Candidates Against COVID- 19 in Healthy Individuals
First Subject First Visit : April 29, 2020
Data Cut -off: Mach 13, 2021
6.1.1 Objectives
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 part icipants without evidence of SARS-CoV- 2 infection
before vaccination.
Endpoint: COVID-19 disease based on laboratory-confi rmed nucleic acid
amplification -based test (NAAT ) in participants with no serological or vi rological
evidence (up to 7 days after Do se 2) of past SARS -CoV-2 infection.
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Page 8 2. To evaluate the efficacy of BNT162b2 against confirmed COVID-19 occurring
from 7 days after Dose 2 in participants with and without evi dence of SARS- CoV-2
infection before vaccination.
Endpoint : COVID- 19 disease based on laboratory- confirmed NAAT
Secondary efficacy obje ctives
• To evaluate the eff icacy of B NT162b2 against confirmed COVID-19 occurring
from 14 day s after Dose 2 in
o participants without ev idence of SARS -CoV-2 infection be fore vaccination
(Dose 1)
o participants with and without evidence of SARS -CoV-2 infection before
vaccination (Dose 1)
Endpoint: COVID-19 disease based on laboratory- confirmed NAAT
• To evaluate the efficacy of BNT162b2 agai nst severe COVID-19 occurring from 7
days and from 14 days after Dose 2 in
o participants without evidence of SARS -CoV-2 in fection be fore vaccination
o participants with and without evidence of SARS -CoV-2 infection before
vaccination
Endpoint : Severe COVID-19 disease
• To describe the efficacy of BNT162b2 against confirmed COVID- 19 (CDC-defined
symptoms) occurr ing from 7 days and from 14 days after Dose 2 in
o participants without evidence of SARS -CoV-2 infe ction before vaccin ation
o partic ipants with and without evidence of infection before vaccination
Endpoint : COVID-19 disease (CDC-defined sympto ms) based on laboratory-
confirmed NAAT
6.1.2 Design Overview
Study C4591001 is an ongoing, randomized, placebo-controlled, observer-blinded Phase
1/2/3 study being conducted in the U .S., Argentina, Brazil, Germany, South Africa and
Turkey. In itially the study was designed as a Phase 1/2 study in healthy adults in the U .S.
for vaccine cand idate and dosage selection , as well as evaluation of immunogenicity and
preliminary efficac y. The protocol was expan ded to include a P hase 2/ 3 portion o f
the study to evaluat e clinical disease efficacy endpoint in individuals 12 years of age and
older in the U .S. an d additional sites outside of the U .S. This review will focus on
data collect ed from participants 16 years of age and older.
The Phase 1 portion of the study was designed to identify a pref erred vaccine
candidate(s) and vaccine dose level(s ) for furthe r development based on safety,
tolerability, and immunogenicity. To this end, two age groups were evaluated in separate
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Page 9 cohorts : younger adult s 18 through 55 years of age (N=45) and older adult s 65 through
85 years of age (N=45). The study population included healthy men and wom en and
excluded participants at high risk of SARS- CoV- 2 infection or with serological evidence
of pr ior or current SA RS-CoV-2 infection. Two different vaccine candidates were
evaluated, a nd younger participants received e scalating d ose levels E valuation of
escalating dose levels in the older age group (65 through 85 years), we re based on
recommendations from an internal review committee that rev iewed safety and
immunogenicity da ta. For each vaccine candidate and dose level, participants were
randomized 4:1, such that 12 participants received the vaccine candi date and 3
particip ants received placebo. Review of the safety and immunogenicity from Phase 1, in
combination with d ata fr om Study BNT162-01 (see S ection 6.2 of this review ), supported
the final vaccine candidate and dose level (BNT162b2 at 30 μ g, given 21 days apart) to
proceed into Phas e 2/3.
In Phase 2/3, participants were initially enrolled with stratification by age (younger
adults: 18 through 55 years of age; older adults: over 55 years of age) and a goal of 40% enrollment in the older adult age group. Adolescents 16- 17 years of age ( and
subsequently 12-15 years of age) were added to the protocol later, based on review of
safety data in younger adults enrolled in the ongoing study. The study population for Phase 2/3 includes participants at higher risk for acquiring COVID-19 and at higher risk
of severe COVID -19 disease, such as participants working in the healthcare field,
participants with autoimmune disease, and participants with chronic but stable medical conditions such as hypertensi on, asthma, diab etes, and infe ction with HIV, hepatitis B or
hepatitis C. Participants were randomized 1:1 to receive 2 doses of either BNT162b2 or
placebo, 21 days apart. The Phase 2 portion of the study evaluated reactogenicity and immunogenicity for 360 participants en rolled early , and these participants also
contribute to the overall efficacy and safety data in the Phase 3 port ion.
The ongoing Phase 3 portion of the study is evalua ting the safety and efficacy of
BNT16 2b2 for the prevention of COV ID-19 disease oc curring at lea st 7 days after the
second dose of vaccine. Efficacy is being assessed throughout a participant’s follow-up in the study through surveillance for potenti al cases of COVID -19. If, at any time, a
participant develops acute respi ratory illness, an illness visit occurs. Assessments for
illness visits include a nasal ( midturbinate ) swab, which is tested at a c entral laboratory
using a reverse transcription -polymerase chain reaction (RT -PCR) test (e.g., Cepheid;
FDA authorized under EUA), or other s ufficiently va lidated NAAT , to detect SARS -
CoV-2. The central laboratory NAAT result is used for the case definition, unless it is not possible to test the sample at t he central laboratory. In that case, the followin g NAAT
results are acceptable: Cepheid Xper t Xpress SA RS-CoV-2, Roche cobas SARS -CoV -2
real-time RT -PCR test (EUA200009/A001), and Abbott Molecular/ RealTim e SARS -
CoV-2 assay (EUA200023/A001). The study d esign inclu ded a planned interim analysi s of the fi rst primary efficacy
endpoint at pre -specified numbe rs of COVID- 19 cases (at least 62, 92, and 120 cases),
and all primary and secondary efficacy endpoints were analyzed in the final efficacy analysis afte r at least 164 CO VID- 19 cases were accrued (see Statistical Analysis sect ion,
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Page 10 below). Participants are expected to participate for a maximum of approximately 26 months. Starting December 14, 2020, following issuance of the Emergency Use Authorization for
the Pfizer -BioNTec h COVID- 19 Vaccine, study particip ants 16 years of age and older
have been unblinded t o their treatment assignment when eligible per local
recommendations, and offered BNT162b2 vaccina tion if they had been randomized to
placebo. The study was unblinded in stage s as each participant was either individually unblinded
upon eligibility for vaccination outside the study or had concluded their 6-month post–Dose 2 study visit. Every p articipant 16 years of age and older who pa rticipated in the
Phase 2/3 study w as given the opportunity to receive BNT162b2 no later than the 6-
month timepoint after the second study vaccination. Participants who originally received
placebo but then went on to receive BNT162b2 were moved to a new visit schedule to receiv e both doses of BNT162b2, 3 weeks apart .
6.1.3 Population
Individuals 12 years of age and older including those with stable infections and common
comorbidities .
6.1.4 Study Treatments or Agents Mandated by the Protocol
Study C4591001 (Phase 1) evaluat ed a 2 -dose series of investigational vaccine or placebo
(0.9% norma l saline) administered at a 21 -day interval. Subjects were randomized to
receive one of three levels of investigational RNA vaccine candidates (or placebo) for
active immunization against COVID-19. The investigational RNA vaccine candidates
included:
• BNT162b1 ( BNT162 RNA- LNP vaccine uti lizing modRNA and encoding the
RBD): dose levels 10 μg, 20 μg, 30 μg, 100 μg
• BNT162b2 (BNT162 RNA- LNP vaccine utilizing modRNA and encoding the P2
S): dose levels 10 μg, 20 μg, 30 μg
Based upon the preliminary results, the vaccine candidate selected for f urther evaluation
in the Phase 2/3 studies was BNT162b2 [BNT162 RNA-LNP vaccine utilizing modRNA
mcg/0.5 mL] at a dose o f 30 μg.
6.1.6 Sites and Centers
The study was conducted in a total of 153 sites: 131 in the U.S., 9 in Turkey, 6 in
Germany , 4 in South Africa , 2 in Brazil , and 1 in Argentina.
6.1.7 Surveillance/Monitoring
Please refer to Drs. Susan Wollersheim and Ann Schwartz ’s clinical rev iew memo.
(b) (4)
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Page 11 6.1.8 Endpoints and Criteria for Study Success
Please refer to Section 6.1.1 for efficacy endpoints.
Study success criteria:
In Phase 2/3, the assess ment of VE is based on posterior probability of VE
1>30% and
VE 2>30%, where VE 1 represents VE for prophylac tic B NT162b2 against conf irmed
COVID-19 in participants without evidence of infection before vaccination, and VE 2
represents VE for p rophylactic BNT162b2 aga inst confirmed COVID -19 in all
participants after vaccin ation. Only the first prima ry endpoint was analyzed at interim
analys es. The criteri a for success at an inter im analysis are based on the posterior
probability , i.e. P r(VE>30%|data) at the current number of cases. Efficacy will be
declared if the posterior probability is higher than the success threshold, where the
success threshold for each interim analysis was calibrated to maintain a familywis e type I
error rate of 2.5%. I f the first primary objective is met, t he second primary objective will
be evaluated at the final analysis.
6.1.9 Stati stical Considerations & Statistical Analysis Plan
The statistical analyses for the Phase 1 portion w ere descriptive.
For Phase 2/3 , the evaluable efficacy population, which included all randomized
partici pants who received all study interventions as randomized wi thin the predefined
window and had no other important protocol deviations as determined by the clinicians ,
was t he primary ana lysis population for all efficacy anal yses. Additional analyses based
on the all- available efficacy population, which included a ll randomized subjects 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 th e corresponding illness rate in
the placebo group. Assu ming 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, t he total numb er 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 potenti al early stop for efficacy or futility. Four
interim analyses were planned to be performed after accr ual of at least 32, 62, 92, and
120 cas es. 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- binomial model and the posterior pro bability of VE being
>30% was assessed. A minimal ly informative beta prior, beta (0.700102, 1), was
proposed for θ = r(1 -VE)/(1+r(1 -VE)), wher e r is the ratio of surveillance time i n the
BNT162b2 group over that in the placebo group. For participants with multiple confirmed cases, only the first case contri buted to the VE calculation. The two primary
efficacy endpoints were evaluated sequent ially to control the familywise type I error rate
at 2.5% (one-sided). For the primary endpoint analysis, missing efficacy data w ere not
imputed; only particip ants with k nown dise ase status were included . A sensitivity
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Page 12 analysis w as performed by imputing missing values with the assumption of missing at
random ( MAR ). Secondary endpoints were evaluat ed similarly to the primary endpoints.
After the final efficacy analyses at 170 cases, updated efficacy analyses on primary and
secondary efficacy endpoints were p erformed with additional data accrued. The point
estimate of VE in the blinded follow -up period and associated 2-sided 95% C I were
derived using the Clopper- Pearson m ethod, adjus ting for surveillance time . The posterior
probability, P r(VE>30%|data) , was also provided.
6.1.10 Study Population and Disposition
6.1.10.1 Populations Enrolled/Analy zed
Parti cipants 18 through 55 years of age a nd 56 years of age and older began
enrollment into Phase 2/3 from July 27, 2020 and participants 16 through 17 years of age
began enrollment from September 16, 2020. 6.1.10.1.1 Demographics The population for the updated anal ysis of vaccine efficacy endpoint (March 2021 data
cutoff) included 42,436 participants 16 years of age and older (21,136 in the BNT162b2 group and 21,300 in the placebo group), with or without evidence of prior infection with
SARS -CoV-2 through 7 days after the second dose. Table 2 presents the specific
demographic characteristics in the studied population. The evaluable efficacy population who received BNT162b2 included 48.6% females, 81.9% White, 9.5% African American, 4.4% Asian, and <3% from o ther racial groups;
25.6% of participants were Hispanic/Latino. The median age was 51 years. One or more comorbidities that increase the risk of severe COVID -19 disease were present among
46% of participants. Evidence of p rior SARS -CoV- 2 infection was observed in 3% of
partici pants . Geographically, <2% of participants lived in Germany, Turkey and South
Africa, 6.8% lived in Brazil, 12.7% lived in Argentina, and 76.4% of participants lived in the U.S.
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Page 13 Table 2. De mographic s and Other Ba seline Character istics, P articipants 16 Years of Age
and O lder, With or Without Evidence of Infection Prior to 7 D ays After Dose 2,
Evaluable Efficacy Population (Data Cutoff March 13, 2021)
Characteristic BNT162b2 (30 μg)
(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 (1 6.0) 49.7 (16.0 ) 49.7 (16.0 )
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 to <18 years 370 (1.8) 362 (1.7) 732 (1.7)
Age Group: 18 to 55 years 12120 (57.3) 12252 (57.5) 24372 (57.4)
Age Grou p: >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 repor ted 89 (0.4) 112 (0.5) 201 (0.5)
Ethnici ty: Hispa nic 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)
Comorbidities: No 11424 (54.0) 11564 (54.3) 22988 (54.2)
Baseline evidence of prior SA RS-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)
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Page 14 Characteristic BNT162b2 (30 μg)
(Na=21136)
nb (%) Placebo
(Na=21300)
nb (%) Total
(Na=42436)
nb (%)
Country: United States of Ame rica 1614 1 (76.4) 16285 (76.5) 32426 (76.4)
Abbreviation: SARS -CoV -2 = severe acute respiratory syndrome coronavirus 2.
Note: HIV -positive subjects are included in this summary but not included in the analyses of the overall
study objectives. a. N = number of subjects in the specified group, or the total sample. This value is the denominator for
the percentage calculations.
Note: The analysis was based on t reatment group as randomized.
b. n = Number of subjects with the specified characteristi c.
c. Subjec ts who had BMI ≥30 kg/m
2.
d. Number of subjects who have 1 or more comorbidities that increase the risk of severe C OVID -19
disease: defined as subjects who had at least one Charlson comorbidity index category or BMI ≥30 kg/m2.
e. Positive N -binding antibo dy 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.
Source: Table F of C4591001- 508-efficacy -tables submitted to STN 125742 /0.32.
6.1.10.1.2 Medical/Behavioral Characterization o f the Enrolled Population
Please refer to Drs. Susan Wollersheim and Ann Schwartz’s clinical review memo.
6.1.10.1.3 Subject Disposition The disposition of all Phase 2/3 participants 16 years of age and old er is presented in
Table 3. During the blinded placebo- controlled follow -up period, most participants
randomized received Dose 1 (99.7%) and Dose 2 (98.0%). Table 3. Disposition of Participants 16 Years of Age and Older, Phase 2/3 Subjects,
Efficacy Popu lation (Data Cu toff March 13, 2021)
BNT162b2
(30 μg)
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)
Subjects without evidence of infection before Dose 1 21172 (95.9) 21168
(95.9) 42340
(95.9)
Subjects 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 poten tially unreliable due to lack of PI oversight
identified as significant quality event 21 (0.1) 22 (0.1) 43 (0.1)
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Page 15 BNT162b2
(30 μg)
na (%) Placebo
na (%) Total
na (%)
Dose 2 all -available efficacy population 21648 (98.0) 21624
(97.9) 43272
(98.0)
Subjects without evidence of infection pri or to 7 days after Dose
2 20536 (93.0) 20487
(92.8) 41023
(92.9)
Subjects 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 (9 5.7) 21300
(96.5) 42436
(96.1)
Subjects without evidence of infection prior to 7 days after Dose
2 20064 (90.8) 20197
(91.5) 40261
(91.2)
Subjects excluded from evaluable efficacy (7 days) population 949 (4.3) 780 (3.5) 1729 (3.9)
Reason for exclusi onc
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 rece ive all vaccina tions as randomized or did not receive
Dose 2 within the predefined window (19 -42 days after Dos e 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 pr ior to 7 days
after Dose 2 240 (1.1) 58 (0.3) 298 (0.7)
Note: HIV -positive subjects are included in this summary but not included in the analyses of the overall
study objectives. Note: The analysis was based on t reatment group as randomized.
a. n = Number of subjects with the specified char acteristic.
b. These values are the denominators for the percentage calcul ations.
c. Subjects may have been excluded for more than 1 reason.
Source: Table D of C4591001 -508-efficacy -tables submitted to STN 125742 /0.32.
Reviewer Comment
1. There were more protocol deviations leading to exclusion from analyses in the
BNT162b2 group than in the placebo group. The majority of protocol deviations were in the category of investigational products, including dosing /administration
error and investigational product deemed not suitable for use. Protocol deviations in other categories appeared balanced across the two treatment groups. The additional analysis on the all-available efficacy population may be
regarded as a sensitivity analysis and showed very simila r efficacy resu lts.
2. The Dose 1 all-available efficacy population excluded 43 subjects ( 21 in t he
BNT162b2 group and 22 in the placebo group) due to a specific protocol
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Page 16 deviation, i.e. data considered poten tially u nreliable due to lack of PI oversight
identified as a sig nificant quality event, while the Dose 1 all-av ailable set is
defined as all randomized participants who received at least 1 vaccination in the
SAP. I conducted a sensitivity analysi s without ex cluding these 43 subjects for
efficacy analyses using the Dose 1 all-available population, when applicable, and it show ed minimal impact on VE r esults.
6.1
.11 Efficacy Analyses
6.1.11.1 Analyses of Primary Endpoints
The Interim and Final Analyses
At the inter im analysis, there were 4 confirmed COVID -19 cases in the BNT 162b2 group
and 90 confirmed cases in the placebo group among subjects without evidence of prior SARS -CoV- 2 infection prior to 7 days after Dose 2, resulting in a VE point estimate of
95.5% (95% credible interval: 88.8 %, 98.4%) and a 99.99% posterior pr obability for the
true VE being >30%, which met the prespecified success criterion of posterior probability
>99.5%. The median follow -up duration for subjects included in the first interim efficacy
analysis was slightly less than the planned 2 months. In the final analysis, the case spl it
between the BNT162b2 and placebo groups was 8:162 (VE: 95.0%; 95% credible interval: 90.3%, 97.6%) among subjects without evidence of prior SARS- CoV-2
infectio n prior to 7 days after Dose 2, and 9:169 (VE: 94.6%; 95% cre dible interval:
89.9%, 97.3%) among subjects with and without evidence of prior SARS -CoV-2
infection prior to 7 days after Dose 2. The final analysis extended the median follow-up for these subje cts to greater than 2 months , and the results indicate that the conclusions
from the first int erim efficacy analysis would not change when including additional
follow -up to November 14, 2020. This pre- specified primary efficacy analysis was the
basis for i ssuan ce of the Emergency Use Authorization ( EUA) for the Pfiz er-BioNTech
COVID-19 Vaccine on December 10, 2020. Reviewer Comment
1. The efficacy results presented above included 88 subjects 12-15 years of age (46
in the BNT162b2 group and 42 in the placebo group). Since none of these 12-15 years old subjects developed protocol defined cases and the number of subjects is small relative to the evaluable population, the efficacy results excluding these subjects are very similar to the results including them. Based on my calculation, VE fo r 16 years and older subj ects is 9 4.6% (95% credible interval: 90. 3%,
97.6%).
2. The interim and final analyses were reviewed under EUA 27034, and hence the review is not replicated for this BLA submission.
Updated Efficacy Analyses
Updated efficacy analyses were performed with additional co nfirmed COVID- 19 cases
accrued during blinded placebo- controlled follow -up through March 13, 2021,
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Page 17 representing up to 6 months of follow-up after Dose 2 for participants in the efficacy population. For participants without evidence of SARS -CoV -2 infe ction 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 cas es in the BNT162b2 group compared to 833
COVID- 19 cases in the placebo group (Table 4 ).
Table 4. Updated Efficacy of BNT162b2 Against Confirmed COVID-19 From 7 Days
After Dose 2 in Participants Without Evidence of Prior SARS -CoV-2 Infection
– Evaluable Efficacy Population, 16 Years and Olde r (Da ta Cutoff March 13, 2021)
Pre-specified Age Group BNT 162b 2
(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 to 55 years 52
3.593
(11517) 568
3.439
(11533) 91.2
(88.3, 93.5)
>55 years and older 25
2.499
(8194) 265
2.417
(8208) 90.9
(86.2, 94.2)
Abbreviations: N -binding = SARS -CoV -2 nucleoprotein –binding; NA AT = nucleic acid amplification test;
SARS -CoV -2 = severe acute respiratory syndrome coronavirus 2; VE = vaccine efficacy.
Note: Subjects who had no serological or virological evidence (pri or to 7 days after receipt of the last dose)
of past SARS -CoV -2 infection (i.e. , N-binding antibody [ser um] n egative at Visit 1 and SARS -CoV -2 not
detected by NAA T [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 subjects in the specif ied g roup.
b. n1 = Number of subjects meeting the endpoin t definition.
c. Total surveillance time in 1000 person -years for the given endpoint a cross all subjects within each
group at risk for the endpoint. Tim e period for COVID -19 case accrual is from 7 days after Dose 2 to the
end of the surveillance period .
d. n2 = Number of subjects at risk for the endpoint.
e. Confidence interval (CI) for VE is derived based on the Clopper and Pearson method adjuste d for
surveillance time.
Source: Table H of C4591001 -508-efficacy -tables submitted to STN 125742 /0.32.
Reviewer Comment
1. One s ubject (C4591001 ) reported “ covid -19 antibody test
positive” in medical history but was included in the VE analysis in participants
without evidence of pr ior infection in Table 4. An information request ( IR) was
sent on J uly 22, 2021. In the IR response submitted on July 26, 2021, the
applicant clarified that “without evidence of prior infection” was based only on
the NAAT test s at Vis its 1 and 2 and the N-bi nding assay results due to the
(b) (6)
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Page 18 potential uncer tainty of a me dical history entry without knowledge of
circumstances, assay performed, etc. Because this subject received placebo and was not a case, inclusion of subject would result in no real change to the VE
estimate .
2. A total of 9 participants in the placebo group w ith COVID-19 symptoms start ing
on the same day of unblinding with PCR confirmation either on the same day or a
few days after, were included in these analyses as pos itive cases.
3. Initially, there was one additional case reported in the plac ebo group, for Subject
C4591001 . This subject reported three COVID symptom
episodes : from Octo ber 8, 2020 to October 16, 2020, N ovember 2, 2020 to
December 11, 2020, and December 17, 2020 to January 16, 2021 ( referred to as
Episodes A, B and C, r espectively ). The PCR tests were negative for the first two
episodes and positive for Episode C. Since t he three episodes were more than 4
days apart, they should be t reated as separate episodes per the statist ical analysis
plan ( SAP) . Hence, this s ubject should be considered to be a case with an onset
on December 17, 2020, one day after the unblinding on December 16, 2020, and should be excluded from the analysis. In the IR response submitted on July 26, 2021, the applicant explained that Episodes B and C were merged into one episode as this subject was hospitalized from to
, connecting Episodes B and C. We did not agree with t he me rging of the two
episodes, because hospi taliza tion is not a sympt om or criterion pre- specified in
the protocol for COVID -19 definition and there were no other data that could
corroborate th at this hospitalization was due to COVID-19. The applicant agreed
to remove this case and updated efficacy tables were submitted on August 5,
2021.
4. The set of subjects used for efficacy analyses excluded those who had reported
COVID sympt oms but had missing or unknown PCR results at any time. It may be
reasonable to exclude subjects who had reported COVID symptoms but had
missing/unknown PCR r esult s prior to 7 days after Dose 2 for efficacy analyses in
participants without e vidence of prior infection . However, subjects who reported
sympt oms and had missing/unknow n PCR results after 7 days post D ose 2 were
also excluded from the risk set, while they were at risk for the efficacy endpoint
(lab-confirmed COVI D-19 starting from 7 days pos t Dose 2 ). An IR was sent to
the applicant on July 22, 2021. In the IR response submitted on July 26, 2021, the applicant explained that subjects who reported symptoms and had
missing/unknown PCR results do not have a chance to be counted in the numerator and inclusion of these subjects may result in an underestimation of the incidence rate . Since the percentages of such subjects were smal l and sligh tly
higher in the placebo group, excluding them from the analyses likely had minimal
impact on VE results. Per our request, the applicant also provided a sensitivity
analys is under the missi ng at random ( MAR) assumption, where missing efficacy
endpoint s were imputed based on predicted probability from logistic regression
model using the fully conditio nal specifica tion method for a total of 648 subjects
(279 in BNT162b2 group and 369 in placebo group) in the evaluable population
who reported COVID-19 symptoms from 7 days post Dose 2 but had missing/unknown PCR resu lts. As a supplementary sensitivity analysis, the
(b) (6)
(b) (6)
(b) (6)
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Page 19 applicant also applied a conservative approach to the model by as sumin g a
higher than the observed case rate when imput ing missing effi cacy endpoints from
participants in the BNT162b2 group onl y, to reflect poten tially unknow able
missing not at random effects that are unfavorable for effi cacy result of the study.
As sh own i n Table 5, the average VE after imputati on was 90.76% under the M AR
assumption, which is consistent with the efficacy resul ts reported in Table 4. The
sensiti vity analyses under the missing -not-at-random assumptions show that the
efficacy results are robust, e.g. at least a 16-fold increase of positivity rate in the
BNT162b2 group is require d for the average VE to fall below 70% , which we do
not consider to be a pl ausible scenario.
Table 5. Sensit ivity and Robustness Analysis of Missing Laboratory Results for V accine
Efficacy – First COVI D-19 Oc currence From 7 Days Aft er Dose 2 – Subject s Without
Evidence of Infection Prior to 7 Days After Dose 2 – Evaluable Ef ficacy (7 Days )
Population
Assumed
Missing Data
Mechanism Average Positive
Rate (% ) Across
all Imputations
(BNT162b2:
Placebo )a Infectio n Rates
Based on Existin g
and Imputed
Values
(BNT162b2:
Placebo )b Median
Posterior
Probab ility
of
VE>30%
Median of
Lower
Limit of
95% CI for
VE
Median
VE ( %)
Average
VE ( %)
MAR 4.0:28.5 4.21:45.31 100.00 88.56 90.78 90.76
MNAR1 10.1:2 8.5 5.01:45.31 100.00 86.55 88.97 88.98
MNAR2 23.3:28.5 6.76:45.31 100.00 82.30 85.12 85.14
MNAR 3 45.3:28.5 9.69:45.31 100.00 75.36 78.79 78.69
MNAR 4 69.1:28.5 12.85 :45.31 100.00 67.71 71.78 71.75
MNAR 5 85.9:28.5 15.08 :45.31 100.00 62.36 66.81 66.85
Abbre viations: MAR = missing at random; MNAR = m issing not at random; VE = vacc ine efficacy.
Note: Each row of this table represents summary results from 500 imp utations that were generated using
SAS PROC MI Ful ly Conditional Specification (FCS) method. Ea ch im putation filled in the m issing
laboratory r esults based on a logistic regr ession model at the subject level, under the assumed missing data
mechanism.
a. Av erage positive rate for each vaccine group was cal culated as the mean of positive rates across all
imput ations among subject s with missing data after each imputation. Under t he MAR assumption, the
imputation model assumes the probability of positive cases for each vaccine group to be the same as
observed from subjects with no missing data in that gr oup. Unde r each MNAR assumpti on, while keeping
the imputation model for placebo group unchanged, an increase in the positive rate for the BTN162b2
group was assu med to reflect a potential conservative and unknow able MNAR scenario for efficacy results
of the study.
b. Infection rate in each vaccine group was the number of cases divide d by a total number of subjects in
that vaccine group times 1000.
Source: Adapted from Table 1 of response -22jul2021 -followup submitted to STN 125742 /0.28.
For participants wit h and without evidence of SAR S-CoV- 2 infection b efore and during
vaccination re gimen, the updated VE against confirmed COVID -19 occurring at least 7
days after Dose 2 was 90.9%, with 81 and 854 cases in the BNT162b2 and placebo
groups, respectively ( Table 6).
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Page 20
Table 6. Updated Efficac y of BNT162b2 Agains t Confirmed COV ID-19 From 7 Da ys
After Dose 2 in Participants With or Without Evidence of Prior SARS -CoV- 2 Infection
– Evaluable Efficacy Population, 16 Years and Older (Data Cutoff March 13, 2021)
Pre-speci fied Age Group BNT162b2
(Na=21047)
Cases
n1b
Surveillance Timec
(n2d) Placebo
(Na=21210)
Cases
n1b
Surveillance Timec
(n2d) Vaccin e Efficacy %
(95% CI)e
All participants 81
6.340
(20533) 854
6.110
(20595) 90.9
(88.5, 92.8)
16 to 55 years 56
3.766
(12088) 584
3.619
(12142) 90.8
(87.9, 93.1)
>55 yea rs and older 25
2.573
(8445) 270
2.492
(8453) 91.0
(86.5, 94.3)
Abbreviations: SARS -CoV- 2 = severe acute r espiratory syndrome coronavirus 2; VE = vaccine efficacy.
a. N = number of subjects in the spec ified group.
b. n1 = Num ber of subje cts meet ing the endpoint definition.
c. Total surveillance time in 1000 person -years for the given endpoint across all subjects within each
group at risk for the endpoint. Time period for COVID -19 case accrual i s from 7 days after Dose 2 to the
end of the sur veillance period .
d. n2 = N umber of subjects at risk for the endpoint.
e. Confidence interval (CI) fo r VE is derived based on the Clopper and Pearson method adjusted for
surveillance time.
Source: Tab le I of C4591001- 508-efficacy -tables submitted to STN 125742/0.3 2.
VE in parti cipants in the all -available efficacy population was similar to results in the
evaluable efficacy population (Table 7). The VE for the prevention of COVID -19 disease
after Dose 1 is 87.6%, in the all- availa ble efficacy popula tion. Based on the number of
cases accumulated after Dose 1 and before Dose 2, t here seem s to be some protection
against COVID- 19 disease following one dos e (VE=56.4% ); however, these data do not
provide info rmation a bout longer term protection beyond 21 days after a si ngle dose.
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Page 21 Table 7. Primary Efficacy Endpoint – Participants 16 Years of Age and Older –
Dose 1 All -Available Efficacy Population (Data Cutoff March 13, 2021)
Efficacy Endpoint Subgroup BNT162 b2
(Na=21909)
Cases
n1b
Surve illance Timec
(n2d) Placebo
(Na=21908)
Cases
n1b
Surveillance Timec
(n2d) Vaccine Efficacy %
(95% CI)e
First COVID -19 occu rrence 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) 90.0
(68.0, 98.1)
≥7 Days after Dose 2 82
6.479
(21019) 870
6.207
(20901) 91.0
(88.7, 92.9)
Abbreviation: VE = vaccine ef ficacy.
a. N = number of subjects in the specified group.
b. n1 = Number of subjects meeting the endpoint definition.
c. Total surveillance time in 1000 person -years for the given endpoint across all subjects within each
group at risk for the e ndpoi nt. Time p eriod for COVI D-19 case accrual is from Dose 1 to the end of the
surveillance period.
d. n2 = Number of subjects at risk for t he endpoint.
e. Confidence interval (CI) for VE is derived based on the Clopper and Pearson method adjusted for
surveillan ce time.
Sourc e: Table O of C4591001 -508-efficacy -tables submitted to STN 125742 /0.32.
Reviewer Comment
As mentioned, the Dose 1 all-availa ble efficacy population excluded 43 subjects with a
protocol deviation of data being considered pote ntially u nreliable due to lack of PI
oversight identified as a signifi cant quality event . In my additional analys is with these
subject s included, t he case split for the first COVID- 19 occurrence after dose 1 is
129:1003, result ing in a n estimated VE of 87.6% ( 95% CI: 85.1%, 89.7% ). Hen ce, the
exclusion of these subjects likely had minimal impact on the VE results.
6.1.11.2 Ana lyses of Secondary End points
Protocol -Defined Severe cases
Updated efficacy analyses of the secondary efficacy endpoint f or the use of BN T162b2
for the preventio n of severe COVID- 19 were also evaluated. Vaccine efficacy against
severe COVID -19 is presented in Table 8 for par ticipant s without prior SARS -CoV- 2
infection. In the updated analysis, among participants without evidence of pr ior in fection,
the estimated V E against severe COVID -19 disease occurring at least 7 days after Dose 2
was 95.3% (71.0%, 99.9%) , with one subject who rec eived BNT162b2 and 21
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Page 22 participants who received placebo experiencing severe disease. The same number of
severe cases were reported a mong partic ipants with or without evidence of prior infection
and the estimated VE was the same (95.3%). These updated analyses of the secondary
vaccine efficacy with a larger number of severe cases now shows more definitive
evidence of protec tion against s evere COVID- 19 disease offered by BNT162b2 (the data
from the November 14, 2020 cut -off were limited to 4 total seve re cases ).
Table 8. First Severe COVI D-19 Occ urrence From 7 Days After Dose 2 – Subjects
Without Evidence of Infection Prior to 7 Days Afte r Dos e 2 – Participant s 16 Years of
Age and Older – Evaluable Efficacy Population (Data Cutoff March 13, 2021)
Secon dary Effi cacy Endpoint BNT162b2
(Na=19993)
Cases
n1b
Surveillance
Timec
(n2d) Placebo
(Na=20118)
Cases
n1b
Surveillance
Timec
(n2d) Vaccine
Effic acy %
(95% CI)e
First severe COVID -19 occurrence from 7 days after Dose
2 in participants without evidence of pri or SARS -CoV -2
infection 1
6.103
(19711) 21
5.971
(19741) 95.3
(71.0, 99.9)
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: Subjects who ha d no ser ological 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 (n asal swab) at any
unscheduled visit prior to 7 days after Dose 2 were included i n the analysis .
a. N = number of subjects in the specified group.
b. n1 = Number of subjects meeting the endpoint definit ion.
c. Total surveillance time in 1000 pe rson-years for the given endpoint across all subjects within each
group at risk for the endpoi nt. T ime period for CO VID- 19 case accrual is fro m 7 days after Dose 2 to the
end of the surveillance period.
d. n2 = Number of subjects at risk for the endpoint.
e. Confidence interval (CI) for VE is derived based on the Clopper and P earson method adjus ted for
surveilla nce time.
Source: Table M of C4591001 -508-efficacy -tables submitted to STN 125742 /0.32.
In the all -available efficacy population, 31 parti cipants had severe COVID- 19 disease
after Dose 1 (one subject who received BNT162b2 and 30 par ticipants who received
placebo) as summarized in Table 9.
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Page 23 Table 9. First Severe COVID -19 Occurrence After Dose 1 – Participants 16 Years of Age
and O lder – Dose 1 All -Available Efficacy Population (Data Cutoff March 13, 2021)
Secondary Eff icacy Endpoint BNT1 62b2
(Na=21909)
Cases
n1b
Surveillance Timec
(n2d) Placebo
(Na=21908)
Cases
n1b
Surveillance Timec
(n2d) Vaccin e Efficacy %
(95% CI)e
First sev ere case occurrence after Dose 1 1
8.181
(21385) 30
8.032
(21316) 96.7
(80.3, 99.9)
After Dose 1 to befor e Dose 2 0
1.285
(21385) 6
1.293
(21316) 100.0
(14.6, 100.0)
Dose 2 to 7 days after Dose 2 0
0.403
(21056) 1
0.402
(20962) 100.0
NA
≥7 Days after Dose 2 1
6.493
(21029) 23
6.337
(20940) 95.8
(73.9, 99.9)
Abbrev iation: VE = vaccin e efficacy.
a. N = number of subjects in the specified group.
b. n1 = Number of subjects meeting the e ndpoint definition.
c. Total surv eillance time in 1000 person -years for the given endpoint across all subjects within each
group at risk for the endpoi nt. Time period for COVID -19 case accrual is from Dose 1 to the end of the
surveillance period.
d. n2 = Number of subjects at risk for the endpoint.
e. Confidence interval (CI) for VE is derived based on the Clopper and Pearson method adju sted for
surveill ance time.
Source: Table N of C4591001- 508-efficacy -tables submitted to STN 125742 /0.32.
Severe Case Based on CDC -Definition
Vaccine efficacy against severe COVID -19 based on the CDC defin ition is presented for
particip ants with or withou t prior S ARS -CoV- 2 infection (Table 10) as the COVID- 19
case counts in participants without prior SAR S-CoV-2 infection were the same as those
in part icipants with or without prior SAR SCoV2 infection in both the vaccine and
placebo groups .
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Page 24 Table 10. Firs t Severe COVID- 19 O ccurrence Based on CDC -Definition From 7 Days
After Dose 2 – Subjects With or Without Evide nce of Infection Prior to 7 Days After
Dose 2 – Participants 16 Years of Age and Older – Evaluable Efficacy Population (Data
Cutoff March 13, 2021)
Efficacy Endpoint BNT162b2
(Na=21047)
Cases
n1b
Surveillance
Timec
(n2d) Placebo
(Na=21210)
Cases
n1b
Surveillance
Timec
(n2d) Vaccine
Efficacy %
(95% CI)e
First severe COVID -19 occurrence based on CDC -
defin ition from 7 days after Dose 2 0
6.345
(20513) 31
6.225
(20593) 100.0
(87.6, 100.0)
Abbreviations: VE = vaccine efficacy.
a. N = number of s ubjects in the specified group.
b. n1 = Number of subjects meeting the endpoint definition.
c. Total surveillance time in 1000 pe rson-years for the g iven endpo int across all subjects within each
group at risk for the endpoint. Time period for COVI D-19 case accrual is fro m 7 days after Dos e 2 to the
end of the surveillance period.
d. n2 = Number of subjects at risk for the endpoint.
e. Confidenc e interval (CI) for VE is derived based on the Clopper and Pearson method adjusted for
surveillanc e time.
Source: Adapted from Table ADC19EF _VE_ SEV_7PD2_CDC_EVAL of C4591001 -ve-tables submitted to
STN 125742 /0.38.
6.1.11.3 Subpopulation Analyses
VE point e stimates for the primary end point in participants with out evidence of prior
infection were compa rable across sex , age groups ( 16 to 55 years and >55 years ), race,
ethnicity, and country, excluding categories with too few cases to analyze. Additional
subgroup analyses wer e performed for the second vaccine efficacy endpoint ( i.e.
COVID- 19 for participants with and without ev idence of infection prior to vaccination )
because this endpoint may generalize better to the population who may receive the
vaccine, as baseline ev idence of prior infection may not be known by all people who
might re ceive the vaccine. VE point estimat es were generally high ( >84% ) across the
subgroups examined (i.e. sex, age, race, ethnicity, comorb idity, baseline SARS -CoV- 2
status, and country) with the except ion of participants identified as positive or unknown
for baseline SARS -CoV- 2 status and with un- reported ethnicity , for which there were too
few COVI D-19 cases to interpret efficacy data for t hese subgroups .
6.1.11.4 Dropouts and/or Discontinuations
Dropout s and dis continuations are generally balanced across the gro ups. There were 352
(1.6%) participants in the BNT162b2 group and 528 (2.4%) participants in the placebo
group who discontinued from the vaccinatio n period (Dose 1 to 1 month after Dose 2) .
Most participants completed the visit at 1 month post -Dose 2 ( ≥96.4%). Few partic ipants
in the BNT162b2 and placebo groups were withdrawn from the study (1.6% and 2.2%,
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Page 25 respectively), and most were due to withdraw als by the participant, or they were lost to
follow -up without other ca use given .
Starting December 14, 2020, following issuance of the Emergency Use Authorization fo r
the Pfizer -BioNTec h COVID- 19 Vaccine, study particip ants 16 years of age and older
have been unblinded t o their treatment assignment when eligible per local
recommendations , and offere d BNT162 b2 vaccination if they had been r andomized to
placebo. The length of blind ed follow -up appears to be balanced between the BNT 162b2
and placebo groups. During the blinded placebo -controlled follow -up period, 52.4% of
participants in the BNT162b2 group and 52.6% of participants in the placebo group in the
evalua ble efficacy population with or without evidence of infection prior to 7 days a fter
dose 2 had follow -up time between ≥4 months to <6 months after Dose 2, and 8.4% in
the BNT1 62b2 group and 6.1% in the pl acebo group had follow up ≥ 6 months .
6.1.11.5 Exploratory and Pos t Hoc Analyse s
Not Applicable .
6.1.12 Safety Analyses
Please re fer to Dr. Ye Yang ’s memo for the statistical review of the clinical safety data of
Study C4591001.
7. INTEGRATED OVERVIEW OF EFFICACY
Data supporting the e ffectiveness of the vacc ine were pr imarily generated in Study
C4591001. Consequently, no pooled efficacy ana lyses were performed.
8. INTEGR ATED OVERVIEW OF SAFETY
Please re fer to Dr. Ye Yang ’s memo for the statistical rev iew of the clinical safety data.
9. ADDITIONAL STATISTICAL ISSUES
Not Applicable.
10. CONCLUSIONS
10.1 Statistical Issues and Collective Evidence
In the updated effic acy analysis f or cases accrued during blinded placebo -controlled
follow -up (cutoff date: Marc h 13, 2021) of Study C4591001 in participants 16 years of
age and ol der, the estimated vaccine efficacy ( VE) against confirmed COVID -19
occurring at least 7 days after Dose 2 was 91. 1% (95% CI: 88.8%, 93.1% ), with 77
COVID- 19 cases in the BNT162b2 group compared to 833 cases in the placebo group
among participants withou t evidence of SARS -CoV -2 infection before and during the
vaccination regimen; the estimated vaccine effi cacy ( VE) against confirmed COVID -19
occurring at least 7 days after Dose 2 was 9 0.9% (95% CI: 88.5%, 92.8% ), with 81
COVID- 19 cases in the BNT162b2 group compared to 854 cases in the placebo group
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Page 26 among participants with or without evidence of SARS -CoV- 2 infection before and during
the vaccination regimen.
With respect to efficacy agains t severe COVID- 19 cases occurring at least 7 days after
Dose 2, the estimated V E was 95.3% ( 95% CI: 71.0%, 99.9%), with 1 and 21 cases in the
BNT162b2 and placebo groups, respectively , among participants without evidence of
SARS -CoV- 2 infection ; the VE r esult wa s the same among participants with or w ithout
evidence of SA RS-CoV- 2 infection .
10.2 Conclusions and Recommendations
Overall, the updated efficacy an alysis results show that BNT162b2 provided hi gh VE in
preventing symptomatic COVID -19 and severe COVID -19 cases th at is consistent with
the VE resul ts reported in the interim and final analyses .