Document text
Statistical 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 Manager Michael Smith; Laura Gottschalk
Priority Review Yes
Reviewer Name Ye Yang , Mathematical Statistician, DB/VEB
Review Completion Date /
Stamped Date
Concurrence Lei Huang, Concurring Reviewer , DB /VEB
Supervisory Concurrence Tsai-Lien Lin , Branch Chief , DB/VEB
Supervisory Concurrence John Scott, Director , DB
Applicant BioNTech Manufacturing GmbH (in
partnership with Pfizer, Inc.)
Established Name COVID -19 Vaccine , mRNA
(Proposed) Trade Name COMIRNATY
Dosage Form(s) and Route(s) of
Administration Injectable Suspension, Intramuscular
Dosing Regimen Two 0.3 mL doses, three 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
Statistical Review
STN: 125742/0
Page ii Table of Contents
Glossary ............................................................................................................................. 3
1. Executive Summary ...................................................................................................... 4
2. Clinical and Regulatory Background ......................................................................... 4
3. Submission Quality and Good Clinical Practices ...................................................... 5
3.1 Submission Quality and Completeness ............................................................................................. 5
3.2 Compliance With Good Clinical Practices And Data Integrity ......................................................... 5
4. Significant Efficacy/Safety Issues Related to Other Review Disciplines.................. 5
5. Sources of Clinical Data and Other Information Considered in the 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 Trials ........................................................ 6
6.1 Study C4591001 ................................................................................................................................ 6
6.1.1 Objectives ................................................................................................................................ 6
6.1.2 Design Overview ..................................................................................................................... 6
6.1.3 Population ............................................................................................................................... 7
6.1.4 Study Treatments or Agents Mandated by the Protocol .......................................................... 7
6.1.6 Sites and Centers ..................................................................................................................... 7
6.1.7 Surveillance/Mo nitoring .......................................................................................................... 7
6.1.8 Endpoints and Criteria for Study Success ............................................................................... 7
6.1.9 Statistical Considerations & Statistical Analysis Plan ............................................................ 8
6.1.10 Study Population and Disposition ......................................................................................... 8
6.1.11 Efficacy Analyses .................................................................................................................. 9
6.1.12 Safety Analyses ..................................................................................................................... 9
7. Integrated Overview of Efficacy ................................................................................ 15
8. Integrated Overvi ew of Safety ................................................................................... 15
9. Additional Statistical Issues ....................................................................................... 15
10. Conclusions ................................................................................................................ 15
10.1 Statistical Issues and Collective Evidence ..................................................................................... 15
10.2 Conclusions and Recommendations .............................................................................................. 1 6
Statistical Review
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Page 3 GLOSSARY
ADaM Analysis Data Model
AE Adverse Event
BIMO Bioresearch Monitoring
BLA Biologics License Application
BNT162b2 Pfizer -BioNTech COVID-19 Vaccine
COVID-19 Coronavirus Disease 2019 EUA Emergency Use Authorization
HIV Human Immunodeficiency Virus RT-PCR R everse T ranscription -Polymerase Chain R eaction
SAE Serious Adverse Event
SAP Statistical Analysis Plan
SARS -CoV-2 Severe Acute Respiratory Syndrome Coronavirus 2
SDTM Study Data Tabulation model
Statistical Review
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Page 4 1. Executive Summary
Pfizer submitted a Biologics License 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 Coronavirus 2 ( SARS -CoV- 2) in individuals 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 safety
data from subjects aged 16 years and above in the Phase 2/3 part of Study C4591001
collected up to the March 13, 2021 da ta cut -off.
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 Turkey. 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 (younger adults 18 through 55 years of age
and older adult s >55 years of age ; adolescents 16 to 17 were later added via a protocol
amendment ) with 40.6% of the final study population being older adult s. Since December
14, 2020, following issuance of the EUA, participants 16 years of age and older were
systematically unblinded when eligible per local recommendations and offered
BNT162b2 vaccination if they had been randomized to placebo.
For all 44,047 randomized participants who received at least one dose of the study intervention, unsolicited a dverse events (AEs) and serious AEs (SAEs) were collect ed
from Dose 1 up to the March 13, 2021 data cut -off. A reactogenicity subset of
approximately 4,900 participants per arm who received at least one dose of the study intervention recorded local reactions, systemic events, and antipyretic/pain medication
usage from Day 1 through Day 7 after each dose.
No major statistical issues were identified for the safety data during review. A higher percentage of subjects in the BNT162b2 group report ed solicited local and systemic
reactions than placebo recipients in both the younger (16 to 55 years) and older (>55 years) adult age groups after both doses. There was an imbalance in the frequenc ies of
unsolicited AEs in the vaccine group , driven largel y by increased reactogenicity . In
addition, one report of pericarditis was identified in a 66 -year-old male participant 28
days after receiving Dose 2 of BNT162b2. There were no reports of myocarditis in the
vaccine arm up to the data cut -off. There were n o major imbalances in reported SAEs,
AEs leading to withdrawal, or deaths between the treatment groups at one month and up
to six months after the second dose or unblinding /data cut -off.
2. Clinical and Regulatory Background
The Pfizer- BioNTech COVID- 19 Vaccine (BNT162b2) was granted Fast Track
Designation for individuals ≥18 years of age on July 7, 2020, and was authorized under an Emergency Use Authorization ( EUA) on December 11, 2020 for individuals ≥16 years
of age. The EUA wa s amended to include individuals ≥12 years of age on May 10, 2021.
Pfizer submitted a BLA on May 18, 2021 to seek licensure of the vaccine for active
Statistical Review
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Page 5 immunization to prevent COVID -19 caused by SARS -CoV- 2 in individuals 16 years of
age and older.
3. SUBMISSION QUALITY AND GOOD CLINICAL PRACTICES
3.1 Submission Quality and Completeness
The submission was adequately organized for conducting a complete statistical review
without unreasonable difficulty.
3.2 Compliance With Good Clinical Practices And Data Integ rity
Please refer to Haecin Chun’s Bioresearch Monitoring inspections review memo .
4. SIGNIFICANT EFFICACY /SAFETY ISSUES RELATED TO OTHER REVIEW
DISCIPLINES
Please refer to reviews of other review disciplines.
5. SOURCES OF CLINICAL DATA AND OTHER INFORMATION CONSIDERED IN
THE REVIEW
5.1 Review Strategy
This statistical review focuses on safety data from subjects aged 16 years and above in the Phase 2/3 part of Study C4591001 collected up to the March 13, 2021 data cut -off.
5.2 BLA/IND Documents Th at Serve as the Basis for the Statistical Review
The following documents submitted to the BLA are reviewed:
125742/0 (submitted on 5/ 6/2021)
Module 2. Common Technical Document Summaries
• Clinical Overview
• Summary of Clinical Safety
Module 5. Clinical Study Reports
125742/0/1 (submitted on 5/18/2021)
Module 1. Administrative Information and Prescribing Information
125742/0/3 (submitted on 5/19/2021)
Module 1. Administrative Information and Prescribing Information
• Response to May 18, 2021 Information Request
125742/0/26 (submitted on 8/2/2021)
Module 1. Administrative Information and Prescribing Information
• Response to July 29, 2021 Information Request
125742/0/37 (submitted on 8/9/2021)
Statistical Review
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Page 6 Module 5. Clinical Study Reports
• C4591001 – 508 Saf ety Tables
5.3 Table of Studies/Clinical Trials
Data from two ongoing clinical studies were submitted to support the BLA for
BNT162b2 and are summarized in Table 1 below. Study C4591001 is a multi -center ,
Phase 1 /2/3, randomized, double -blinded, placebo -controlled safety, immunogenicity,
and efficacy study and Study BNT162- 01 is a Phase 1 safety and immunogenicity study
evaluat ing various vaccine candidates and dose levels.
Table 1. Clinical Trials Supporting Licensure of the Pfizer -BioNTech COVID -19 Vaccine
Study Number/
Country Description BNT162b2 (30 µg)
participants (N) Placebo
participants (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 1: 24 (U.S.A.)
Phase 2/3: 22085
Argentina: 2887
Brazil:1452
Germany: 250
South Africa: 401
Turkey: 251
U.S.A.: 16844 Phase 1: 6 (U.S.A.)
Phase 2/3: 22080
Argentina: 2889
Brazil:1448
Germany: 250
South Africa: 399
Turkey: 249
U.S.A.: 16845 Ongoing
BNT162 -01
Germany Phase 1/2 randomized,
open -label; to evaluate
safety and immunogenicity,
Phase 1: 24 (Germany) 0 Ongoing
Source: Summarized by the reviewer based on information provided in Module 2. Clinical Overview.
6. DISCUSSION OF INDIVIDUAL STUDIES /CLINICAL TRIALS
6.1 Study C4591001
Title of Study : A 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
First Subject First Visit : April 29, 2020
Data Cut -off: Mach 13, 2021
6.1.1 Objectives
Primary Safety Objective (Phase 2/3) :
• To characterize the safety profile of prophylactic BNT162b2 in all participants
randomized in Phase 2/3
6.1.2 Design Overview
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 Turkey. In the Phase 2/3 portion of the study, 43,998 subjects were planned
Statistical Review
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Page 7 to be randomized 1:1 to receive two doses of BNT162b2 or placebo 21 days apart .
Randomization was stratified by age group (younger adults 18 through 55 years of age ,
older adult s >55 years of age) with a goal of 40% enrollment among older adult s.
Eligibility was later expanded to include a dolescents 16 to 17 years of age.
Efficacy was assessed throughout the study via surveillance for potential cases of
COVID- 19. Participants who developed acute respiratory illness were tested for SARS -
CoV- 2 infection using reverse transcription -polymerase chain reaction (RT -PCR) in an
illness visit. The study included planned interim analys es of the primary efficacy
endpoint at 62, 92, and 120 cases, and a final analysis of all primary and seco ndary
efficacy endpoints after at least 164 COVID -19 cases were accrued. Participants were to
be followed for a maximum of 26 months. Efficacy assessments and results are covered in detail in Dr. Lei Huang’s statistical review memo.
Since December 14, 2020 following issuance of the EUA, participants 16 years of age
and older were systematically unblinded and, when eligible per local recommendations,
offered BNT162b2 vaccination no later than the 6- month timepoint after the second study
vaccination if they had been randomized to placebo.
A subset of at least 6 ,000 participants ( the reactogenicity subset , planned to be the first
6,000 or more patients randomized) were to record local reactions, systemic events, and
antipyretic/pain medication usage from Day 1 through Day 7 after each dose. For all participants, unsolicited a dverse events (AEs) and s erious AEs (SAEs) were collected
from Dose 1 up to the March 13, 2021 data cut -off.
6.1.3 Population
The Phase 2/3 study population consisted of participants 12 years of age and older at
higher risk for acquiring COVID -19 (including, but not limited to, use of mass
transportation, relevant demographics, and frontline essential workers).
6.1.4 Study Treatments or Agents Mandated by the Protocol
The study interventions were 30µg of BNT162b2 and saline placebo.
6.1.6 Sites and Centers
A total of 153 sites across the United States (131), Turkey (9), Germany (6), South
Africa, (4), Brazil (2) and Argentina (1) particip ated in the study.
6.1.7 Surveillance/Monitoring
Please refer to Drs. Susan Wollersheim and Ann Schwartz’s clinical review memo .
6.1.8 Endpoints and Criteria for Study Success The safety endpoints for all subjects include the occurrence of AEs and SAEs from Dose
1 up to one month post Dose 2 or unblinding (whichever is earlier), and from Dose 1 up
to six months post Dose 2 or unblinding. For the reactogenicity subset, safety endpoints
additionally include the occurrence of local reactions (redness, swelling, and injection
Statistical Review
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Page 8 site pain) and systemic reactions (fever, fatigue, headache, chills, vomiting, diarrhea, and
muscle and joint pain) within seven days of each dose.
6.1.9 Statistical Considerations & Statistical Analysis Plan
Solicited safety analys es were based on subjects in the reactogenicity subset who
received at least one dose of the study intervention and responded yes or no to any
reaction within seven days of each dose. Unsolicited safety analyses were based the
Safety Population, which cons isted of all subjects randomized in the Phase 2/3 study who
received at least one dose of study intervention , analyzed according to the intervention
received. Safety endpoints were summarized descriptively by computing the number and
percentage of particip ants within the analysis set who report ed at least one event.
6.1.10 Study Population and Disposition
6.1.10.1 Populations Enrolled/Analyzed
Table 2 shows the disposition of randomized subjects ≥16 years of age in the Phase 2/3
portion of the study. A total of 44 ,165 subjects were randomized. The percentages of
subjects who received each dose were similar between the vaccine and placebo groups. More subjects withdrew from the study in the placebo group than in the vaccine group.
Table 2. Subject Disposition
Source: Adapted from Table 31 of Summary of Clinical Safety.
6.1.10.1.1 Demographics
Table 3 presents demographic characteristics for the Safety Population. Demographic characteristics were generally similar with regard to age, gender, race, and ethnicity - BNT162b2
N=22085
n (%) Placebo
N=22080
n (%) Total
N=44165
n (%)
Randomized 22085 (100.0) 22080 (100.0) 44165 (100.0)
Not vaccinated 55 (0.2) 50 (0.2) 105 (0.2)
Vaccinat ed 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)
Withdrawn from the study 343 (1.6) 484 (2.2) 827 (1.9)
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 (<0.1) 24 (0.1) 35 (0.1)
Death 16 (0.1) 15 (0.1) 31 (0.1)
Adverse event 9 (<0.1) 8 (<0.1) 17 (<0.1)
Physician decision 3 (<0.1) 6 (<0.1) 9 (<0.1)
No longer meets eligibility criteria 1 (<0.1) 4 (<0.1) 5 (<0.1)
Pregnancy 0 1 (<0.1) 1 (<0.1)
Medication error without AE 1 (<0.1) 0 1 (<0.1)
Withdrawal by parent/guardian 1 (<0.1) 0 1 (<0.1)
Other 5 (<0.1) 9 (<0.1) 14 (<0.1)
Statistical Review
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Page 9 among participants who received BNT162b2 and those who received placebo. Overall,
among all the participants who received either BNT162b2 or placebo, 50.9% were male
and 49.1% were female, 82.0% were White, 9.6% were Black or African American, 4.3% were Asian, and 1.0% were American Indian or Alaska Native.
Table 3. Demographics Character istics of the Safety Population
Source: Table 4 of Summary of Clinical Safety.
6.1.11 Efficacy Analyses
Please refer to Dr. Lei Huang’s statistical review memo .
6.1.12 Safety Analyses
Solicited Local and Systemic Reactions
Tables 4 and 5 present the frequency by severity of each solicited local and systemic reaction within seven days of each dose for the 16- to-55 and 56- and-above year -old age - BNT162b2
N=22026
n (%) Placebo
N=22021
n (%) Total
N=44047
n (%)
Sex
Male 11322 (51.4) 11098 (50.4) 22420 (50.9)
Female 10704 (48.6) 10923 (49.6) 21627 (49.1)
Race
White 18056 (82.0) 18064 (82.0) 36120 (82.0)
Black/African -American 2098 (9.5) 2118 (9.6) 4216 (9.6)
American Indian/Alaskan Native 221 (1.0) 217 (1.0) 438 (1.0)
Asian 952 (4.3) 942 (4.3) 1894 (4.3)
Native Hawaiian/Other Pacific Islander 58 (0.3) 32 (0.1) 90 (0.2)
Multiracial 550 (2.5) 533 (2.4) 1083 (2.5)
Not Reported 91 (0.4) 115 (0.5) 206 (0.5)
Ethnicity
Hispanic/Latino 5704 (25.9) 5695 (25.9) 11399 (25.9)
Non-Hispanic/Non -Latino 16211 (73.6) 16212 (73.6) 32423 (73.6)
Not Reported 111 (0.5) 114 (0.5) 225 (0.5)
Country
Argentina 2883 (13.1) 2881 (13.1) 5764 (13.1)
Brazil 1452 (6.6) 1448 (6.6) 2900 (6.6)
Germany 249 (1.1) 250 (1.1) 499 (1.1)
South Africa 401 (1.8) 399 (1.8) 800 (1.8)
Turkey 249 (1.1) 249 (1.1) 498 (1.1)
USA 16792 (76.2) 16794 (76.3) 33586 (76.3)
Age Group
16-55 Years 13069 (59.3) 13095 (59.5) 26164 (59.4)
>55 Years 8957 (40.7) 8926 (40.5) 17883 (40.6)
Age
Mean (Standard Deviation) 49.7 (16.0) 49.6 (16.1) 49.7 (16.0)
Median 51.0 51.0 51.0
Minimum, Maximum (16, 89) (16, 91) (16, 91)
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Page 10 groups, respectively. In general, incidence of any redness, swelling, injection site pain,
fever, fatigue, headache, chills, new or worse muscle pain, and new or worse joint pain was higher among vaccine recipients than among placebo recipients. There were no notable difference s between vaccine and placebo recipients or between vaccine Dose 1
and Dose 2 for vomiting or diarrhea.
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 the
older age group (78.3% vs 66.1%) . A similar pattern was observed after Dose 1.
Frequencies of any i njection site redness and swelling were generally similar after each
dose and for both age groups. Among BNT162b2 recipients 16 to 55 years of age, the mean duration (not shown in
tables) of pain at the injection site after Dose 2 was 2.5 days (range 1 to 70 days), 2.2
days for redness (range 1 to 9 days), and 2.1 days for swelling (range 1 to 8 days).
Among BNT162b2 recipients 56 ye ars of age and older the mean duration of pain at the
injection site after Dose 2 was 2.4 days (range 1 to 36 days), 3.0 days for redness (range 1
to 34 days), and 2.6 days for swelling (range 1 to 34 days).
The frequency and severity of systemic AEs were generally higher in the younger age
group. Within each age group, the frequency and severity of systemic AEs w ere higher
after Dose 2 than Dose 1, except for vomiting and diarrhea, which w ere generally similar
regardless of dose. For both age groups, fatigue, headache and new/worsened muscle pain were the most common reactions after Dose 2.
Table 4. Frequency of Sol icited Reactions Within Seven Days of each Dose (16 to 55 Years )
- BNT162b2
Dose 1
N=2899
n (%) Placebo
Dose 1
N=2908
n (%) BNT162b2
Dose 2
N=2682
n (%) Placebo
Dose 2
N=2684
n (%)
Redness - - - -
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
Swelling - - - -
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 site - - - -
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
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)
Statistical Review
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Page 11 - BNT162b2
Dose 1
N=2899
n (%) Placebo
Dose 1
N=2908
n (%) BNT162b2
Dose 2
N=2682
n (%) Placebo
Dose 2
N=2684
n (%)
>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 1 (0.0) 0
Fatigue - - - -
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)
Headache - - - -
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)
Chills - - - -
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)
Vomiting - - - -
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 1 (0.0) 4 (0.1) 0
Diarrhea - - - -
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 pain - - - -
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 pain - - - -
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
medication 805 (27.8) 398 (13.7) 1213 (45.2) 320 (11.9)
N=number of subjects responding yes or no for any reaction within seven days of dosing.
n=number of subjects with the specified reaction.
Source: Adapted from Table 14.68 of C4591001 Interim Clinical Study Report .
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Page 12 Table 5. Frequency of Solicited Reactions Within Seven Days of each Dose (>55 Years)
- BNT162b2
Dose 1
N=2008
n (%) Placebo
Dose 1
N=1989
n (%) BNT162b2
Dose 2
N=1860
n (%) Placebo
Dose 2
N=1833
n (%)
Redness - - - -
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)
Swelling - - - -
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 4 (0.2) 1 (0.1)
Pain at the injection site - - - -
Any 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 10 (0.5) 0
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
Fatigue - - - -
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
Headache - - - -
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)
Chills - - - -
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
Vomiting - - - -
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
Statistical Review
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Page 13 - BNT162b2
Dose 1
N=2008
n (%) Placebo
Dose 1
N=1989
n (%) BNT162b2
Dose 2
N=1860
n (%) Placebo
Dose 2
N=1833
n (%)
Diarrhea - - - -
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 pain
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 pain - - - -
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
medication 382 (19.0) 224 (11.3) 688 (37.0) 170 (9.3)
N=number of subjects responding yes or no for any reaction within seven days of dosing.
n=number of subjects with the specified reaction.
Source: Adapted from Table 14.68 of C4591001 Interim Clinical Study Report .
Reviewer Comment:
• Three placebo recipients 16 to 55 years of age who reported fever of >42 °C
within seven days of the first or second dose were excluded from the analysis. As
the subjects received placebo and the se measurements were likely due to error,
this is unlikely to affect safety conclusions.
Unsolicited Safety
Table 6 presents the number s and percentages of subjects ≥16 years of age who reported
any unsolicited AE, SAE, AE leading to withdrawal , or death after the first dose . These
numbers are reported for three separate risk windows: a) Dose 1 to one month post Dose 2 or unblinding (whichever is first), b) Dose 1 to six months post Dose 2 or unblinding (whichever is first), and c) (for placebo patients who received crossover vaccination) from crossover to March 13, 2021. The percentages of subjects reporting any SAE, AE leading to withdrawal, or death were generally similar between the vaccine an d placebo
groups from Dose 1 to one month after Dose 2 and from Dose 1 to six months after Dose
2 regardless of severity . A higher percentage of vaccine recipients reported any
unsolicited AE after Dose 1 than placebo recipients. Four vaccine recipients reported
SAEs up to six months post Dose 2 that were considered by the investigator to be related
to the study intervention. In these analyses, 58.2% of study participants had at least four
months of blinded follow -up after Dose 2.
Statistical Review
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Page 14 A total of 19 ,525 subjects originally randomized to placebo received at least one dose of
BNT162b2 after unblinding (Dose 3 and Dose 4) and before the March 13, 2021 data cutoff. Among these subjects, one (<0.1%) subject reported an SAE of anaphylactoid reaction after Dose 3 that was considered by the investigator to be related to the study intervention. Two subjects (<0.1%) died after receiving Dos e 3, but neither were
considered by the investigator to be related to the intervention .
Table 6. Number of Subjects ≥16 Years of Age Reporting at Least One AE by Time Period
- BNT162b2
1MPD2a
N=21926
n (%) Placebo
1MPD2a
N=21921
n (%) BNT162b2
6MPD2b
N=21926
n (%) Placebo
6MPD2b
N=21921
n (%) BNT162b2
PD3c
N=19525d
n (%)
Any AE 6617 (30.2) 3048 (13.9) 6947 (31.7) 3568 (16.3) 4885 (25.0)
Related 5241 (23.9) 1311 (6.0) 5246 (23.9) 1313 (6.0) 4508 (23.1)
Severe 262 (1.2) 150 (0.7) 356 (1.6) 256 (1.2) 142 (0.7)
Life-Threatening 21 (0.1) 26 (0.1) 48 (0.2) 54 (0.2) 11 (0.1)
Any SAE 127 (0.6) 116 (0.5) 268 (1.2) 268 (1.2) 65 (0.3)
Related 3 (<0.1) 0 4 (<0.1) 1 (<0.1) 1 (<0.1)
Severe 71 (0.3) 66 (0.3) 148 (0.7) 156 (0.7) 37 (0.2)
Life-Threatening 21 (0.1) 26 (0.1) 48 (0.2) 54 (0.2) 11 (0.1)
Any AE leading to withdrawal 32 (0.1) 36 (0.2) 45 (0.2) 51 (0.2) 19 (0.1)
Related 13 (0.1) 11 (0.1) 13 (0.1) 12 (0.1) 12 (0.1)
Severe 10 (<0.1) 10 (<0.1) 10 (<0.1) 12 (0.1) 2 (<0.1)
Life-Threatening 3 (<0.1) 7 (<0.1) 15 (0.1) 16 (0.1) 4 (<0.1)
Death 3 (<0.1) 5 (<0.1) 15 (0.1) 14 (0.1) 2 (<0.1)
N=number of subjects who received at least one dose of the study intervention .
n=number of subjects reporting at least one event.
aIncludes all events from Dose 1 up to the earlier of one month post Dose 2 or unblinding.
bIncludes all events from Dose 1 up to the earlier of six months post Dose 2 or unblinding.
cInclude s all events from crossover vaccination (Dose 3) to March 13, 2021.
dInclude s all subjects randomized to placebo who received BNT162b2 after unblinding.
Source: Adapted from Tables 5 , 7, and 14 of Summary of Clinical Safety .
Reviewer Comments:
• The solicited and unsolicited AEs reported in the clinical study report were
consistent with the Study Data Tabulation Model ( SDTM ) data.
• The solicited and unsolicited AE analyses presented do not include the 200
Human Immunodeficiency Virus ( HIV)-positive participants. Similar safety results
were observed in HIV -positive subjects.
• The i mbalance in the frequencies of unsolicited AEs is driven largely by increased
reactogenicity in the vaccine arm, in that many events associated with
reactogenicity (e.g. injection site pain, fatig ue, etc.) occurring within days of
vaccination were reported as unsolicited AEs.
• Two subjects who received BNT162b2 and experienced an AE or SAE were not
reported in the blinded follow -up safety analysis:
1. One s ubject (C4591001 ) received two doses of BNT162b2
and reported an SAE of acute hepatic failure on Day 100 that was not considered by the investigator to be related to the study intervention . The
(b) (6)
Statistical Review
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Page 15 subject was unblinded and withdrew from the study on the same day that the SAE was reported. As the safety analyses included only events up to the day before unblinding (regardless of the reason for unblinding), this event was not considered to have occurred during blinded follow-up.
2. One subject (C4591001 ) received one dose of BNT162b2
and reported a case of tinnitus with unknown start and end dates.
I defer to the clinical reviewer regarding the interpretation of these events.
• The applicant stated that 58.2% of subjects in the unsolicited safety analysis completed at least four months of follow-up post Dose 2. Of note, it appears that the applicant considered a month to be equivalent to 28 days. The median follow -
up from Dose 2 to six months post Dose 2 or unblinding among ≥16- year-old
participants in the Safety Population was approximately 120 days.
• Ten subjects ( six vaccine and four placebo) who received at least one dose of the
study intervention were excluded from the Safety Set due to “lack of PI [Principal Investigator] oversight,” which was not documented in the Statistical Analysis Plan. Among the six vaccine recipients, one non- serious AE of “excessive
cerumen production” was reported that was not considered by the investigator to be related to the study intervention , and no SAEs were reported.
Myocarditis and Pericarditis
One report of pericarditis was identified in a 66 -year-old male participant 28 days after
receiving Dose 2 of BNT162b2. One report of myocar ditis was identified in a 25 -year-old
male participant in the placebo group five days after the second placebo dose.
7. INTEGRATED OVERVIEW OF EFFICACY
No integrated analysis of efficacy was performed.
8. INTEGRATED OVERVIEW OF SAFETY
No integrated analysis of safety was performed.
9. ADDITIONAL STATISTICAL ISSUES
There are no additional statistical issues.
10. CONCLUSIONS
10.1 Statistical Issues and Collective Evidence
No major statistical issues were identified for the safety data during review. A higher percentage of subjects in the BNT162b2 group reported solicited local and systemic reactions than placebo recipients in both the younger (16 to 55 years) and older (>55 years) adult age groups after each dose. There were no major imbalances in reported
SAEs , AEs leading to withdrawal, or deaths between the treatment groups at one month
and up to six months after the second dose or unblinding /data cut -off.
(b) (6)
Statistical Review
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Page 16 10.2 Conclusions and Recommendations
There is evidence of reactogenicity associated with BNT162b2; the overwhelming
majority of events were o f mild or moderate severity and short duration. There was no
evidence of increased risk of unsolicited SAE or death associated with BNT162b2 in Study C4591001. I defer to Drs. Susan Wollersheim and Ann Schwartz’s clinical review
memo on the overall safety conclusion for BNT162b2.