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BNT162b2
2.7.4 Summary of Clinical Safety
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Page 12.7.4 SUMMARY OF CLI NICAL SAFETY
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Page 2TABLE OF CONTENTS
LIST OF IN -TEXT TABL ES................................ ................................ ................................ ....5
LIST OF IN -TEXT FIGU RES................................ ................................ ................................ ...8
ABBREVIAT IONS ................................ ................................ ................................ ................. 10
2.7.4. SUMMARY OF CLIN ICAL SAFETY ................................ ................................ ......... 13
2.7.4.1. Exposure to BNT162b2 ................................ ................................ ..................... 17
2.7.4.1.1. Overall Safety Evaluation Plan and Narratives of Safet y Studies ........ 17
2.7.4.1.1.1. Phase 1/2 Study BNT162 -01................................ ............... 18
2.7.4.1.1.2. Pivotal Phase 1/2/3 Safety , Immunogenicity , and
Efficacy Study C4591001 ................................ ................................ ..21
2.7.4.1.1.3. Narratives ................................ ................................ ............ 33
2.7.4.1.2. Overall Extent of Exposure, Disposition, and Study Population
Characteristics ................................ ................................ ................................ ..34
2.7.4.1.2.1. Study BNT162 -01 ................................ ............................... 34
2.7.4.1.2.2. Phase 1 (Study C4591001) ................................ .................. 35
2.7.4.1.2.3. Phase 2 (Study C4591001) ................................ .................. 37
2.7.4.1.2.4. Phase 3 (Study C4591001) ................................ .................. 38
2.7.4.2. Safet y Results for BNT162b2 ................................ ................................ ........... 46
2.7.4.2.1. Study BNT162-01................................ ................................ ................. 47
2.7.4.2.1.1. Reactogenicity (Phase 1, Study BNT162 -01) ..................... 47
2.7.4.2.1.2. Summary of Treatment -Emergent Adverse Events
(Phase 1, Study BNT162 -01) ................................ ............................ 48
2.7.4.2.1.3. Analy sis of Treatment- Emergent Adverse Events
(Phase 1, Study BNT162-01) ................................ ............................ 48
2.7.4.2.1.4. Deaths, Serious Adverse Events, Safety -Related
Participant Withdrawals, and Other Significant Adverse Events
(Phase 1, Study BNT162-01) ................................ ............................ 49
2.7.4.2.1.5. Clinical L aboratory Evaluations (Phase 1, Study
BNT162 -01)................................ ................................ ...................... 50
2.7.4.2.1.6. Vital Signs, Phy sical Findings, and Other
Observations Related to Safety (Phase 1, Study BNT162 -01).......... 50
2.7.4.2.1.7. Conclusions (Phase 1, Study BNT162-01) ......................... 51
2.7.4.2.2. Phase 1 (Study C4591001) ................................ ................................ ...51
2.7.4.2.2.1. Reactogenicity (Phase 1, Study C4591001) ........................ 51
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Page 32.7.4.2.2.2. Summary of Adverse Events (Phase 1, Study
C4591001) ................................ ................................ ......................... 52
2.7.4.2.2.3. Analy sis of Adverse Events (Phase 1, Study
C4591001) ................................ ................................ ......................... 53
2.7.4.2.2.4. Deaths, Serious Adverse Events, Safety -Related
Participant Withdrawals, and Other Significant Adverse Events
(Phase 1, Study C4591001) ................................ ............................... 54
2.7.4.2.2.5. Clinical L aboratory Evaluations (Phase 1, Study
C4591001) ................................ ................................ ......................... 55
2.7.4.2.2.6. Phy sical Examination Findings (Phase 1, Study
C4591001) ................................ ................................ ......................... 55
2.7.4.2.2.7. Narratives (Phase 1, Study C4591001) ............................... 55
2.7.4.2.2.8. Conclusions (Phase 1, Study C4591001) ............................ 56
2.7.4.2.3. Phase 2 (Study C4591001) ................................ ................................ ...56
2.7.4.2.3.1. Reactogenicity (Phase 2, Study C4591001) ........................ 56
2.7.4.2.3.2. Summary of Adverse Events (Phase 2, Study
C4591001) ................................ ................................ ......................... 58
2.7.4.2.3.3. Analy sis of Adverse Events (Phase 2, Study
C4591001) ................................ ................................ ......................... 59
2.7.4.2.3.4. Deaths, Serious Adverse Events, Safety -Related
Participant Withdrawals, and Other Significant Adverse Events
(Phase 2, Study C4591001) ................................ ............................... 60
2.7.4.2.3.5. Narratives (Phase 2, Study C4591001) ............................... 60
2.7.4.2.3.6. Conclusions (Phase 2, Study C4591001) ............................ 60
2.7.4.2.4. Phase 3 (Study C4591001) ................................ ................................ ...61
2.7.4.2.4.1. Reactogenicity (Phase 3, Study C4591001) ........................ 61
2.7.4.2.4.2. Adver se Events (Phase 3, Study C4591001) ....................... 73
2.7.4.2.4.3. Deaths, Serious Adverse Events, Safety -Related
Participant Withdrawals, and Other Significant Adverse Events
(Phase 3, Study C4591001) ................................ ............................. 218
2.7.4.2.4.4. Narratives (Phase 3, Study C4591001) ............................. 290
2.7.4.2.4.5. Conclusions (Phase 3, Study C4591001) .......................... 291
2.7.4.2.5. Discussion................................ ................................ ........................... 291
2.7.4.3. Safet y in Special Groups and Situations ................................ ......................... 294
2.7.4.3.1. I ntrinsic Factors ................................ ................................ .................. 294
2.7.4.3.1.1. Geriatric Use ................................ ................................ .....294
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Page 42.7.4. 3.1.2. Pediatric Use ................................ ................................ .....294
2.7.4.3.1.3. Use in Immunocompromised Individuals ......................... 294
2.7.4.3.2. Extrinsic Factors ................................ ................................ ................. 295
2.7.4.3.3. Drug Interactions ................................ ................................ ................ 295
2.7.4.3.4. Use in Pregnancy and Lactation ................................ ......................... 295
2.7.4.3.5. Overdose ................................ ................................ ............................. 295
2.7.4.3.6. Drug Abuse ................................ ................................ ......................... 295
2.7.4.3.7. Withdrawal and Rebound ................................ ................................ ...296
2.7.4.3.8. Effects on Ability to Drive or Operate Machinery or Impairment
of Mental Ability ................................ ................................ ............................ 296
2.7.4.4. Post -Authorization Data ................................ ................................ .................. 296
2.7.4.5. Overall Conclusions ................................ ................................ ........................ 296
2.7.4.6. APPENDI CES ................................ ................................ ................................ .298
2.7.4.6.1. Appendix A: Study BNT162 -01 Safet y Evaluation Plan ................... 298
2.7.4.6.1.1. Study BNT162 -01 Part A Study Schema .......................... 298
2.7.4.6.1.2. Schedule of Activities (Study BNT162 -01) ...................... 299
2.7.4.6.1.3. Study BNT162 -01: Safet y Assessments ........................... 302
2.7.4.6.2. Appendix B: Study C4591001 Safet y Evaluation Plan ...................... 305
2.7.4.6.2.1. Study C4591001 Study Schema ................................ ........ 305
2.7.4.6.2.2. Schedule of Activities (Study C4591001) ......................... 306
2.7.4.6.2.3. Study C4591001: Safety Assessments .............................. 320
2.7.4.6.3. Appendix C: Phase 2 Study C4591001 Post -text Tables .................... 327
2.7.4.6.3.1. Reactogenicity (Phase 2, Study C4591001, Post -text
Tables and Figures) ................................ ................................ ......... 327
2.7.4.6.4. Appendix D: Phase 3 Study C4591001 Post -text Tables ................... 333
2.7.4.6.4.1. E xposure, Disposition, and Study Population
Characteristics (Phase 3, Study C4591001, Post -text Tables) ........ 333
2.7.4.7. REFERENCES ................................ ................................ ................................ 344
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Page 5LIST OF IN -TEXT TABL ES
Table 1. Cutoff Dates for Safet y Data Presented in Summary of Clinical
Safety ................................ ................................ ................................ ........ 16
Table 2. Safety Objectives and Endpoints for Study BNT162 -01.......................... 18
Table 3. Safety Objectives, Estimands, and Endpoints for Study C4591001 ......... 22
Table 4. Demographic Characteristics – Phase 2/3 Subjects ≥16 Years of
Age –Safet y Population ................................ ................................ ........... 43
Table 5. Number (%) of Subjects Reporting at Least 1 Adverse Event From
Dose 1 to 1 Month After Dose 2 – Blinded Placebo- Controlled
Follow -up Period – Phase 2/3 Subjects ≥16 Years of Age – Safety
Population ................................ ................................ ................................ .76
Table 6. Number (%) of Subjects Reporting at Least 1 Adverse Event From
Dose 1 to 1 Month After Dose 2, b y System Organ Class and
Preferred Term –Blinded Placebo -Controlled Follow -up Period –
Phase 2/3 Subjects ≥16 Years of Age – Safet y Population ...................... 82
Table 7. Incidence Rates of at Least 1 Adverse Event From Dose 1 to
Unblinding Date –Phase 2/3 Subjects ≥16 Years of Age – Safety
Population ................................ ................................ ............................... 116
Table 8. Incidence Rates of at Least 1 Adverse E vent From Dose 1 to
Unblinding Date, b y System Organ Class and Preferred Term –
Phase 2/3 Subjects ≥16 Years of Age – Safet y Population .................... 120
Table 9. Incidence Rates of at Least 1 Adverse Event From Unblinding Date
to Data Cutoff Date (13MAR2021) – Open -Label Follow -up Period
–Subjects Who Originally Received BNT162b2 –Phase 2/3
Subjects ≥16 Years of Age – Safet y Population ................................ .....160
Table 10. Incidence Rates of at Least 1 Adverse Event From Unblinding Date
to Data Cutoff Date (13MAR2021), by System Organ Class and
Preferred Term –Open -Label Follow -up Period –Subjects Who
Originall y Received BNT162b2 – Phase 2/3 Subjects ≥16 Years of
Age –Safet y Population ................................ ................................ ......... 162
Table 11. Number (%) of Subjects Reporting at Least 1 Adverse Event From
Dose 1 to 6 Months After Dose 2 –Subjects With at Least 6
Months of Follow- up Time After Dose 2 – Phase 2/3 Subjects ≥16
Years of Age (Subjects Who Orig inally Received BNT162b2) –
Safety Population ................................ ................................ .................... 170
Table 12. Number (%) of Subjects Reporting at Least 1 Adverse Event From
Dose 1 to 6 Months After Dose 2, b y Time Period – Subjects With
at Least 6 Months of Follow- up Time After Dose 2 – Phase 2/3
Subjects ≥16 Years of Age (Subjects Who Originally Received
BNT162b2) –Safet y Population ................................ ............................ 171
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Page 6Table 13. Number (%) of Subjects Reporting at Least 1 Adverse Event From
Dose 1 to 6 Months After Dose 2, b y System Organ Class and
Preferred Term –Subjects With at Least 6 Mont hs of Follow -up
Time After Dose 2 –Phase 2/3 Subjects ≥16 Years of Age
(Subjects Who Originally Received BNT162b2) –Safety
Population ................................ ................................ ............................... 173
Table 14. Incidence Rates of at Least 1 Adverse Event From Dose 3 to Data
Cutoff Date (13MAR2021) –Open -Label Follow -up Period –
Subjects Who Originally Received Placebo and Then Received
BNT162b2 After Unblinding –Phase 2/3 Subjects ≥16 Years of
Age –Safet y Population ................................ ................................ ......... 197
Table 15. Incidence Rates of at Least 1 Adverse Event From Dose 3 to Data
Cutoff Date (13MAR2021), by System Organ Class and Preferred
Term –Open -Label Follow -up Period – Subjects Who Originally
Received Placebo and Then Received BNT162b2 After Unblinding
– Phase 2/3 Subjects ≥16 Years of Age – Safet y Population ................. 201
Table 16. Incidence Rates of Deaths From Dose 1 to Unblinding Date –
Blinded Placebo -Controlled Follow- up Period – Phase 2/3 Subjects
≥16 Years of Age –Safety Population ................................ ................... 219
Table 17. Number (%) of Subjects Reporting at Least 1 Serious Adverse
Event From Dose 1 to 1 Month After Dos e 2, b y System Organ
Class and Preferred Term –Blinded Placebo -Controlled Follow -up
Period – Phase 2/3 Subjects ≥16 Years of Age – Safet y Population ......222
Table 18. Incidence Rates of at Least 1 Serious Adverse Event From Dose 1
to Unblinding Date, b y System Organ Class and Preferred Term –
Phase 2/3 Subjects ≥16 Years of Age – Safet y Population .................... 229
Table 19. Incidence Rates of at Least 1 Serious Adverse Event From
Unblinding Date to Data Cutoff Date (13MAR2021), by System
Organ Class and Preferred Term – Open-Label Follow -up Period –
Subjects Who Originally Received BNT162b2 – Phase 2/3 Subjects
≥16 Years of Age – Safety Population ................................ ................... 242
Table 20. Number (%) of Subjects Reporting at Least 1 Serious Adverse
Event From Dose 1 to 6 Months After Dose 2, b y System Organ
Class and Preferred Term –Subjects With at L east 6 Months of
Follow -up Time After Dose 2 – Phase 2/3 Subjects ≥16 Years of
Age (Subjects Who Originally Received BNT162b2) –Safet y
Population ................................ ................................ ............................... 246
Table 21. Incidence Rates of at Least 1 Serious Adverse Event From Dose 3
to Data Cutoff Date (13MAR2021), by System Organ Class and
Preferred Term –Open -Label Follow -up Period –Subjects Who
Originall y Received Placebo and Then Received BNT162b2 After
Unblinding – Phase 2/3 Subjects ≥16 Years of Age –Safety
Popula tion................................ ................................ ............................... 253
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Page 7Table 22. Number (%) of Subjects Withdrawn Because of Adverse Events
From Dose 1 to 1 Month After Dose 2, b y System Organ Class and
Preferred Term –Blinded Placebo -Controlled Follow -up Period –
Phase 2/3 Subjects ≥16 Years of Age – Safet y Population .................... 259
Table 23. Incidence Rates of Subjects Withdrawn Because of Adverse Events
From Dose 1 to Unblinding Date, b y System Organ Class and
Preferred Term –Phase 2/3 Subjects ≥16 Years of Age – Safet y
Population ................................ ................................ ............................... 263
Table 24. Incidence Rates of Subjects Withdrawn Because of Adverse Events
From Unblinding Date to Data Cutoff Date (13MAR2021), by
System Organ Class and Preferred Term –Open -Labe l Follow-up
Period – Subjects Who Originall y Received BNT162b2 –Phase 2/3
Subjects ≥16 Years of Age – Safet y Population ................................ .....267
Table 25. Number (%) of Subjects Withdrawn Because of Adverse Events
From Dose 1 to 6 Months After Dose 2, b y System Organ Class and
Preferred Term – Subjects With at Least 6 Months of Follow -up
Time After Dose 2 –Phase 2/3 Subjects ≥16 Years of Age
(Subjects Who Originally Received BNT162b2) –Safety
Population ................................ ................................ ............................... 268
Table 26. Incidence Rates of Subjects Withdrawn Because of Adverse Events
From Dose 3 to Data Cutoff Date (13MAR2021), by System Organ
Class and Preferred Term –Open -Label Follow -up Period –
Subjects Who Originally Received Placebo and Then Received
BNT162b2 After Unblinding –Phase 2/3 Subjects ≥16 Years of
Age –Safet y Population ................................ ................................ ......... 269
Table 27. Selected Standard MedDRA Queries From Dose 1 to Unblinding
Date –Blinded Placebo -Controlled Follow- up Period –Phase 2/3
Subjects ≥16 Years of Age – Safet y Population ................................ .....274
Table 28. Incidence Rates of at Least 1 Adverse Event Category of Special
Interest From Dose 1 to Unblinding Date, b y Adverse Event
Category and Preferred Term –Blinded Placebo -Controlled
Follow -up Period – Phase 2/3 Subjects ≥16 Years of Age – Safety
Population ................................ ................................ ............................... 281
Table 29. Local Reaction Grading Scale (Study C4591001) ................................ ..321
Table 30. Systemic Event Grading Scale (Study C4591001) ................................ .322
Table 31. Disposition of All Randomized Subjects – Phase 2/3 Subjects ≥16
Years of Age ................................ ................................ ........................... 333
Table 32. Vaccine as Administered by Vaccine Group – Phase 2/3 Subjects
≥16 Years of Age – All Randomized Subjects ................................ .......336
Table 33. Vaccine Administration Timing – Phase 2/3 Subjects ≥16 Years of
Age – All Randomized Subjects................................ ............................. 337
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Page 8Table 34. Safety Population – Phase 2/3 Subjects ≥16 Yea rs of Age .................... 338
Table 35. Follow -up Time After Dose 2 – Phase 2/3 Subjects ≥16 Years of
Age –Safet y Population ................................ ................................ ......... 339
Table 36. Demographic Characteristics –Subjects With at Least 6 Months of
Follow -up Time After Dose 2 – Phase 2/3 Subjects ≥16 Years of
Age (Subjects Who Originally Received BNT162b2) –Safet y
Population ................................ ................................ ............................... 340
Table 37. Demographic Characteristics –Subjects Who Originall y Received
Placebo and Then Received BNT162b2 After Unblinding – Phase
2/3 Subjects ≥16 Years of Age – Safety Population ............................... 342
LIST OF IN -TEXT FIGU RES
Figure 1. Subjects Reporting Local Reactions, by Maximum Severity , Within
7 Day s After Each Dose, by Age Group (Reactogenicity Subset) –
Phase 2/3 Subjects ≥16 Years of Age – Safet y Population Age
Group: 16 Through 55 Years of Age –Safety Population ....................... 63
Figure 2. Subjects Reporting Local Reactions, by Maximum Severity , Within
7 Day s After Each Dose, by Age Group (Reactogenicity Subset) –
Phase 2/3 Subjects ≥16 Years of Age – Safet y Population Age
Group: >55 Years of Age ................................ ................................ ......... 64
Figure 3. Subjects Reporting Local Reactions, by Maximum Severity , Within
7 Day s After Each Dose (Reactogenicity Subset) – Blinded
Placebo- Controlled Follow -up Period – Phase 2/3 HIV -Positive
Subjects ≥16 Years of Age – Safet yPopulation ................................ .......66
Figure 4. Subjects Reporting S ystemic Events, by Maximum Severity ,
Within 7 Day s After Each Dose, by Age Group (Reacto genicit y
Subset) – Phase 2/3 Subjects ≥16 Years of Age –Safety Population
Age Group: 16 Through 55 Years ................................ ............................ 69
Figure 5. Subjects Reporting S ystemic Events, by Maximum Severity ,
Within 7 Day s After Each Dose, Age Group (Reactogenicity
Subset) – Phase 2/3 Subjects ≥16 Years of Age –Safety Population
Age Group: >55 Years ................................ ................................ .............. 70
Figure 6. Subjects Reporting S ystemic Events, by Maximum Severity ,
Within 7 Day s After Each Dose (Reactogenicit y Subset) –Blinded
Placebo- Controlled Follow -up Period – Phase 2/3 HIV -Positive
Subjects ≥16 Years of Age – Safet y Population ................................ .......72
Figure 7 Study C4591001 Phase 3 Safety Anal yses: Time Periods and
Analy sis Groups ................................ ................................ ........................ 74
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Page 9Figure 8. Forest Plot of Tier 2 Adverse Events Reported From Dose 1 to 1
Month After Dose 2 –Blinded Placebo -Controlled Follow -up
Period – Phase 2/3 Subjects ≥16 Years of Age – Safet y Population ........ 78
Figure 9. Subjects Reporting Local Reactions, by Maximum Severit y, Within
7 Day s After Each Dose –Phase 2 – Safet y Population ......................... 327
Figure 10. Subjects Reporting Local Reactions, by Maximum Severity , Within
7 Day s After Each Dose, Phase 2 - Age Group: 18- 55 Years –
Safety Population ................................ ................................ .................... 328
Figure 11. Subjects Reporting Local Reacti ons, by Maximum Severity , Within
7 Day s After Each Dose, Phase 2 –Age Group: 56 -85 Years –
Safety Population ................................ ................................ .................... 329
Figure 12. Subjects Reporting S ystemic Events, by Maximum Severity ,
Within 7 Day s After Each Dose –Phase 2 – Safety Population ............ 330
Figure 13. Subjects Reporting S ystemic Events, by Maximum Severity ,
Within 7 Day s After Each Dose, Phase 2 –Age Group: 18-55 Years
–Safety Population ................................ ................................ ................. 331
Figure 14. Subjects Reporting S ystemic Events, by Maximum Severity ,
Within 7 Day s After Each Dose, Phase 2 –Age Group: 56-85 Years
–Phase 2 – Safet y Population ................................ ................................ 332
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Page 10ABBREVIATIONS
Abbreviation Definition
ADR adverse drug reaction
AE adverse event
AESI adverse events of special interest
ALT alanine aminotransferase
AST aspartate aminotransferase
BLA Biologics License Application
BMI body mass index
BUN blood urea nitrogen
C4591001 Efficacy
Final Analysis
Interim CSRStudy C4591001 interim clinical study report including prespecified final analysis of
efficacy and available immunogenicity and safety data up to data cutoff date of 14
November 2 020
C4591001 6 -Month
Update Interim CSRStudy C4591001 interim clinical study report including updated efficacy,
immunogenicity, and safety up to 6 months after Dose 2 up to data cutoff date of 13
March 2021
CBER (US Food and Drug Administration) Center for Biologics Evaluation and Research
CDC (US) Centers for Disease Control and Prevention
CDS Core Data Sheet
CI confidence interval
CO Clinical Overview
COVID -19 Coronavirus Disease 2019
CRF case report form
CRP c-reactive protein
CSR Clinical Study Report
CTA Clinical Trial A pplication
DART Developmental and Reproductive Toxicology
DMC (US Study C4591001) Data Monitoring Committee
ECG electrocardiogram
EoS endofstudy
FDA (US) Food and Drug Administration
FIH first-in-human
FU follow -up
HBV hepatitis B virus
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Page 11Abbreviation Definition
HBc Abs hepatitis B core antibodies
HBsAg hepatitis B surface antigen
HCV hepatitis C virus
HCV Abs hepatitis C virus antibodies
HIV human immunodeficiency virus
HLT high level term
ICD informed consent document
IgG immunoglobulin G
IgM immunoglobulin M
IM intramuscular(ly)
IND Investigational New Drug
IR incidence rate
IRC (US Study C4591001) Internal Revie w Committee
IRT interactive response technology
IV intravenous
IWR interactive Web -based response
LLN lower limit of normal
MedDRA Medical Dictionary for Regulatory Activities
MIS-C multisystem inflammatory syndrome in children
NAAT nucleic acid amplification testing
NHP non-human primate
P/B prime/boost: dosing regimen of a priming immunization and a booster immunization
PCR polymerase chain reaction
PT Preferred Term
PY person -years
RNA ribonucleic acid
SAF Safety Set
SAP statistical analysis plan
SAE serious adverse event
SARS -CoV-2 SARS Coronavirus -2; virus causing the disease COVID -19
SCE Summary of Clinical Efficacy
SCS Summary of Clinical Safety
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Page 12Abbreviation Definition
SIRVA shoulder injury related to vaccine administration
SMQ Standardised MedDRA Queries
SoA schedule of activities
SOC System Organ Class
SRC Safety Review Committee
US United States
VOC variant of concern
TEAE treatment -emergent adverse events
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Page 132.7.4.SUMMARY OF CLINICAL SAFETY
This SCS presents the safety and tolerability data for BNT162b2. BNT162b2 (BioNTech
code number BNT162, Pfizer code number PF- 07302048) is an investigational vaccine
developed b y BioNTech and Pfizer intended to prevent COVID- 19, which is caused b y
SARS -CoV -2.The data are derived from the pivotal registration study , Phase 1/2/3 Study
C4591001 (BNT162 -02),conducted under IND 19736. Supporting data are presented from
the FIH, dose level -finding, Phase 1/2 Stud y BNT162 -01 conducted in Germany (which is
not being conducted under the IND, but under a CTA ).
The proposed indication and dosing administration for BNT162b2 (30 µg) is:
Proposed indication: Active immunization against COVID -19disease caused by
SARS -CoV -2 virus in individuals ≥16years of age .
Proposed dosing administration: single 0.3 mL intramuscular (IM) dose followed by a
second 0.3 mL dose 21 day s later.
Nonclinical studies in this development program are summarized in the CO (Module 2.5
Section 2. 5.1.2.3.1 ).
Phase 1 of Study C4591001 evaluated 2 vaccine candidates, BNT162b1 and BNT162b2.
These 2 candidates were selected based on safet y and immunogenicit y data from
Study BNT162 -01 (which is evaluating four vaccine candidates). Phase 1 of Study C4591001
comprised of dose-level finding evaluations of the 2 selected vaccine candidates ; multiple
dose levels were evaluated ,including some that correspond edto those evaluated in
Study BNT162 -01(BNT162b1 and BNT162b2 at 10 µg, 20 µg, and 30 µg ). Study vaccine
was administere d using the same 2- dose regimen as in Study BNT162 -01 (21 days apart).
Dose level swere administered first to an 18 to 55 years of age cohort, then to a 65 to
85years ofage cohort .
Evaluation of Phase 1 safety and immunogenicity results led to the selection of a single
candidate . Both construct swere safe and well tolerated (except for BNT162b1 at 100 μg) .
Given that the reactogenicity profile for BNT162b2 was more favorable than BNT162b1 in
both y ounger and older adults with similar immunogenicity results, andwith non- human
primate (NHP) challenge studies showing that BNT162b2 led to earlier virus clearance and
no evidence of virus in the lung , BNT162b2 at the 30 µg dose level was selected and
advanced into the Phase 2/3 expanded cohort and effica cy evaluation.
Phase 2 of the stud y (for which enrol lment has completed) comprised the evaluation of safet y
and immunogenicit y data for the first 360 participants (180 from active vaccine group and
180 from placebo group) that enter edthe study after completion of Phase 1.
The Phase 3 part of the study is ongoing, and participants (including the first 360 participants
from Phase 2) are continuing to be evaluated at the time of this SCS .The minimum age for
inclusion in Phase 3 was lowered from 18 to 16 y ears of age after the approval of
Study C4591001 protocol amendment 6 and from 16to12years of age after the approval of
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Page 14Study C4591001 protocol amendment 7. As such, Phase 3 has complet ed enrollment of
adolescents ≥ 12 years of age ( stratified as 12 -15, 16 -55, or >55 years of age ).
C4591001 protocol amendment 10 allowed participants ≥16 y ears of age who originall y
received placebo the opportunity to receive BNT162b2 following local or national
recommendations, or following completion of the active safet y surveillance period .On
14 December 2020, the process of disclosing vaccine assignments for all trial participants
≥16 y ears of age began. Hence, for each trial participant, there are 2 periods in the study :
enrollment into the observer-blind phase until the date of vaccine disclosure and the time in
the study after disclosure. Participants who originally were randomized to BNT162b2, are
continuing to be followed for safety as specified in the protocol. The safety data for
participants who originally were randomized to and received placebo prior to disclosure of
vaccine assignment are standard blinded data that contribute to controlled assessment of
safet y compared to individuals who rand omly assigned to BNT162b2. After vaccine
treatment disclosure and the administration of BNT162b2, the placebo participants can no
longer be used for direct comparison with those who originall y were randomized to
BNT162b2. Given that individuals were unblin ded on different day s after
14December 2020, the analy sis of the observer -blinded, placebo -controlled portion of the
study as well as the open -label portion display s rates of AEs adjusted for exposure time.
Safety data for Phase 3 of Study C4591001, based on the data cutoff date of 13 March 2021 ,
presented in this SCS include:
Blinded placebo -controlled period: Dose 1 to 1 month after Dose 2 and to unblinding
date:
oPhase 1 participants randomized to BNT162b2 30 µg (up to ~6 months after
Dose 2)
oPhase 2/3 ≥ 16 years of age participants including HIV+ subset (up to ~ 6
months after Dose 2)
Open -label observational period: from time of unblinding to data cutoff date:
oPhase 2/3 participants ≥16 years of age originall y randomized to BNT162b2
oPhase 2/3 participan ts ≥16 years of age originall y randomized to placebo who
then received BNT162b2
Cumulative follow -up from Dose 1 to 6 months after Dose 2: Phase 2/3 participants
originall y randomized to BNT162b2 (inclusive of blinded data and open -label data)
comprised of at least 3000 in each age group (16 to 55 y ears of age, >55 y ears of age)
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Page 15Overall, t his SC Ssummarizes the safet y data obtained from Study C4591001 (Phases 1 to 3)
and Study BNT162 -01 (Phase 1) to support registration of BNT162b2 . The following data
arepresented in this document by study and phase:
The overall safety evaluation plans for each stud y (including objectives, endpoints,
methods, and criteria for narratives) arepresented in Section 2.7.4.1.1.
Data regarding exposure, disposition, and study population characteristics are
presented in Section 2.7.4.1.2 .
The results of safet y evaluations are presented in Section 2.7.4.2 . These evaluations
include:
oReactogenicit y (local reactions and systemic events)
oAEs (by SOC, related, immediate, severe, deaths, SAEs, and withdrawals due
to AEs)
oOther safety assessments
oNarratives
Safety in special groups and s ituations is presented in Section 2.7.4.3 .
Post-Authorization Data in Section 2.7.4.4 .
Overall conclusions are stated in Section 2.7.4.5 .
The safet y results presented in this SCS demonstrate that BNT162b2 is both safe and
well-tolerated when administered on a 2 -dose schedule (21 days apart) in individuals
≥16yearsof age. The cutoff dates for safet y data presented in this SCS are show ninTable 1.
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Page 16Table 1.Cutoff Dates for Safety Data Presented in Summary of Clinical Safety
Phase/Study Safety Data Available (Through) N(number
randomized)Age
(years of age)Data Cutoff
Date
Study
BNT162 -01Reactogenicity: up to 7 days after
each dose
AEs: 1 month post-dose 2216 Younger: 18 to 55
Older: 56 to 8523Oct 2020
Phase 1
(Study
C4591001)Reactogenicity: up to 7 days after
each dose
AEs: 1 m onth post-dose 2
SAEs: through the data cutoff date
Laboratory Data: 7 days post -dose 2
BNT162b1 100 µg dose level
(younger age group): 3 w eeks post -
dose 1 or to before Dose 2 (based on
the data cutoff date)195 Younger: 18 to 55
Older: 65 to 8524 Aug
2020
Long -term follow -up for AEs & SAEs
for BNT162b2 30 µ ggroup only :
From 1 month post-dose 2 to
unblinding date
(approximately 6months
post-dose 2 )3013Mar 2021
Phase 2
(Study
C4591001)Reactogenicity: up to 7 days after
each dose
AEs/SAEs: 7days post-dose 2a360b 18 to 85
Younger: 18
to 55
Older: 56 to
8502 Sep 2020
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Page 17Table 1.Cutoff Dates for Safety Data Presented in Summary of Clinical Safety
Phase/Study Safety Data Available (Through) N(number
randomized)Age
(years of age)Data Cutoff
Date
Phase 3
(Study
C4591001)Reactogenicity: up to 7 days after
each dose
Blinded AEs/SAEs:
1 month post -dose 2
(including HIV positive
subset)
up to unblinding date
(including HIV positive
subset)d
Open -label AEs/SAEs ( participants
originally randomized to BNT162b2 ):
Date of unblinding to data
cutoff
Blinded and open -label AEs/SAEs
BNT162b2 p articipants with
at least 6 months follow -up
post-dose 2
Open -label AEs/SAEs (participants
originally randomized to placebo but
were vaccinated with BNT162b2 after
treatment disclosure):
Date of BNT162b2
vaccination (after treatment
disclosure) to data cutoff9839c
43,847
20,309
12,006
19,525Younger: 16 to 55
Older: >5513Mar 2021
a.Adverse event results beyond 7 days after Dose 2, as defined in the protocol objectives, are included in
Phase 3 analyses.
b.The 360 Phase 2 participants are included in the Phase 3 analyses.
c.This subset of 9839 participants (which includes Phase 2 participants) completed the e -diary f or
reporting local reactions and systemic events.
d.Up to ~ 6months after Dose 2
2.7.4.1. Exposure to BNT162b2
2.7.4.1.1. Overall Safety Evaluation Plan and Narratives of Safety Studies
The overall safet y evaluation plan for Study BNT162 -01 is presented in Section 2.7.4.1.1.1 .
The overall safet y evaluation plan for Study C4591001 is presented in Section 2.7.4.1.1.2 .
Study BNT162- 01 and Study C4591001 use different designs and safety data collection
methods and definitions. For these reasons, s afety data from Study BNT162- 01 and
Study C4591001 will not be pooled for anal ysis. As BNT162b1 and BNT162b2 were the 2
vaccine candidates evaluated in Phase 1 of the C4591001 study , only these 2 constructs will
be discussed in the SCS as it relates to how the final candidate and dose level was
determined.
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Page 182.7.4.1.1.1. Phase 1/2 Study BNT162 -01
Safety and immunogenicity data from Study BNT162 -01 are summarized in this BLA in
support of the larger dataset from Phase 1/2/3 registration Study C4591001.
2.7.4.1.1.1.1. Safety Objectives and Endpoints (Study BNT162-01)
The safet y objectives and endpoints for Study BNT162 -01 are presented in Table 2.
Table2. Safety Objectives and Endpoints for Study BNT162-01a
Objective Endpoint
Primary:
To describe the safety and tolerability profiles of
prophylactic BNT162 vaccines in healthy adults
after single dose (prime only) or P/B immunization.Solicited local reactions at the injection site
(pain, tenderness, erythema/redness,
induration/swelling) recorded up to 7 ±1 day
after each immunization.
Solicited systemic reactions (nausea, vomiting,
diarrhea, headache, fatigue, myalgia, arthralgia,
chills, loss of appetite, malaise, and fever)
recorded up to 7 ±1 dayafter each
immunization.
The proportion of subjects w ith at least 1
unsolicited TEAE:
For BNT162a1, BNT162b1, BNT162b2,
and BNT162c2 (P/B): occurring up to
21±2 d after the pr ime immunization and
28±4 d after the boost immunization.
For BNT162c2 ( single dose ): The
proportion of subjects with at least 1
unsolicited TEAE occurring up to 28 ±4
daysafter the immunization.
a.Only BNT162b1 and BNT162b2 are discussed in this SCS.
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Page 192.7.4.1.1.1.2. Overall Design (Study BNT162 -01)
Details regarding the study design of Study BNT162 -01 are presented in the study protocol
(Module 5.3.5.1 BNT162 -01 Protocol Section 4).
German Stud y BNT162 -01 is the ongoing, FIH, Phase 1/2 dose level- finding stud y, in which
healthy adults aged 18 to 55 or 56 to 85 all receive active vaccine (open -label and
non-randomized). Four vaccine candidates from 3 different RNA platforms are being tested.
The trial has two parts: a dose -finding part (Part A) and a part dedicated to recruiting
expansion cohorts with dose levels which were selected from data generated in Part A
(Part B). The stud y schema for Part A is presented in Appendix A (Section 2.7.4.6.1 ).
BNT162b1 and BNT162b2 were administered in a prime /boost two-dose regimen separated
by approximately 21 days:
BNT162b1 (dose levels: 1, 3, 10, 20, 30, 50, 60 µg)
BNT162b2 (dose levels: 1, 3, 10, 20, 30 µg).
The safet y review committee ( SRC) recommended that a second dose of BNT162b1 at the
60µg dose level not be administered due to the reactogenicit y after the first dose.
Subject safety was to be monitored from Visit 0(screening) until approximately 6 months
after thelastimmunization.
The following data are summarized and presented in this SCS as primary endpoints:
Local reactions and s ystemic event data (acquired through the subject paper diaries)
through Vis it 5 ( up to 7 day s post -dose 2)
TEAEs through Visit 7 (1- month follow -up visit post -dose 2)
Complete details regarding p lanned time points for all safet y assessments during Phase 2/3
are provided in the SoA in Appendix A (Section 2.7.4.6.1 ).
2.7.4.1.1.1.3. Study Population (Study BNT162-01)
The full eligibility criteria for Study BNT162- 01 can be found in the protocol
(Module 5.3.5.1 BNT162 -01 Protocol Section 5.1.1 and5.2.1 ).
The study enrolled healthy adults 18 to 85 years of age. Healthy participants with preexisting
stable disease, defined as disease not requiring significant change in therapy or
hospitalization for worsen ing disease during the 6 weeks prior to enrollment, were eligible
for the stud y. Individuals with certain medical conditions that could affect participant safety
or evaluation of vaccine safet y or immunogenicity were excluded. A complete list of
inclusion and exclusion criteria is available in the protocol (Module 5.3.5.1 BNT162-01
Protocol Section 5).
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Page 202.7.4.1.1.1.4. Analysis Sets (Study BNT162 -01)
Populations from Study BNT162 -01 discussed in this SCS include the following:
Population Description
Screened Set Thescreened setisdefined asallsubjects who signed informed consent
Safety Set ( SAF) Thesafety setis defined as allsubjects who received atleast onedose ofstudy
intervention
2.7.4.1.1.1.5. Safety Assessments (Study BNT162 -01)
Details regarding safet y assessments for Study BNT162 -01 are found in Module 5.3.5.1
BNT162 -01 Protocol Section 8.2.
Safety assessments were collected at planned time points as described in the Schedule of
Activities ( Appendix A, Section 2.7.4.6.1.2) . Key Safety Assessments included:
Physical examinations, Vital Signs, ECGs
Clinical laboratory tests were performed at the times defined in the SoA and th e
specific tests are presented in Module 5.3.5.1 BNT162-01 Protocol Section 10.2 . The
classification of laboratory tests is presented in Module 5.3.5.1 BNT162 -01 Statistical
Analysis PlanSection 6.7.2 .
Local reactions after IM immunization were assessed by the investigator at the times
given in the SoA ( Appendix A, Section 2.7.4.6.1.2 ).In the 7 day s after administration
of the study intervention, participants used subject diaries to record an y reactions
between visits :solicited local reactions at the injection site and solicited sy stemic
reactions (see Appendix A [Section 2.7.4.6.1.3.2 ] for further details). Grading scales
used in this study to assess local reactions and sy stemic events are derived from the
FDA CBER guidelines on t oxicity grading scales for health y adult volunteers
enrolled in preventive vaccine clinical trials.1
SARS -CoV -2 testing (PCR -based and antibod y-based ). This includes PCR -based
testing for SARS -CoV -2 as an eligibility criterion and blood draws for
anti-SARS -CoV -2 antibody testing as baseline reference for immunogenicity
analysis. If required, this reference will allow the discrimination between vaccinat ed
and infected subjects.
AEs and SAEs were collected, recorded, and reported as defined in Module 5.3.5.1
BNT162 -01 Protocol Section 8.3and further discussed in Appendix A
(Section 2.7.4.6.1.3.3 ).
AESI were considered to be enhanced respiratory disease or flu -like s ymptomatology
that did not resolve after 7 day s or with sy mptom kinetics that are inconsistent with a
relationship to RNA immunization.
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Page 212.7.4.1.1.1.6. Statistical Methods (Study BNT162 -01)
There is no h ypothesis testing in Study BNT162 -01. Statistical methods are described in the
study protocol ( Module 5.3.5.1 BNT162- 01 Protocol Section 9.4) and in the SAP ( Module
5.3.5.1 B NT162 -01 SAP) .
In general, data will be summarized by groups and groups may be combined as appropriate.
Part A and Part B will be anal yzed separatel y and may be combined as appropriate.
All AEs will be coded using MedDRA terms. TEAEs will be summarized us ing the safet y set
(SAF). In general, AEs will be analy zed by group (ie, by type and dose level) and for each
immunization. Additionally , AEs will be summarized for all dose levels combined for each
type. For each anal ysis, the number and percentage of sub jects reporting at least one AE will
be summarized by PT nested within SOC for each AE ty pe. The number and percentage of
subjects with any AE will be summarized by worst grade b y PT nested within SOC.
For each immunization, the number and percentage of su bjects reporting at least one local
reaction or s ystemic reaction (ie, solicited data collected using subject diaries) will be
summarized for an y local reactions or s ystemic reactions and for Grade ≥3 local reactions or
systemic reactions in the SAF.
The a nalysis of local and sy stemic reactions will be repeated with a reduced set of terms
(called the “comparability anal ysis”), to facilitate like -for-like comparisons between different
trials in the clinical development program for BNT162 vaccines. The number and percentage
of subjects reporting at least one local reaction will be summarized by worst grade using the
SAF.
Safety data other than AEs that will be summarized includes clinical laboratory parameters,
vital signs, and ECGs. Allsafet yanalyses will be based on the safet yset and willbe
summarized descriptively by group unless otherwise stated.
Clinical laboratory parameters at each timepoint and change from baseline to each post -
baseline time point willbesummarized using descriptive summary statistics foreach
parameter bygroup.
Theoccurrence ofclinically significant abnormal laboratory results within a study subject
will beanalyzed using descriptive summary statistics for each parameter andvisit bygroup.
Abnormal laboratory results willbegraded using criteria based ontheguidance given inthe
FDA CBER guidelines on toxicity grading scales for health y adult volunteers enrolled in
preventive vaccine clinical trials.1
2.7.4.1.1.2. Pivotal Phase 1/2/3 Safety, Immunogenicity, and Efficacy Study C4591001
2.7.4.1.1.2.1. Safety Objectives, Estimands, Endpoints (Study C4591001)
Safety objectives, estimands, and endpoints for Study C4591001 are presented in Table 3.
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Page 22Table3.SafetyObjectives, Estimands, and Endpoints for Study C4591001
ObjectivesaEstimands Endpoints Reference
Primary: Primary: Primary:
PHASE 1
To describe the safety and tolerability
profiles of prophylactic BNT162
vaccines in healthy adults after 1 or 2
dosesIn participants receiving at least 1 dose of
study intervention, the percentage of
participants reporting:
Local reactions for up to 7 days
following each dose
Systemic events for up to 7 days
following each dose
AEs from Dose 1 to 1 month after
the last dose
SAEs from Dose 1 to 6 months after
the last dose Local reactions (pain at the injection
site, redness, and swelling)
Systemic events (fever, fatigue,
headache, chills, vomiting, diarrhea,
new or worsened muscle pain, and
new or worsened joint pain)
AEs
SAEsInterim data for local reactions and
systemic events reported up to 7 days after
each dose, and AEs and SAEs are reported
from Dose 1 to 1 month after the last dose
for all groups evaluated, and to the cutoff
date after Dose 2 for the BNT162b2 30 µg
group only in final analysis interim CSR
dated 03 December 2020.
AEs and SAEs from Dose 1 to the
unblinding date for the BNT162b2 30 µg
group only are reported in thisCSR.
In addition, the percentage of participants
with:
Abnormal hematology and
chemistry laboratory values 1 and 7
days after Dose 1; and 7 days after
Dose 2
Grading shifts in hematology and
chemistry laboratory assessments
between baseline and 1 and 7 days
after Dose 1; and before Dose 2 and
7 days after Dose 2Hematology and chemistry laboratory
parameters detailed in Module 5.3.5.1
C4591001 Protocol Section 10.2.Interim data are reported in final analysis
interim CSR dated 03 December 2020.
Exploratory
To describe the safety profile of a third
dose of prophylactic BNT162b2
administered to healthy adults 6 to 12
months after the second dose of either
BNT162b1 or BNT162b2In participants receiving a third dose of
BNT162b2, the percentage of participants
reporting:
Local reactions for up to 7 days after
Dose 3
Systemic events for up to 7 days
after Dose 3
AEs and SAEs from Dose 3 to
1month after Dose 3 Local reactions (pain at the injection
site, redness, and swelling)
Systemic events (fever, fatigue,
headache, chills, vomiting, diarrhea,
new or worsened muscle pain, and
new or worsened joint pain)
AEs
SAEsData will be reported at a later time.
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Page 23Table3.SafetyObjectives, Estimands, and Endpoints for Study C4591001
ObjectivesaEstimands Endpoints Reference
PHASE 2/3
Primary Safety
To define the safety profile of
prophylactic BNT162b2 in the first 360
participants randomized (Phase 2)In participants receiving at least 1 dose of
study intervention, the percentage of
participants reporting:
Local reactions for up to 7 days
following each dose
Systemic events for up to 7 days
following each dose
AEs from Dose 1 to 7 days after the
second dose
SAEs from Dose 1 to 7 days after
the second dose Local reactions (pain at the injection
site, redness, and swelling)
Systemic events (fever, fatigue,
headache, chills, vomiting, diarrhea,
new or worsened muscle pain, and
new or worsened joint pain)
AEs
SAEsInterim data are reported in final analysis
interim CSR dated 03 December 2020.
To define the safety profile of
prophylactic BNT162b2 in all
participants randomized in Phase 2/3In participants receiving at least 1 dose of
study intervention, the percentage of
participants reporting:
Local reactions for up to 7 days
following each dos e
Systemic events for up to 7 days
following each dose
AEs from Dose 1 to 1 month after
the second dose
SAEs from Dose 1 to 6 months after
the second dose AEs
SAEs
In a subset of at least 6000
participants:
o Local reactions (pain at the
injection site, redn ess, and
swelling)
o Systemic events (fever, fatigue,
headache, chills, vomiting,
diarrhea, new or worsened
muscle pain, and new or
worsened joint pain)Interim data are reported up to 1 month
after Dose 2 and to the data cutoff date
(14 November 2020) in fi nal analysis
interim CSR dated 03 December 2020.
Cumulative interim data up to cutoff date
are reported in this CSR.
To define the safety profile of
prophylactic BNT162b2 in participants
12 to 15 years of age in Phase 3In participants receiving at least 1 dose of
study intervention, the percentage of
participants reporting:
Local reactions for up to 7 days
following each dose
Systemic events for up to 7 days
following each dose
AEs from Dose 1 to 1 month after
the second dose
SAEs from Dose 1 to 6 months after
the second dose Local reactions (pain at the injection
site, redness, and swelling)
Systemic events (fever, fatigue,
headache, chills, vomiting, diarrhea,
new or worsened muscle pain, and
new or worsened joint pain)
AEs
SAEsData will be reported separately.
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Page 24Table3.SafetyObjectives, Estimands, and Endpoints for Study C4591001
ObjectivesaEstimands Endpoints Reference
To describe the safety and tolerability
profile of BNT162b2 SAgiven as 1 or 2
doses to BNT162b2 -experienced
participants, or as 2 doses to BNT162b2 -
naïve participants
To describe the safety and tolerability
profile of BNT162b2 given as a third
dose to BNT162b2 -experienced
participantsIn participants receiving at least 1 dose of
study intervention, the percentage of
participants reporting:
Local reactions for up to 7 days
following each dose
Systemic events for up to 7 days
following each dose
AEs from Dose 1 to 1 month after the
second dose
SAEs from Dose 1 to 5or6 months
after the second doseLocal reactions (pain at the injection
site, redness, and swelling)
Systemic events (fever, fatigue,
headache, chills, vomiting, diarrhea,
new or worsened muscle pain, and
new or worsened joint pain)
AEs
SAEsData will be reported at a later time.
Exploratory
To describe the safety, immunogenicity,
and efficacy of prophylactic BNT162b2
in individuals with confirmed stable HIV
diseaseAll safety, immunogenicity, and efficacy
endpoints described aboveSafety data only in participants with
confirmed stable HIV disease are
reported in this CSR.
To describe the safety and
immunogenicity of prophylactic
BNT162b2 in individuals 16 to 55 years
of age vaccinated with study intervention
produced by manufacturing “Process 1”
or “Process 2”b AEs
SAEs
SARS -CoV -2 neutralizing titersData will be reported at a later time.
a.HIV-positive participants in Phase 3 will not be included in analyses of the objectives, with the exception of the specific explo ratory objective.
b.See Module 5.3.5.1 C4591001 Protocol Section 6.1.1 for a description of the manufacturing process. The safety results for individuals 16 to 55 years of
age vaccinated with study intervention produced by manufacturing “Process 1” or “Process 2” w ill be summarized descriptively when data become available .
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Page 252.7.4.1.1.2.2. Overall Design (Study C4591001)
US Study C4591001 is the ongoing, randomized, placebo- controlled , observer- blind , Phase
1/2/3 pivotal registration study . The stud y consists of 2 parts:
1.Phase 1: to identify preferred vaccine candidate(s) and dose level(s);
2.Phase 2/3: an expanded cohort and efficacy part.
These parts, and the progression between them, are detailed in the schema presented in
Appendix B (Section 2.7.4.6.2.1 ).
Study C4591001 was conducted at sites in the US, Brazil, Argentina, Turkey , South Africa,
and German y
Phase 1
InPhase 1 , 13 groups were studied, corresponding to a total of 195 participants. Each group
(vaccine candidate/dose level/age group) was comprised of 15 participants randomi zed 4:1 to
receive active vaccine or placebo (12 participants randomized to active vaccine and 3 to
placebo, such that the placebo participants across the groups would produce a roughl y
comparabl y-sized cohort). Study intervention was to be administered i ntramuscularly into
the deltoid muscle, preferably of the nondominant arm to 2 age cohorts (18 to 55 and 65 to
85 years of age,) in a two -dose regimen separated by 21 day s at the following dose levels:
BNT162b1 (dose levels: 10, 20, 30, 100 µg)
BNT162b2 (dose levels: 10, 20, 30 µg).
The Internal Review Committee ( IRC)recommended that a second dose of BNT162b1 at
100 µg not be administered due to reactogenicit y after the first dose in the y ounger age
group. Participants in this group of younger adults instead received a second dose of
BNT162b1 at the 10 µg dose level.
Participants received active vaccine or placebo at Visit 1, with next day and 1 -week follow -
up visits (Visits 2 and 3) post -dose 1. Participants received dose 2 at Visit 4 (19 to 23 day s
after Visit 1). Follow -up visits were scheduled at 1-week, 2 -weeks, 1- month, 6 -months, 12-
months- and 24- months.
Participants who originally received placebo may have become eligible for receipt of
BNT162b2 or another COVID -19 vaccine .
Phase 1 participan ts who originall y received BNT162b1 or BNT162b2 at dose levels of
10,20, or 30 µg at Doses 1 and 2 were offered an additional dose of BNT162b2 at 30 µg
approximately 6 to 12 months after their second dose of BNT162. This would provide an
early assessment of the safet y of a third dose of BNT162, as well as its immunogenicit y.The
booster anal yses will be reported at a later time.
Participants were expected to participate for up to a maximum of approximately 26 months.
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Page 26All participants in Phase 1 recorded local reactions, sy stemic events, and antipy retic/pain
medication usage for 7 days, each evening following administration of study intervention
using an e -diary . This allowed recording of these assessments only within a fixed time
window, thus providing the accurate representation of the participant’s experience at that
time.
The following data are summarized and presented in this SCS as Phase 1 safety endpoints:
Local reactions and s ystemic event data (acquired throug h the e -diaries) for up to 7
days after Dose 1 and Dose 2
AEs through Visit 7 (1- month follow -up visit post-dose 2) and SAEs through the data
cutoff date of 24 August 2020 (safet y results for BNT162b1 at the 100 µg dose level
in the y ounger age group are p resented up to 3 weeks after Dose 1 or to before Dose 2
based on the data cutoff date).
Long -term follow -up (approximately 6months after Dose 2 [as of cutoff date
13March 2021]) of AEs and SAEs for Phase 1 participants who were randomized to
receive BNT162b2 30 µgor control .
Abnormal hematology and chemistry laboratory values, as well as grading shifts in
hematology and chemistry laboratory assessments , through Visit 5 (7 day s post-
dose 2).
Complete d etails regarding planned time points for all safe ty assessments during Phase 1 are
provided in the SoA in Appendix B (Section 2.7.4.6.2.2.1 ). The investigator may have
scheduled visits (unplanned visits) in addition to those listed in the SoA table in order to
conduct evaluations or assessments required to protect the well -being of the participant.
Safety assessments for Study C4591001 are detailed in Section 2.7.4.1.1.2.5 and 2.7.4.6.2.3 .
The Sponsor/agent study team was not blinded in this part of the study . Participants enrolled
in Phase 1 were followed for cases of COVID -19 but did not contribute to the overall
efficacy assessment. Details regarding efficacy and immunogenicit y methods, results, and
conclusions are presented in the SCE ( Module 2.7.3).
Based upon review of safety and immunogenicity from the Phase 1 part of the study , a final
candidate and dose level of 30 µg BNT162b2 was selected.
Phase 2/3
BNT162b2 at the 30 µg dose level was the vaccine candidate chosen b y Pfizer/BioNTech to
proceed into Phase 2/3. Participants ≥12 y ears of age (stratified as 12 -15, 16 -55 or >55 years
of age, with the intention that a minimum of 40% of participants would be in the >55 -year
stratum) were randomized 1:1 to receive vaccine or placebo. The Pha se 2 part of the study
evaluated safet y and immunogenicit y for the first 360 participants enrolled (180 to active
vaccine and 180 to placebo) in order to confirm the safet y profile of BNT162b2 as seen in
Phase 1. Participants enrolled into Phase 2 contribu ted to the overall efficacy assessment.
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Page 27It was planned for t he Phase 2/3 part of the study to comprise of approximately 21,999
vaccine recipients per group, for a total sample size of 43,998. The 12 -to 15 -year stratum
will be comprised of up to approximately 2000 participants (1000 vaccine recipients)
enrolled at selected investigational sites.
Participants received active vaccine or placebo at Visit 1 (dose 1) and Visit 2 (dose 2, 19 to
23 day s after Visit 1) . Follow -up visits were scheduled at1-month, 6 -months, 12- months-
and 24- months (as described in the SoA, Appendix B, Section 2.7.4.6.2.2.2 ).
Participants ≥16 y ears of age who originall y received placebo and bec ame eligible for receipt
of BNT162b2 according to recommendations detailed separately , had the opportunity to
receive BNT162b2 in a phased manner as part of the study (no later than 6 months after
Vaccination 2 [at the ti me of the originall y planned Visit 4]). The investigator ensure dthat
the participant met at least 1 of the recommendation criteria. An y participant ≥16 yearsof
age who originall y received placebo but then went on to receive BNT162b2 moved to a new
visit schedule ( 2.7.4.6.2.2.3 ) and receive d1 dose of BNT162b2 at each additional
vaccination visit (Visits 101 and 102 , receiving Dose 3 and Dose 4, respec tively ).
The following data are summarized and presented in this SCS as Phase 2/3 safet y endpoints:
For Phase 2 (first 360 participants), reactogenicit y results for up to 7 day s after Dose
1 and Dose 2, AEs and SAEs through the data cutoff date ( 2 Septembe r 2020) ,which
includes up to 7 day s follow -up after Dose 2 .
For Phase 3, reactogenicity results for up to 7 day s after Dose 1 and Dose 2, AEs and
SAEs through the data cutoff date (13March 2021), which includes up to 6 months
follow -up after Dose 2 (see Section 2.7.4.2.4.2 for more details).
Complete d etails regarding p lanned time points for all safet y assessments during Phase 2/3
are provided in the SoA in Appendix B (Section 2.7.4.6.2.2.2 ). An unplanned potential
COVID -19 illness visit and unplanned potential COVID- 19 convalescent visit were required
at an y time between Visit 1 and Visit 6 (24 -month follow -up visit) that potential COVI D-19
symptoms were reported, including MIS- C.
Prior infec tion with SARS -CoV -2 was assessed at baseline and evaluated perserological
samples over 24 months to explore efficacy against asy mptomatic SARS -CoV -2 infections
and to ensure safet y in both sero- negative and sero -positive participants. Safet y assessments
for Study C4591001 are detailed in Section 2.7.4.1.1.2.5 and 2.7.4.6.2.3 .
Planned Analy ses
The following anal yses are not included in this report and will be reported at a later time:
For evaluation of boostability , a subset of Phase 3 participants 18 to 55 y ears of age
will receive a third dose of BNT162b2 or a third and potentially a fourth dose of
prototy pe BNT162b2 VOC(based upon the South African variant and hereafter referred
to as BNT162b2 SA). The third dose of BNT162b2 or BNT162b2 SAwill be
administered app roximately 5 to 7 months after their second dose of BNT162 (at
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Page 28Visit 301) and a subset of those participants who received the third dose of
BNT162b2 SAwill receive a further dose of BNT162b2 SAone month after Dose 1 of
BNT162b2 SA(at Visit 303).
To furthe r describe potential homologous and heterologous protection against
emerging SARS -CoV -2 VOCs, a new cohort of participants will be enrolled who are
COVID -19 vaccine-naïve (ie, BNT162b2- naïve) and have not experienced
COVID -19. They will receive BNT162b2 SAgiven as a 2- dose series, separated by
21days.
2.7.4.1.1.2.3. Study Population (Study C4591001)
The full eligibility criteria for Study C4591001 can be found in the protocol ( Module 5.3.5.1
C4591001 Protocol Section 5 ).
The following eligibility criteria were designed to select participants for whom participation
in the study was considered appropriate .
Key inclusion criteria:
Participants were eligible to be included in the study only if all of the following criteria
apply :
Male or female participants in the following age groups:
oPhase 1: Between the ages of 18 and 55 years, inclusive, and between 65 and
85 years, inclusive, at randomization
oPhase 2/3: ≥1 2years, at randomization
Health y participants as determined b y medical history, ph ysical examination (if
required), and clinical judgment of the investigator to be eligible for inclusion in the
study
Note: Health y participants with preexisting stable disease, defined as disease not
requiring significant change in therap y or hospitalization for worsening disease
during the 6 weeks before enrollment, could be included. Specific criteria for Phase 3
participants with known stable infection with HIV, HCV, or HBV can be found in
Module 5.3.5.1 C4591001 Protocol Section 10.8.
Phase 2/3 only: Participants who, in the judgment of the investigator, were at higher
risk for acquiring COVID -19(including, but not limited to, use of mass transportation,
relevant demographics, and frontline essential workers) .
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Page 29Key exclusion criteria:
Participants wereexcluded from the stud y if an y of the following criteria appl ied:
Other medical or psy chiatric condition including recent (within the past year) or
active suicidal ideation/behavior or laboratory abnormality that may increase the risk
of study participati on or, in the investigator’s judgment, make the participant
inappropriate for the study .
Phases 1 and 2 only : Known infection with HIV, HCV, or HBV.
History of severe adverse reaction associated with a vaccine and/or severe allergic
reaction (eg, anaph ylaxis) to any component of the study intervention(s).
Receipt of medications intended to prevent COVID 19.
Previous clinical (based on COVID -19 s ymptoms/signs alone, if a SARS -CoV -2
NAAT result was not available) or microbiological (based on COVID -19
symptom s/signs and a positive SARS -CoV -2 NAAT result) diagnosis of COVID 19.
Phase 1 only: Individuals at high risk for severe COVID -19, including those with any
of the following risk factors:
Hypertension
Diabetes mellitus
Chronic pulmonary disease
Asthma
Current vaping or smoking
History of chronic smoking within the prior y ear
Chronic liver disease
Stage 3 or worse chronic kidney disease (glomerular filtration rate
<60mL/min/1.73 m2)
Resident in a long- term facility
BMI >30 kg/m2
Anticipating the need fo r immunosuppressive treatment within the next 6 months
Phase 1 only: Individuals currentl y working in occupations with high risk of
exposure to SARS -CoV -2 (eg, healthcare worker, emergency response personnel).
Immunocompromised individuals with known or su spected immunodeficiency , as
determined b y history and/or laboratory /physical examination.
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Page 30Phase 1 only: Individuals with a history of autoimmune disease or an active
autoimmune disease requiring therapeutic intervention, including but not limited to:
systemic or cutaneous lupus ery thematosus, autoimmune arthritis/rheumatoid
arthritis, Guillain -Barré syndrome, multiple sclerosis, Sjögren’s s yndrome, idiopathic
thrombocy topenia purpura, glomerulonephritis, autoimmune thy roiditis, giant cell
arteritis (tempor al arteritis), psoriasis, and insulin -dependent diabetes mellitus
(type1).
Bleeding diathesis or condition associated with prolonged bleeding that would, in the
opinion of the investigator, contraindicate intramuscular injection.
Women who are pregnant or breastfeeding.
Previous vaccination with any coronavirus vaccine.
Individuals who receive treatment with immunosuppressive therapy .
Phase 1 only: Regular receipt of inhaled/nebulized corticosteroids.
Receipt of blood/plasma products or immunoglobulin, fro m 60 day s before study
intervention administration or planned receipt throughout the stud y.
Participation in other studies involving study intervention within 28 day s prior to
study entry through and including 6 months after the last dose of study interven tion,
with the exception of interventional studies for prevention of COVID 19, which are
prohibited throughout study participation.
Previous participation in other studies involving study intervention containing lipid
nanoparticles.
For Phase 1 onl y:
oPositive serological test for SARS -CoV -2 IgM and/or IgG antibodies at the
screening visit.
oAny screening hematology and/or blood chemistry laboratory value that meets
the definition of a ≥ Grade 1 abnormalit y.
oPositive test for HIV, HBsAg, HBc Abs, or HCV Abs at the screening visit.
oSARS -CoV -2 NAAT- positive nasal swab within 24 hours before receipt of
study intervention.
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Page 312.7.4.1.1.2.4. Analysis Sets (Study C4591001)
Populations discussed in this SCS include the following:
Population Description
Enrolled All participants who hada signed ICD
Randomized All participants who were assigned a randomization number in the I WR
system
Safety All randomized participants who received at least 1 dose of the study
intervention .
Analy ses of reactogenicity endpoints will be based on a subset of the
safet y population that includes participants with any e- diary data
reported after vaccination.
2.7.4.1.1.2.5. Safety Assessments (Study C4591001)
Safety assessments were collected at planned time points as described in Appendix B
(Section 2.7.4.6.2 ). Key safety assessments included:
A clinical assessment, including medical history , was performed on all participants at
his/her first visi t to establish a baseline. Significant medical history and observations
from an y physical examination, if performed, were documented in the CRF.
The safet y parameters included reactogenicit y e-diary reports of local reactions and
systemic events , fever, and use of antip yretic medication that occurred in the 7 days
after administration of the study intervention in a subset of participants (see
Appendix B [Section 2.7.4.6.2.3.1 ]for further details) . Grading scales used in this
study to assess local reactions and sy stemic events were derived from the FDA CBER
guidelines on toxicity grading scales for health y adult volunteers enrolled in
preventive vaccine clinical trials.1
AEs and SAEs were collected, recorded, and reported as defined in Module 5.3.5.1
C4591001 Protocol Section 8.3 and further discussed below in Appendix B (Section
2.7.4.6.2.3.2 ).
Acute reactions within the first 4 hours after administration of the study intervention
(for the first 5 participants vaccinated in each Phase 1 group), and within the first 30
minutes (for the remainder of participants ), were assessed and documented in the AE
CRF.
Safety subgroup analy ses by age, country , ethnicity , sex, and race were performed.
Targeted medical events of potential clinic al interest by PT, HLT, or SMQ (full
scope, including broad and narrow) were monitored.
Participants in all phases of the study were surveilled for potential COVID -19 illness
from Visit 1 onwards. Further details are in Appendix B (Section 2.7.4.6.2.3.4 ).Note
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Page 32that while this wasmonitored throughout the study , analy ses were onl y planned for
Phase 2/3 as efficacy endpoints.
For Phase 1, safet y laboratory tests were performed at the times defined in the SoA
(Appendix B [Section 2.7.4.6.2.2.1 ]).The specific tests are presented in the Statist ical
Analy sis Plan ( Module 5.3.5.1 C4591001 Statistical Anal ysis Plan Section 3.1.1.6)
and further described in Module 5.3.5.1 C4591001 Protocol Section 8.2.1 . The
primary criterion for abnormality followed the Pfizer safet y rule book.
For Phase 1, a ph ysical examination was performed. I t evaluated any clinically
significant abnormalities within the following body s ystems: general appearance;
skin; head, ey es, ears, nose, and throat; heart; lungs; abdomen; musculoskeletal;
extremities; neurological; and ly mph nodes. Clinically significant abnormal results
were recorded in the CRF.
No adverse events of special interest were defined for Study C4591001; however, targeted
medical events were monitored throughout the study .
2.7.4.1.1.2.6. Statistical Methods (Study C4591001)
Statistical methods are described in the stud y protocol ( Module 5.3.5.1 C4591001 Protocol
Section 9.4 )and in the statistical anal ysis plan ( Module 5.3.5.1 C4591001 Statistical
Analy sis Plan )
Safety objectives were evaluated by descriptive summary statistics for local reactions and
systemic events, AEs/SAEs, and abnormal hematology and chemistry laboratory parameters
(Phase 1 only )for each vaccine group. A 3-tier approach was used to summarize AEs in
Phase 2/3. Under this approach ,AEs were classi fied into 1 of 3 tiers:
Tier 1 events :prespecified events of clinical importance, identified in the product’s
safet y review plan; there are no Tier 1 AEs identified for this program.
Tier 2 events :those that are not Tier 1 but are considered “relativel y common”; a
MedDRA preferred term is defined as a Tier 2 event if there are at least 1% of
participants in at least 1 vaccine group reporting the event; and
Tier 3 events :those that are neither Tier 1 nor Tier 2 events.
ForTier 2 events, 2- sided 95% CI s for the difference between the vaccine and placebo
groups in the percentage of participants reporting the events based on the Miettinen and
Nurminen method will be provided.2For Tier 3 events, cou nts and percentages for each
vaccine group will be provided. The safety anal yses are based on the safet y population.
Analy ses of reactogenicity endpoints are based on a subset of the safet y population that
includes participants with any e-diary data report ed after vaccination . Participants will be
summarized by vaccine group according to the study intervention s they actually received.
Missing reactogenicit y e-diary data will not be imputed; missing AE dates will be handled
according to the Pfizer safety rules.
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Page 33AEs and SAEs reported during the open- label follow -up period will be summarized
separately for participants who were unblinded at the time of being eligible for receipt of
BNT162b2 according to recommendations detailed separately , and available in the electronic
study reference portal, or no later than at approximately Visit 4.
AE anal yses of participants who had different durations of follow -up time due to unblinding
in the study (per protocol) were summarized as incidence rates (IR) adjusted for exposure
time. This was calculated as: (number of participants reporting event) / (total exposure time
across all participants in the specified group). This accounts for variable exposure since
unblinding began for individual participants. Two -sided 95% CI s for the IRs were provided
based on Poisson distribution.
Planned Analyses
For Phase 3 participants enrolled for assessment of boostability and protection against
emerging VOCs, descriptive summary statistics will be provided at a later time.
2.7.4.1.1.3. Narratives
Narrative summaries were written for the following participants in Study BNT162 -01:
Participants who died;
Participants who experienced SAEs assessed as related to study intervention by the
investigator ;
Participants with any AEs leading to withdrawal from the study
Participants with COVID -19
These participant narratives are available in Module 5.3.5.1 BNT162-01 CSR Section 12.6 .
Narrative summaries were written for the following participants in Study C4591001:
Deaths, vaccine -related SAEs, all other SAEs, safety -related withdrawals
AEs of interest requested by FDA: anaphy laxis, Bell’s palsy , lymphadenopathy ,
appendicitis, and pregnancy exposures and outcomes
AESI s with a numerical imbalance with a higher frequency (or incidence rate) in the
vaccine group v s placebo group that led to withdrawal, were related, or had biological
plausibility
COVID -19 cases (participants with severe and/or multiple episodes).
These participant narratives are available in Module 5.3.5.1 C4591001 Efficacy Final
Analy sis Interim CSR Section 14 Subject Narratives (for data available as of the
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Page 3414November 2020 cutoff date) or Module 5.3.5.1 C4591001 6 -Month Update Interim CSR
Section 14 Subject Narratives (for data available as of the 13 March 2021 cutoff date)
2.7.4.1.2. Overall Extent of Exp osure, Disposition, and Study Population
Characteristics
2.7.4.1.2.1. Study BNT162-01
Study results presented below are for Part A through the data cutoff date of 23 October 2020
and may not be representative of the final data. The full interim CSR for Study BNT162 -01
is provided in Module 5.3.5.1 BNT162 -01CSR.
2.7.4.1.2.1.1. Disposition ( Phase 1, Study BNT162-01)
In the BNT162b1 younger age group, atotal of 84 participants were enrolled, with
12 participants in each dose group (1 µg, 3 µg, 10 µg, 20, µg, 30 µg, 50 µg, and 60 µg dose
groups) (note: 60 µg group received only Dose 1 per SRC decision due to Dose 1
reactogenicity ). In the BNT162b1 older age group, a total of 36 participants were enrolled,
with 12 participants in each dose group (10 µg, 20, µg, 30 µg dose groups) (note: 10 µg
group had data to 1 month after Dose 2; 20 and 30 µg groups had available data to 7 day s
after Dose 2). 80/84 y oung er and 11/36 older participants in the BNT162b1 group completed
the study (ie, through the end of treatment visit) , and 4 premature discontinuations have
occurred (none in the 30 µg dose group or the older participant age group) .
In the BNT162b2 younger ag e group, atotal of 60 participants were enrolled, with
12participants in each dose group (1 µg, 3 µg, 10 µg, 20, µg, and 30 µg groups). In the
BNT162b2 older age group, a total of 36 participants were enrolled, with 12 participants in
each dose group (10 µg, 20, µg, 30 µg dose groups). 53/60 y ounger and 30/36 older
participants in the BNT162b2 group completed the study (ie, through end of treatment visit).
Two premature discontinuations have occurred (none in the 30 µg dose group or the older
participant age group).
2.7.4.1.2.1.2. Exposure ( Phase 1, Study BNT162 -01)
For BNT162b1, dosing of participants in the y ounger age group with the second 60 µg
BNT162b1 dose was not performed. After 12 participants had received Dose 1, the SRC
decided not to administer Dose 2 to thes e participants. 95.8% (6 9/72) of participants in all
other dose levels received Dose 2. In the BNT162b1 older age group, 97.2% (35/36) of
participants in all dose levels received Dose 2.
For the BNT162b2 group, 96.7% (58/60) and 100% (36/36) of participant sin the y ounger
and older age groups, respectively ( in all dose levels) received Dose 2 .
2.7.4.1.2.1.3. Safety Data Sets Analyzed (Phase 1, Study BNT162 -01)
For BNT162b1 and BNT162b2, all participants randomized to receive study intervention in
the y ounger and older age groups were included in the SAF.
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Page 352.7.4.1.2.1.4. Demographic and Other Characteristics of Study Population ( Phase 1,
Study BNT162-01)
In the BNT162b1 younger age group, BNT162b1 was administered to 84 participants, among
whom 52% were male and 48% were female, 96% were White and 2% were
Hispanic/Latino, with a median 36 y ears of age. In the BNT162b1 older age group (56 to 85
years of age), BNT162b1 was administered to 36 participants, among whom 36% were male
and 64% were female, all were White and none were Hispanic/Latino, with a median 67
years of age.
In the BNT162b2 younger age group, BNT162b2 was administered to 60 participants, among
whom 43% were male and 57% were female, 100% were White, none were Hispanic/Latino,
with a median 42 years of age. In the BNT62b2 older age group, BNT162b2 was
administered to 36 participants, among whom 50% were male and 50% were female, 100%
were White, none were Hispanic/Latino, with a median 65 years of age.
Baseline Medical History
Participants in both the BNT162b1 and BNT162b1 groups were healthy with a medical
history profile consistent with that of a health y general population in the younger age group.
2.7.4.1.2.1.5. Diary Compliance (Phase 1, Study BNT162 -01)
For BNT162b1 and BNT162b2, the participant’s diary compliance for reporting
reactogenicity was ≥99% 0 to 6 day safter Dose 1. The participant’s diary compliance for
reporting reactogenicit ywas ≥64% and ≥92% from 0 to 6 day safter Dose 2 for BNT162b1
and BNT162b2, respectively .
Overall, lower percentages postdose 2 were due to the ongoing nature of thestudy . These
results are as of the data cutoff date and may not be representative of the final data.
2.7.4.1.2.2. Phase 1(Study C4591001)
Results for healthy adults 18 to 85 years of age (y ounger age group: 18 to 55; older age
group: 65 to 85) in the Phase 1 portion of Study C4591001 are presented through the data
cutoff date of 24 August 2020. Updated disposition is provide dthrough the cutoff date of
13March 2021 . For the BNT162b1 100 µg dose group in the younger age group, results are
only presented after Dose 1 but before Dose 2.
Full details and outputs regarding disposition, exposure, data sets, d emographic s, and diary
compliance for Phase 1 of Study C4591001 through the data cutoff date of 24 August 2020
(to 1 month after Dose 2) are in Module 5.3.5.1 C4591001 Efficacy Final Analy sisInterim
CSR Section 10.1.1, Section 10.3.1, Section 10.4.1, Section 10.5.1 ,and Sectio n 10.6.2.1 ,
respectivel y. Full details and outputs regarding disposition through the data cutoff date of
13 March 2021 for the BNT162b2 (30 μg) group are in Module 5.3.5.1 C4591001 6 -Month
Update Interim CSR Section 10.1.1 .
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Page 362.7.4.1.2.2.1. Disposition (Phase 1, Study C4591001)
Overall, 195 participants were randomized. No participants have been withdrawn due to an
AEas of the data cutoff date (24 August 2020) .
In the BNT162b1 y ounger age group , 12 participants were randomized to each of the 3 dose
groups ( 10 µg , 20 µg , and 30 µg dose groups )and 9participants to the placebo group (inthe
100µg dose group , 12 participants were randomized to vaccine and 3 participants were
randomized to placebo). In the BNT162b1 older age group, 12 participants were randomized
to each of the 3 dose groups and 9 participants were randomized to the placebo group .
In the BNT162b2 group, both the younger and older age groups, 12 participants were
randomized to each of the 3 dose grou ps and 9 participants were randomized to placebo.
To the Data Cutoff Date of 13 March 2021 for BNT162b2 (30 μg)
All participants in each age group randomized to receive BNT162b2 30 μg completed the
visit at 6 months after Dose 2, with most of these 6- month visits occurring during the open -
label follow -up period. All participants in each age group randomized to the placebo group
received both doses of BNT162b2 (Dose 3 and Dose 4 in the study ) during the open -label
period and completed the visit at 1 month after Dose 4, as of the data cutoff date of
13March 2021. No participants were withdrawn from the study up to the data cutoff date.
2.7.4.1.2.2.2. Exposure (Phase 1, Study C4591001)
In the BNT162b1 younger age group, all participants randomized to the 10 µg, 20 µg, and 30
µg dose groups received both doses of BNT162b1 or placebo ,and all participants
randomized to the 100 µg dose group (from y ounger age group onl y) received Dose 1 of
BNT162b1 or placebo. The I RC determined not to administer the second dose of 100 µg due
to reactogenicity (these participants receive dBNT162b1 at 10 µg as their second dose). All
participants in the BNT162b1 older age group randomized to each dose group received both
doses of BNT162b1 or placebo. (No participants in the older age group rece ived BNT162b1
100 μg.) All participants in the BNT162b1 group received Dose 2 within the protocol
specified time.
In the BNT162b2 group, a ll participants randomized to each dose group in the y ounger and
older age groups received both doses of study intervention , and a ll participants received
Dose 2 within the protocol -specified time.
2.7.4.1.2.2.3. Safety Data Sets Analyzed (Phase 1, Study C4591001)
For BNT162b1 and BNT162b2, all participants randomized to receive study intervention in
the y ounger and older age group swere included in the safet y population.
2.7.4.1.2.2.4. Demographic and Other Characteristics of Study Population (Phase 1,
Study C4591001)
Demographic characteristics were similar across the vaccine groups within each age group
for participants who received BNT162b1.
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Page 37Most participants in the BNT162b1 group were Whitein both the younger age group and
older age group. Median age for this group was 35.0 years in the younger age group and 69.0
years in the older age group. In the BNT162b1 younger age group (up to 30 µg), 1 7 (37.8%)
were female and 28 (62.2%) were male (9 [60%] female and 6 [40%] male in the 100 µg
dose group) ; in the older age group, 32 (71.1%) were female and 13 (28.9%) were male.
Most participants in the BNT162b2 group were White in the y ounger age group, and all
participants were White in the older age group. Median age in this group was 37.0 y ears in
the y ounger age group and 68.0 y ears in the older age group. In the BNT162b2 younger age
group, 26 (57.8%) were female and 19 (42.2%) were male ; in the older age group, 28
(62.2%) were female and 17 (37.8%) were male.
Baseline Medical History
The study population of the BNT162b1 and BNT162b2 groups were healthy with medical
history profiles consistent with those of the healthy general population in each age group.
2.7.4.1.2.2.5. E-Diary Compliance (Phase 1, Study C4591001)
Transmission of e -diary data after either dose of BNT162b1 or placebo was ≥77.8% for each
day during the 7 day s following an y vaccination in the y ounger age group and older ag e
group, and tra nsmission rates were similar across dose groups in both age groups.
Transmission of e -diary data after either dose of BNT162b2 or placebo was ≥75.0% for each
day during the 7 day s following an y vaccination in the y ounger and older age group s, and
transmission rates were s imilar across dose groups in both age groups.
2.7.4.1.2.3. Phase 2(Study C4591001)
Results for participants in the y ounger (18 to 55 years) and older (56 to 85 y ears) age groups
in the Phase 2 portion of Study C4591001 are presented through the data cutoff date of
02September 2020.
Full details and outputs regarding disposition, exposure, data sets, demographics, and diary
compliance for Phase 2 of Study C4591001 are in Module 5.3.5.1 C4591001 Efficacy Final
Analy sis Interim CSR Section 10.1.2, Section 10.3.2 , Section 10.4.2 , Section 10.5.2 , and
Section 10.6.2.2 , respectively .
2.7.4.1.2.3.1. Disposition (Phase 2, Study C4591001)
The first 360 participants enrolled as part of Phase 2 were randomized equally
(180 participants each) to the BNT162b 2 and placebo groups. Among participants
randomized to the BNT162b2 group, 88 participants were in the younger age group and 92
participants were in the older age group.
2.7.4.1.2.3.2. Exposure (Phase 2, Study C4591001)
Except for 1 participant in the BNT162b2 younger age group who was withdrawn after
Dose 1 but before Dose 2 and 1 participant in the placebo group ( who had not y et received
Dose 2 at the time of data cutoff [02 September 2020] ), all other participants received both
doses of study intervention. Theparticipant in the BNT162b2 younger group was withdrawn
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Page 38from the study 23 day s after receiving Dose 1 (after Dose 1 but before Dose 2because of an
SAE of gastric adenocarcinoma (Section 2.7.4.2.3.4.2 ). All other participants received both
doses of vaccine .No participants received the incorrect stud y intervention. The majority of
participants received Dose 2 between 19 to 23 days after Do se 1 in the BNT162b2 (97.2%)
and placebo (96.7%) groups .
2.7.4.1.2.3.3. Safety Data Sets Analyzed (Phase 2, Study C4591001)
At the time of the data cutoff (02 September 2020), t he proportions of participants in the
safet y population were the same in the BNT162b2 group and the placebo group
(180 participants each). Within the BNT162b2 group, 88 participants were in the y ounger
age group and 92 were in the older age group.
2.7.4.1.2.3.4. Demographic and Other Characteristics of Study Population (Phase 2,
Study C4591001)
Demographic characteristics for Phase 2 were similar in the BNT162b2 group and the
placebo group for the safety population .For the BNT162b2 y ounger age group, 42 (47.7%)
were female and 46 (52.3%) were male. In the BNT162b2 older age group, 42 (45.7%) were
female and 50 (54.3%) were male. M ost participants were White (85.8%), followed by Black
or African American (9.2%). The proportions of Hispanic/Latino participants were similar in
the BNT162b2 and placebo groups. The median age was 56.0 years across participants a ges
18 to 85 ( 44.0 y ears for the y ounger age group and 65.0 y ears for the older age group ).
Baseline Medical History
The 360 participants in Phase 2 had a diverse medical history profile consistent with
individuals of the same age group in the general popu lation. I n the BNT162b2 group,
conditions in the surgical and medical procedures, immune sy stem disorders, and metabolism
and nutrition disorders SOCs were most frequently reported .
2.7.4.1.2.3.5. E- Diary Compliance (Phase 2, Study C4591001)
Overall, transmission of e -diary data was ≥ 91.7% for each day during the 7 day s after Dose 1
of BNT162b2. After Dose 2 of BNT162b2, transmission of e -diary data was 80.6% on Day
1 and ranged from 88.9% to 91.7% for each day during Day 2 through Day 7. Transmission
rates were similar in the BNT162b2 group and the placebo group .
2.7.4.1.2.4. Phase 3(Study C4591001)
Results for participants ( ≥16years of age) in the Phase 3 portion of Study C4591001 are
presented through the data cutoff date of 13March 2021.
Study population d etails and outputs (including subpopulation analy ses)for Phase 3 of
Study C4591001 are presented fully in the C4591001 6-Month Update Interim CSR:
Disposition : Module 5.3.5.1 C4591001 6-Month Update Interim CSR Section 10.1.2
Protocol deviations : Module 5.3.5.1 C459 1001 6-Month Update Interim CSR
Section 10.2
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Page 39Exposure : Module 5.3.5.1 C4591001 6- Month Update Interim CSR Section 10.3. 2
Safety Data sets: Module 5.3.5.1 C4591001 6-Month Update Interim CSR
Section 10.4. 2
Demographics and Other Characteristics: Module 5.3.5.1 C4591001 6- Month Update
Interim CSR Section 10.5.2
Diary compliance : Module 5.3.5.1 C4591001 6-Month Update Interim CSR
Section 10.6.2. 2
Note: Phase 3 tables and figures are titled as “Phase 2/3” to capture the fact that the
360Phase 2 participants are included in the overall phase 3 anal yses.
2.7.4.1.2.4.1. Disposition (Phase 3, Study C4591001)
The disposition of all Phase 2/3 participants randomized is presented for the blinded placebo
controlled and open -label follow -up periods in Table 31(Appendix D).
In this ongoing study , tables summarizing participant withdrawals may include some
participants who were reported as withdrawn but remain in the study and are continuing to be
evaluated. These participants are documented in Module 5.3.5.1 C4591001 6- Month Update
Interim CSR Errata.
2.7.4.1.2.4.1.1. Blinded Placebo -Controlled Follow -Up Period
During the blinded placebo -controlled follow -up period, m ost participants randomized
received Dose 1 (99.8%) and Dose 2 (98.1%). There were 352 (1.6%) participants in the
BNT162b2 group and 528(2.4%) participants in the placebo group who discontinued from
the vaccination period (Dose 1 to 1 month after Dose 2) ( Table 31). Most particip ants
completed the 1 month post- Dose 2 visit 2 (≥96.4%) . Few participants in the BNT162b2 and
placebo groups were withdrawn from the study (1.6% and 2.2%, respectively ), and most
were due to withdrawals by the participant, or they were lost to follow -up.
There were 7 participants with special data issues: 8 participant identification numbers from
4participants who enrolled into the study more than once and 3participants whose vaccine
assignment was not confirmed in I RT at the time of data cutoff.
Three participants who were randomized and vaccinated, but actual vaccine
assignment was not confirmed in I RT at the time of data cutoff .Participants were
vaccinated as per CRF, but dueto the inability to confirm consistency between the
data in the CRF and IRT, these participants were not assigned to an y actual dosing
group . Safet y data from these 3 participants were excluded from safet y summary
tables but their safet y data are listed separate ly(Table 34).
During the conduct of this study , 4 participants were each randomized twice with
different participant identification numbers at 2 different sites. Becaus e the significant
misconduct of these participants compromised the integrit y of the stud y data, results
from these participants were excluded from all efficacy and safety anal yses, including
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Page 40disposition and demographic tabulations. These participants who w ere discontinued
from vaccination and/or from the study are listed separately .
2.7.4.1.2.4.1.2. Open-Label Follow -Up Period
Individuals ≥16 y ears of age have been unblinded as they became locall y eligible and wished
to know their treatment assignment to confirm prior vacc ination with BNT162b2 (if
randomized to this group), or to receive BNT162b2 (if randomized to placebo). Unblinded
recipients originally randomized to BNT162b2 continue to be followed in an open -label
manner. Unblinded recipients originall y randomized to pl acebo are offered BNT162b2
vaccination (Doses 3 and 4 [first and second dose of BNT162b2 30 µg, respectivel y]) and
thereafter followed in an open- label manner.
Most participants in the BNT162b2 (96.8%) and placebo (96.4%) groups completed the
1month post-Dose 2 visit before unblinding (Table 31).
A total of 8 7 (0.4%) Phase 2/3 original BNT162b2 participants received Dose 1 of
BNT162b2 during the blinded placebo -controlled follow -up period and then received Dose 2
of BNT162b2 30 µg during the open- label follow -up period (when they were unblinded).
There were 105 (0.5%) participants withdrawn from the study , and most were due to
withdrawals b y the participant, or the y had a protocol deviation .
During the open- label follow -up period, most participants originally randomized in the
placebo group received Doses 3 and 4 (88.8% and 72.4%, respectively )of BNT162b2. There
were few participants in this group (0.1%) who were w ithdrawn from the study , and most
were due to withdrawals by the participant.
The disposition of HIV -positive participants is included in this summary but summarized
separately in safet y anal yses.
Disposition of all participants ≥16 y ears of age randomiz ed was similar by age group.
There were no clinicall y meaningful differences in disposition by age group, baseline
SARS -CoV -2 status, ethnicity, race, or sex.
2.7.4.1.2.4.2. Exposure (Phase 3, Study C4591001)
Almost all participants were administered study intervention as randomized; 99.7% received
Dose 1 and 98.5% received Dose 2 of BNT162b2 in the BNT162b2 group, and 99.8%
received Dose 1 and 98.0% received Dose 2 of placebo in the placebo group ( Table 32in
Appendix D ).
For Dose 1, 4 participants randomized to the placebo group received BNT162b2, and
2 participants randomized to the BNT162b2 group received placebo. Two par ticipants
randomized to the BNT162b2 group and 1 participant randomized to the placebo group
received an indeterminate vaccine for Dose 1.
For Dose 2, 5participants randomized to the placebo group received BNT162b2, and
3participants randomized to the B NT162b2 group received placebo.
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Page 41After unblinding, 88.8% of original placebo participants received Dose 3 (first dose of
BNT162b2 30 µg) and 72.4% received Dose 4 (second dose of BNT162b2 30 µg)at the time
of the data cutoff date.
The majority of participants received Dose 2 between 21 to 27 day s after Dose 1 in the
BNT162b2 (62.6%) and placebo (62.7%) groups ( Table 33in Appendix D). After
unblinding, most original placebo participants received Dose 4 (second dose of BNT162b2
30µg) between 14 to 20 (22.6 %) and 21 to 27 ( 48.1%) day safter Dose 3.
2.7.4.1.2.4.3. Safety Data Sets Analyzed (Phase 3, Study C4591001)
The safet y population included a total of 44,050 participants: 22,026 participants in the
BNT162b2 group and 22,021 participants in the placebo group ( Table 34in Appendix D).
Most of the total 115 (0.3%) participants excluded from the safety population were excluded
because those participants did not receive stud y vaccine.
There were no clinicall y meaningful differences in t he safet y population by age group,
baseline SARS -CoV -2 status, ethnicity , race, or sex.
During the blinded placebo -controlled follow -up period, 51.1% of participants in the
BNT162b2 group and 51.4% of participants in the placebo group had follow -up time
between ≥4 months to <6 months after Dose 2 ( Table 35in Appendix D ).From Dose 2 to
the cutoff date, 54.5% of participants in the BNT162b2 group had a total follow -up time of
≥6months.
In the younger age group, 48.5% of participants in the BNT 162b2 group and 48.3% of
participants in the placebo group had follow -up time between ≥4 months to <6 months after
Dose 2 during the blinded placebo-controlled follow up period. From Dose 2 to the cutoff
date, 51.0% of participants in the BNT162b2 group had a total follow- up time of ≥6months.
In the older age group, 54.8% of participants in the BNT162b2 group and 55.9% of
participants in the placebo group had follow -up time between ≥4 months to <6 months after
Dose 2 during the blinded placebo- controlled follow -up period. From Dose 2 to the cutoff
date, 59.6% of participants in the BNT162b2 group had a total follow -up time of ≥6months.
During the open- label follow -up period, 47.5% of original placebo participants had follow -up
time between ≥1 month to <2 months after Dose 1 of BNT162b2.
2.7.4.1.2.4.4. Demographic and Other Characteristics of Study Population (Phase 3,
Study C4591001)
2.7.4.1.2.4.4.1. Overall –Participants ≥ 16 Years of Age (Phase 3, Study C4591001,
Demographic and Other Characteristics of Study Population)
Demographic characteristics for all Phase 3 participants ≥16 years of age were similar in the
BNT162b2 and placebo groups ( Table 4).Overall, most participants were White (82.0%),
with 9.6% Black or African American participants and 4.3% Asian participants, and all other
racial groups were ≤2.5%. There were 25.9% Hispani c/Latino participants. Median age was
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Page 4251.0 years and 50.9% of participants were male. Obesity was reported in 34.4% of
participants in this safet y population.
Baseline SARS -CoV -2 status was positive (defined as a positive N -binding antibody result at
Visit 1, positive NAAT result at Visit 1, or medical history of COVID -19) in 3.1% of
participants in the BNT162b2 group and 3.3% of participants in the placebo group.
Demographic data including participants 12 through 15 years of age enrolled in this study are
summarized in Section 2.7.4.1.2.4.4.4. S afety data for participants 12 through 15 years of age
will be reported separately .
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Page 43Table4.Demographic Characteristics – Phase 2/3 Subjects ≥ 16 Years of Age –
Safety Population
Vaccine Group (as Administered)
BNT162b2 (30 μg)
(Na=22026)
nb(%)Placebo
(Na=22021)
nb(%)Total
(Na=44047)
nb(%)
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 or African American 2098 (9.5) 2118 (9.6) 4216 (9.6)
American Indian or Alaska Native 221 (1.0) 217 (1.0) 438 (1.0)
Asian 952 (4.3) 942 (4.3) 1894 (4.3)
Native Hawaiian or 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)
Racial designation
Japanese 78 (0.4) 78 (0.4) 156 (0.4)
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 (at vaccination)
16-55 Years 13069 (59.3) 13095 (59.5) 26164 (59.4)
>55 Years 8957 (40.7) 8926 (40.5) 17883 (40.6)
Age at vaccination (years)
Mean (SD) 49.7 (15.99) 49.6 (16.05) 49.7 (16.02)
Median 51.0 51.0 51.0
Min, max (16, 89) (16, 91) (16, 91)
Baseline SARS -CoV -2 status
Positivec689 (3.1) 716 (3.3) 1405 (3.2)
Negatived21185 (96.2) 21180 (96.2) 42365 (96.2)
Missing 152 (0.7) 125 (0.6) 277 (0.6)
Body mass index (BMI)
Underweight (<18.5 kg/m2) 271 (1.2) 304 (1.4) 575 (1.3)
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Page 44Table4.Demographic Characteristics – Phase 2/3 Subjects ≥ 16 Years of Age –
Safety Population
Vaccine Group (as Administered)
BNT162b2 (30 μg)
(Na=22026)
nb(%)Placebo
(Na=22021)
nb(%)Total
(Na=44047)
nb(%)
Normal weight ( ≥18.5 kg/m2-24.9 kg/m2) 6535 (29.7) 6524 (29.6) 13059 (29.6)
Overweight ( ≥25.0 kg/m2-29.9 kg/m2) 7670 (34.8) 7558 (34.3) 15228 (34.6)
Obese (≥30.0 kg/m2) 7543 (34.2) 7629 (34.6) 15172 (34.4)
Missing 7 (0.0) 6 (0.0) 13 (0.0)
Abbreviation: SARS -CoV -2 = severe acute respiratory syndrome coronavirus 2.
Note: Human immunodeficiency virus (HIV) -positive subjects are included in this summary but analyzed and reported
separately.
a. N = number of subjects in the specified group, or the total sample. This value is the denominator for the percentage
calcu lations.
b. n = Number of subjects with the specified characteristic.
c. Positive N -binding antibody result at Visit 1, positive NAAT result at Visit 1, or medical history of COVID -19.
d. Negative N -binding antibody result at Visit 1, negati ve NAAT result at Visit 1, and no medical history of COVID- 19.
PFIZER CONFIDENTIAL SDTM Creation: 25MAR2021 (23:24) Source Data: adsl Table Generation: 27MAR2021
(15:19)
(Cutoff Date: 13MAR2021, Snapshot Date: 25MAR2021) Output File:
./nda2_unblinded/C45 91001_BLA/adsl_s005_demo_all_p3_saf
Within each age group, most demographic characteristics were similar in the BNT162b2
group and the placebo group. Overall, 4.0% of participants in the y ounger age group were
SARS -CoV -2 baseline positive, and 1.9% of participants in the older age group were
SARS -CoV -2 baseline positive, and the proportions were similar in the BNT162b2 and
placebo groups. There was a lower proportion of non- Hispanic/non -Latino participants in the
younger BNT162b2 and placebo groups (68.6% and 68.8%, respectively) than in the older
BNT162b2 and placebo groups (80.9% and 80.7%, respectively ).
Within each baseline SARS- CoV -2 status group, demographic characteristics were similar in
the BNT162b2 group and the placebo group. Most participants were White regardless of
baseline status; however, there was a higher proportion of White participants with a negative
baseline status (82.9%) than with a positive baseline status (57.7%). The median age was
43.0 y ears in participants with a p ositive baseline status and 51.0 years in participants with a
negative baseline status. There were 41.4% and 34.2% of participants who were obese with
positive and negative baseline status, respectively .
Baseline Medical History
Participants ≥16 y ears of a ge had a diverse medical history profile consistent with that of
individuals in the general population in the same age group. In the BNT162b2 group,
conditions in the surgical and medical procedures ( 8430 [38.3%]), metabolism and nutrition
disorders ( 6587 [29.9 %]), and immune sy stem disorders ( 5987 [27.2 %]; of which 3303
[15.0%] were seasonal allergy )SOCs were most frequentl y reported.
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Page 45Overall , 20.7% had an y comorbidity (per the Charlson comorbidity index) . The most
frequentl y reported comorbidities were diabetes without chronic complications (7.7%),
chronic pulmonary disease ( 8.1%), and any malignancy (3.6%), which were reported at
similar frequencies in each group.
In the younger age group, 13.3% of participants had an y comorbidit y. The most frequently
reported comorbidities were diabetes without chronic complications (3.7%) and chronic
pulmonary disease (7.4%), which were reported at similar frequencies in each vaccine group.
In the older age group, 31.6% of participants had any comorbidity . The most frequentl y
reported comorbidities were diabetes without chronic complications (13.6%) and chronic
pulmonary disease (9.1%), which were reported at similar frequencies in each vaccine group.
2.7.4.1.2.4.4.1.1. Participants With Confirmed Stable HIV Disease (Phase 3, Stu dy
C4591001, Demographic and Other Characteristics of Study Population)
Demographic characteristics for participants with confirmed stable HIV disease were similar
in the BNT162b2 and the placebo groups. Overall, 54.5% of participants were Black or
African American, 40.5% of participants were White, and all other racial groups were ≤1.5%.
There were 16.0% Hispanic/L atino participants . Median age was 49.5 years and 67.5% of
participants were male . Obese participants made up 39.0 % of thispopulation.
2.7.4.1.2.4.4.2. Participants With At Least 6 Months Follow- Up Time –Original
BNT162b2 Participants ≥ 16 Years of Age (Phase 3, Study C4591001, Demographic and
Other Characteristics of Study Population)
Demographic characteristics for all original BNT162b2 Phase 2/3 participants ≥16 y ears of
ageand had at least 6 months of follow -up time after Dose 2 are presented in Table 36in
Appendix D . Overall, most participants were White ( 86.4%), with 7.1% Black or African
American participants and 3.8% Asian participants, and other racial groups were ≤1.6%.
There were 27.8% Hispanic/L atino participants . Median age was 53.0 years and 50.3% of
participants were male . Obese participants made up 34.2 % of t his safet y population.
2.7.4.1.2.4.4.3. Original Placebo Participants ≥16 Years of Age Who Then Received
BNT162b2 (Phase 3, Study C4591001, Demographic and Other Characteristics of Study
Population)
Demographic characteristics for all original placebo Phase 2/3 participants ≥16 y ears of age
who then received BNT162b2 later during the open- label follow -up period are presented in
Table 37in Appendix D. Overall, most participan ts were White ( 83.1%), with 8.3% Black or
African American participants and 4.3% Asian participants, and all other racial groups were
≤2.6%. There were 25.5% Hispanic/Latino participants . Median age was 51.0 years and
50.2% of participants were male . Obese participants made up 34.4% of this safet y
population.
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Page 462.7.4.1.2.4.4.4. All Participants (Phase 3, Study C4591001 ,Demographic and Other
Characteristics of Study Population)
Demographic characteristics for all participants (including adolescents 12 through 15 years
of age) were similar in the BNT162b2 group and the placebo group.
2.7.4.1.2.4.5. E-Diary Compliance (Phase 3, Study C4591001 )
Overall, transmission of e -diary data was ≥90.1% (range: 90.1% to 94.0%) for each day
during the 7 days after Dose 1 of BNT162b2. After Dose 2 of BNT162b2, transmission of
e-diary data was 76.5 % on Day 1 and ranged from 83.8% to 85.6% for each day during
Day 2 through Day 7. Transmission rates were similar in the BNT162b2 group and the
placebo group.
2.7.4.2.Safety Results for BNT162b2
Safety data for the primary and exploratory safety endpoints (as described in Section
2.7.4.1.1.2.1 ) for Phase 1, Phase 2, and Phase 3 for Study C4591001 and for Study BNT162 -
01 are presented in the following sections:
BNT162 -01: Section 2.7.4.2.1
Phase 1: Section 2.7.4.2.2
Phase 2: Section 2.7.4.2.3
Phase 3: Section 2.7.4.2.4
Safety methods are described in Section 2.7.4.1.1 with more details in Appendix B
(Section 2.7.4.6.2 ).
Full details of safety results, including for additional endpoints, are presented as follows:
Study BNT162-01: Module 5.3.5.1 BNT162 -01 CSR.
Study C4591001 :
Phase 1, to 1 month after Dose 2 : Module 5.3.5.1 C4591001 Efficacy Final Analy sis
Interim CSR; to 6 months after Dose 2: Module 5.3.5.1 C4591001 6- Month Update
Interim CSR
Phase 2, to 7 day s after Dose 2: Module 5.3.5.1 C4591001 Efficacy Final Analy sis
Interim CSR
Phase 2/3, to 1 month after Dose 2: Module 5.3.5.1 C4591001 Efficacy Final
Analy sis Interim CSR; to 6 months after Dose 2: Module 5.3.5.1 C4591001 6- Month
Update Interim CSR.
Note that data from Phase 2 participants were included in Phase 3 safety analy ses.
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Page 472.7.4.2.1. Study BNT162-01
Safety data (reactogenicity and AE anal yses)are available up through the data cutoff date
(23October 2020) and are summarized below up to 1 month after Dose 2 for the y ounger and
older age groups. Data from the safet y set are presented. This summary focu ses on the 10 µg,
20 µg, and 30 µg dose levels, which correspond to the primary dose levels investigated in the
Phase 1 part of pivotal registration study , C4591001.
2.7.4.2.1.1. Reactogenicity ( Phase 1, Study BNT162-01)
Reactogenicit y results are up to 7 day s after Dose 1 and Dose 2.
2.7.4.2.1.1.1. Local Reactions ( Phase 1, Study BNT162-01)
Overall, solicited local reactions following administration across doses of BNT162b2 were
milder and less frequent for participants compared with BNT162b1. Local reactions
generall y increased in frequency and/or severity with increasing dose level and number of
doses of BNT162b1 and BNT162b2. Most local reactions were mild or moderate in severit y
and resolved within several day s of onset.
For BNT162b1, the i ncidence of any local reactions after each dose was similar between
younger and older age groups, but local reactions were generally milder in the older group.
For BNT162b2, incidence of local reactions w asgenera llylessafter each dose in the older
group compared with the y ounger grou p, and severity of reactions was similar between both
age groups .
Full details and outputs regarding local reactions for Study BNT162 -01 are in Module 5.3.5.1
BNT162 -01CSR Section 12.3 .
2.7.4.2.1.1.2. Systemic Events ( Phase 1, Study BNT162-01)
Overall, solicited s ystemic events following administration across doses of BNT162b2 were
milder and less frequent for participants compared with BNT162b1. Systemic events
generall y increased in frequency and/or severit y with increasing dose lev el and number of
doses of BNT162b1 and BNT162b2. Most s ystemic events were mild or moderate, arose
within the first 1 to 2 days after dosing, and were short -lived.
For BNT162b1, the incidence of an y systemic events after each dose was similar between
younger and older age groups, but sy stemic events were generally milder in the older group.
For BNT162b2, the incidence of s ystemic events after each dose was similar in the older
group compared with the y ounger group. Reports of severe s ystemic events were similar
between the younger and older BNT162b2 groups and were substantially less frequent than
the severe events reported for younger and older BNT162b1 groups.
Full details and outputs regarding s ystemic events for Study BNT162 -01 are in Module
5.3.5.1 BNT1 62-01CSR Section 12.4 .
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Page 482.7.4.2.1.2. Summary of Treatment -Emergent Adverse Events ( Phase 1,
StudyBNT162-01)
Full details and outputs regarding the summary of adverse events for Study BNT162 -01 are
in Module 5.3.5.1 BNT162 -01 CSR Section 12. 5.1.
Overall, 40% to 45% of participants who received BNT162b1 and BNT162b2 across age
groups and across dose levels reported one or more AEs from Dose 1 through 28 day s (ie,
1 month) after Dose 2. There was no overall pattern between vaccine candidates with regard
to AE incidence or severity ; however, AEs considered b y the investigator as related to study
intervention (after omitting events captured in paper diaries for reactogenicity ) were less
frequentl y reported for BNT162b2 groups compared with BNT162b1.
Most AEs reported were co nsidered b y the investigator as not related to study intervention.
Most AEs were mild to moderate in severity . All AEs were reported as resolved.
In the BNT162b1 group, 2 y ounger participants discontinued from the study (see Section
2.7.4.2.1.4.3 ) and 1 older participant experienced SAE (see Section 2.7.4.2.1.4.2 ). In the
BNT162b2 group, 1 younger participant discontinued from the stud y (see Section
2.7.4.2.1.4.3 ) and 1 older participant experienced an SAE (see Section 2.7.4.2.1.4.2 ).
Nodeaths occurred through the data cutoff date.
2.7.4.2.1.3. Analysis of Treatment -Emergent Adverse Events ( Phase 1, Study BNT162-
01)
Details and outputs regarding AEs b y SOC and PT, related AEs, and severe AEs for
Study BNT162 -01 are in Module 5.3.5.1 BNT162 -01 CSR Section 12.5.2 .
2.7.4.2.1.3.1. Treatment -Emergent Adverse Events by System Organ Class and
Preferred Te rm (Phase 1, Study BNT162 -01)
From Dose 1 up to Day 28 after Dose 2 or Dose 1 (if no Dose 2) , after omitting events
captured in paper diaries for reactogenicit y: In the BNT162b1 younger age group, the most
frequentl y reported SOCs were general d isorders and administration site conditions (most
common PT: injection site reaction) , nervous s ystem disorders (most common PT:
headache) , and respiratory , thoracic and mediastinal disorders (most common PTs: cough
and orophary ngeal pain ). In the BNT162b1 older age group, the most frequently reported
SOC was respiratory , thoracic and mediastinal disorders (most common PTs: cough and
orophary ngeal pain); other SOCs were onl y reported by 1 or 2 participants each.
From Dose 1 up to Day 28 after Dose 2 or Dose 1 (if no Dose 2), after omitting events
captured in paper diaries for reactogenicit y: In the BNT162b2 younger age group, the most
frequentl y reported SOC was general disorders and administration site conditions (most
common PT: vessel punct ure site pain. In the BNT162b2 older age group, the most
frequentl y reported SOC was musculoskeletal and connective tissue disorders (most common
PT: back pain).
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Page 492.7.4.2.1.3.2. Related Treatment -Emergent Adverse Events (Phase 1, Study BNT162 -01)
From Dose 2up to Day 28 after Dose 2: In the BNT162b1 y ounger age group, the most
frequentl y reported related SOCs were general disorders and administration site conditions
(most common PT: influenza like illness ), nervous sy stem disorders (most common PT:
headache), and musculos keletal and connective tissue disorders (most common PT: my algia).
In the BNT162b1 older age group, 1 related TEAE was reported in the 30 μg group in each
of the following SOCs: ear and labyrinth disorders, gastrointestinal disorders, and urinary
disorders .
From Dose 2 up to Day 28 after Dose 2: In the BNT162b 2younger age group, the most
frequentl y reported related SOC was general disorders and administration site conditions
(most common PT: injection site reaction). In the BNT162b 2older age group, 1 rela ted
TEAE was reported in the vascular disorders SOC (PT: hot flush).
2.7.4.2.1.3.3. Severe Treatment -Emergent Adverse Events (Phase 1, Study BNT162 -01)
The most frequentl y reported SOC with severe and related TEAEs was general disorders and
administration site conditions forthe BNT162b1 younger groups. In the BNT162b1 older age
group, nervous s ystem disorders was the most frequently reported SOC with severe TEAEs
(none were sever and related).
The most frequentl y reported SOC with severe TEAEs was musculoskeletal and connective
tissue disorder and nervous sy stem disorders for the BNT162b2 younger and older age
groups, respectively (no severe TEAEs were assessed as related) .
2.7.4.2.1.4. Deaths, Serious Adverse Events, Safety -Related Participant Withdrawals,
and Other Significant Ad verse Events (Phase 1, Study BNT162 -01)
Details and outputs regarding deaths, serious adverse events, safet y-related participant
withdrawals, and other significant adverse events for Study BNT162 -01 are in
Module 5.3.5.1 BNT162 -01 CSR Section 12.6 .
2.7.4.2.1.4.1. Deaths (Phase 1, Study BNT162-01)
There were no Stud y BNT162 -01 participants who died through the data cutoff date of
23October 2020.
2.7.4.2.1.4.2. Treatment -Emergent Serious Adverse Events ( Phase 1, Study BNT162-01)
Among BNT162b1 participants, 1 older participant in the 20 µg group had an SAE of severe
syncope (considered as not related to study intervention) after Dose 1 and study treatment
was withdrawn.
Among BNT162b2 participants, 1 older participant in 20 µg group had an SAE of ankle
fracture (considered as not related to study intervention) after receiving both doses, was listed
as recovering, and remains in follow -up.
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Page 502.7.4.2.1.4.3. Safety-Related Participant Withdrawals ( Phase 1, Study BNT162-01)
Among BNT162b1 recipients, 1 y ounger participant in the 10 µg group discontinued the
study due to a moderate AE of malaise (considered as not related to study intervention) after
Dose 1 and 1 younger participant in the 60 µg group discontinued due to a dose -limiting
toxicity of pyrexia after Dose 1.
Among BNT162b2 recipients, 1 y ounger part icipant in the in the 10 µg group discontinued
the study due to a moderate AE of nasophary ngitis (considered as not related to study
intervention) after Dose 1.
2.7.4.2.1.4.4. Adverse Events of Special Interest ( Phase 1, Study BNT162 -01)
There were no Stud y BNT162 -01 par ticipants who reported any AEs of special interest
through the data cutoff date of 23 October 2020.
2.7.4.2.1.5. Clinical Laboratory Evaluations ( Phase 1, Study BNT162-01)
Full details and outputs regarding clinical laboratory evaluations for Phase 1 of Study
BNT162 -01 are in Module 5.3.5.1 BNT162 -01 CSR Section 12.7 .
Changes from baseline in ly mphocy te (low) count were reported in all dose groups after 48
hours of dosing with both BNT162b1 and BNT162b2 as a pharmacod ynam ics effect .
However, their values came back to normal at the subsequent visit without any clinical
consequence and without sequelae.
Changes from baseline were small in all dose groups following the administration of both
BNT162b1 and BNT162b2. L ikewise, the changes from baseline did not indicate a pa rticular
trend in the time course of all clinical chemistry parameters, except for CRP in both
BNT162b1 and BNT162b2 younger agegroup s, as a pharmacody namics effect. However,
their values came back to normal at the subsequent visit without any clinical co nsequence. In
the older participants group, no elevated values of CRP were seen.
There were a few abnormal urinaly sis parameters, but none were clinically significant except
for 1 elevated value of leukocy tes (on Day 50 in younger participant in 1 μg group ).
2.7.4.2.1.6. Vital Signs, Physical Findings, and Other Observations Related to Safety
(Phase 1, Study BNT162 -01)
Full details and outputs regarding ph ysical examination findings for Phase 1 of Study
BNT162 -01 are in Module 5.3.5.1 BNT162 -01 CSR Section 12. 8.
A few abnormal vital signs were reported but none of them were clinical lyrelevant
abnormalities, except for mild or moderate elevated body temperature reported on Day 2 by 5
participants in the BNT162b1 younger age group . The events were assessed as related
TEAE s, and t he elevated body temperature values came back to normal at the subsequent
visit with medication.
No participants presented clinically significant ECG findings or ph ysical examination
findings at screening or when assessed during the ongoing stud y.
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Page 512.7.4.2.1.7. Conclusions (Phase 1, Study BNT162 -01)
Based on Phase 1 data from the FIH Stud y BNT162 -01, BNT162b2 was safe and well -
tolerated in health y adults 18 to 85 years of age, with no unanticipated safety findings.
Reactogenicit y and AEs tended to increase in incidence and/or severity with increasing dose
of BNT162b2. Reactogenicity was mostl y mild to moderate and short -lived after dosing, and
the AE profile and clinical laboratory results did not suggest any safet y concerns.
2.7.4.2.2. Phase 1(Study C4591001)
Safety data are available up through the data cutoff date s noted below and are summarized at
various time points relative to Dose 1 or Dose 2 as follows:
Safety results for Phase 1 vaccine candidates BNT162b1 and BNT162b2 for both
adult age groups are presented up to 1 month after Dose 2 (or 24 August 2020 data
cutoff date) at the 10 µg, 20µg, and 30 µg dose levels.
Safety results for BNT162b1 at the 10 0µgdose level in the y ounger age group are
presented up to 3 weeks after Dose 1 or to before Dose 2 based on the data cutoff date
of 24 August 2020 . Note thatthe group of participants 18 to 55 y ears of age who
received 100 µg BNT162b1 did not receive a second dose of 100 µg BNT162b2 per
IRC decision, and instead, they were given 10 µg for Dose 2. At the time of the data
cutoff date, 11 of 12 participants in this group received Dose 2 of BNT162b1 at 10 µg
but results for Dose 2 are not y et available at the time of this report.
Long -term follow -up from 1 month after Dose 2 to approximately 6months after
Dose 2 (as of unblinding date) of AEs and SAEs for Phase 1 participants who
received BNT162b2 30µg are also presented (these data are based on the 13
March2021 data cutoff date). Note: Adverse event data for the BNT162b2 30 µg
group, from Dose 1 to the unblinding date ,aresummarized in Module 5.3.5.1
C4591001 6- Month Update CSR Section 12.1.2 and Section 12.1.3 .
All doses tested for BNT162b1 and BNT162b2 (10 µg, 20 µg, and 30 µg) were safe and well
tolerated except for BNT162b1 at 100 µg, which was discontinued after the first dose due to
the reactogenicit y profile. BNT162b2 at 30 µg was selected to proceed into the Phase 2/3
portion of the study because this dose and construct provided the optimum combination of a
favorable reactogenicit y profile and a robust immune response.
2.7.4.2.2.1. Reactogenicity (Phase 1, Study C4591001)
Reactogenicit y results are up to 7 day s after Dose 1 and Dose 2.
2.7.4.2.2.1.1. Local Reactions (Phase 1, Study C4591001)
Overall, for both the BNT162b1 and the BNT162b2 recipients, and in both age groups, pain
at the injection site was the most frequent local reaction. Redness and swelling occurred less
frequentl y in the BNT162b2 group and in the BN T162b1 group. In both the BNT162b1 and
BNT162b2 groups, the frequency of local reactions was lower in the older age group
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Page 52compared to the younger age group, and there was a trend of a higher frequency of local
reactions with increased dose. Local reactions were short -lived.
Full details and outputs regarding local reactions for Phase 1 of Study C4591001 are in
Module 5.3.5.1 C4591001 Efficacy Final Anal ysis Interim CSR Section 12.1.1 .
2.7.4.2.2.1.2. Systemic Events (Phase 1, Study C4591001)
Overall, within 7 day s after Dose 1, fatigue was generall y the most frequently reported
systemic event in the both the y ounger and older BNT162b1 groups and in the older
BNT162b2 group; while headache and fatigue were most frequentl y reported in the younge r
BNT162b2 dose group. Overall, within 7 day s after Dose 2, headache was the most
frequentl y reported s ystemic event in the both the y ounger and older BNT162b1 groups and
fatigue was the most frequently reported s ystemic event in the both the y ounger and older
BNT162b2 groups. Chills was generally reported at a higher frequency after Dose 2 and at a
higher frequency in the BNT162b1 group than in the BNT162b2 group. Fever was reported
more frequently in the y ounger BNT162b1 group after Dose 2 than in the older BNT162b2
group. For both the BNT162b1 and the BNT162b2 recipients, after the first and second dose
and in both age groups, the majority of sy stemic events were mild or moderate in severity (no
Grade 4 s ystemic events) and generally short -lived .
Fulldetails and outputs regarding s ystemic events for Phase 1 of Stud y C4591001 are in
Module 5.3.5.1 C4591001 Efficacy Final Anal ysis Interim CSR Section 12.1.2 .
2.7.4.2.2.2. Summary of Adverse Events (Phase 1, Study C4591001)
Full details and outputs regarding the summ ary of adverse events for Phase 1 of Study
C4591001 (including for participants in the BNT162b1 100µg dose group ) are in Module
5.3.5.1 C4591001 Efficacy Final Analy sis Interim CSR Section 12.1.3. 1(24 August 2020
data cutoff date) .
All AEs from Dose 1 through the data cutoff date of 24 August 2020 were included in the
summary for all dose levels for each vaccine candidate and age group other than
BNT162b1 100 µg group for which AEs from Dose 1 to before Dose 2 were summarized.
Additionally , long -term fo llow-up (from 1 month to approximately 4months after Dose 2 [as
of 14 November 2020 cutoff date]) of AEs for Phase 1 participants who received
BNT162b2 30 µg were summarized.
Overall, fewer participants reported at least 1 AE after Dose 1 in the older BN T162b2 group
(8.3% to 25.0%) compared to the younger (41.7% to 50.0%) and older (25.0% to 58.3%)
BNT162b1 groups and the y ounger BNT162b2 group (33.3% to 41.7%).
No SAEs, AEs leading to withdrawals, or deaths were reported in either age group for either
the BNT162b1 or BNT162b2 groups up to 1 month after Dose 2.
To the Data Cutoff Date of 13 March 2021 for BNT162b2 (30 μg)
For the BNT162b2 30 µg group, during the additional follow- up to the unblinding date
(approximately 6 months of follow -up after Dose 2), no additional AEs were reported in the
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Page 53younger or older age group except for 1 severe SAE (neuritis due to an antecubital fossa
blood draw) reported in the y ounger age group (Section 2.7.4.2.2.3.1).
2.7.4.2.2.3. Analysis of Adverse Events (Phase 1, Study C4591001)
Details and outputs regarding AEs b y SOC and PT, related AEs, immediate AEs, and severe
AEs for Phase 1 of Stud y C4591001 (including for participants in the BNT162b1 100µg
dose group ) are in Module 5.3.5.1 C4591001 Efficacy Final Anal ysis Interim CSR Section
12.1.3.2 .
2.7.4.2.2.3.1. Adverse Events by System Organ Class and Preferred Te rm(Phase 1,
Study C4591001)
AE by SOC and PT summaries included AEs from Dose 1 to 1 month after Dose 2 for all
groups other than BNT162b1 100-ug group for which AEs from Dose 1 to 3 weeks after
Dose 1 or from Dose 1 to before Dose 2 were summarized.
General disorders and administration site conditions was the most commonly reported SOC
in the older BNT162b1 group and the younger BNT162b2 group. The most commonly
reported SOC was gastrointestinal disorders in the y ounger BNT162b1 group and nervous
system disorders in the older BNT162b2 group. Generall y, most PTs were reported b y
≤2participants per dose group.
To the Data Cutoff Date of 13 March 2021 for BNT162b2 (30 μg)
For the BNT162b2 30 µg group, during the additional follow -up to the unblinding date
(approximately 6 months of follow -up after Dose 2), an additional severe SAE (neur itis) was
reported b y 1 participant in the y ounger agegroup; per the participant’s medical examination
and history , this event was linked to a blood draw, and the investigator considered there was
a reasonable possibility that the event neuritis was relat ed to clinical trial procedure
(antecubital fossa blood draw) but unrelated to vaccination.
2.7.4.2.2.3.2. Related Adverse Events (Phase 1, Study C4591001)
Overall, general disorders and administration site conditions was the most commonly
reported SOC for the younger an d older BNT162b1 groups and the y ounger BNT162b2
group. In the older BNT162b2 group, nausea, reported in 1 (8.3%) participant, was the onl y
related AE.
To the Data Cutoff Date of 13 March 2021 for BNT162b2 (30 μg)
Additional follow -up through the unblind ing date (approximately 6 months of follow -up after
Dose 2 )did not identify any additional participants with related AEs in the BNT162b2 30 µg
group .
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Page 542.7.4.2.2.3.3. Immediate Adverse Events (Phase 1, Study C4591001)
In the BNT162b1 group, no participants in the younger group reported an immediate AE
after Dose 1 at the 30 µg dose level, and there were no participants in either age group who
reported an y immediate AEs after Dose 2 of BNT162b1.
In the BNT162b2 group, 3 participants in the y ounger age group reported an im mediate AE
after Dose 1 (including 1 report of injection site pain from a participant in the 30µgdose
group). After Dose 2 of BNT162b2, 1 participant in the 20 µg dose group reported an
immediate AE . There were no participants in the older age group who reported any
immediate AE after an y dose of BNT162b2.
2.7.4.2.2.3.4. Severe Adverse Events (Phase 1, Study C4591001)
In the BNT162b1 group, 2 severe AEs were reported in the y ounger age group (py rexia
[102.4°F] 2 day s after Dose 2 [30 µg dose group] and sleep disorder 1 day after Dose 1 [100
µg dose group]; both were determined b y the investigator to be related to study intervention )
and 2 severe AEs were reported in the older age group (herpes zoster 2 day s after Dose 1 [20
µg dose group], which was considered unrelated , and fatigue 1 day after Dose 2 [30 µg dose
group], which was considered related) .
In the BNT162b2 younger age group, 1 participant with a history of migraines reported a
severe migraine 7 days after Dose 1 (30 µgdose group, considered unrelated). In the
BNT162b2 older age group, 2 participants reported a severe AE: muscle spasms 2 days after
Dose 2 (30 µgdose group, considered unrelated to BNT162b2) and radiculopathy 3days
after Dose 1 (placebo), considered unrelated to study intervention.
To the Data Cutoff Date of 13 March 2021 for BNT162b2 (30 μg)
Additional follow -up through the unblinding date (approximately 6 months of follow -up after
Dose 2 ) for the BNT162b2 30 µg group identified an additional severe SAE (neuritis due to
an antecubital fossa blood draw ),reported in the younger age group (Section 2.7.4.2.2.3.1 ).
2.7.4.2.2.4. Deaths, Serious Adverse Events, Safety -Related P articipant Withdrawals,
and Other Significant Adverse Events (Phase 1, Study C4591001)
Details and outputs regarding deaths, serious adverse events, safet y-related participant
withdrawals, and other significant adverse events for Phase 1 of Stud y C4591001 are in
Module 5.3.5.1 C4591001 Efficacy Final Anal ysis Interim CSR Section 12.1.4 .
2.7.4.2.2.4.1. Deaths(Phase 1, Study C4591001)
There were no Phase 1 participants who died through the 24 August 2020 data cutoff date
and through the unblinding date .
2.7.4.2.2.4.2. Serious Adverse Events(Phase 1, Study C4591001)
There were no Phase 1 participants who reported any SAEs from Dose 1 through the data
cutoff date of 24 August 2020.
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Page 55To the Data Cutoff Date of 13 March 2021 for BNT162b2 (30 μg)
Additional follow -up through the unblinding date (approximately 6 months of follow -up after
Dose 2 ) for the BNT162b2 30 µg group identified an additional severe SAE (neuritis due to
an antecubital fossa blood draw ),reported in the younger age group (Section 2.7.4.2.2.3.1 ).
2.7.4.2.2.4.3. Safety-Related Participant Withdrawals (Phase 1, Study C4591001)
There were no Phase 1 participants with an y AEs leading to withdrawal from the study
through the 24 August 2020 data cutoff date and through the unblinding date .
2.7.4.2.2.4.4. Other Significant Adverse Events (Phase 1, Study C4591001)
AEs of special interest were not defined for Phase 1 of this study .
2.7.4.2.2.4.5. Other Safety Assessments (Phase 1, Study C4591001)
2.7.4.2.2.4.5.1. Pregnancy – Phase 1
Pregnancy was not reported in any Phase 1 participants through the 24 August 2020 data
cutoff date and through the unblinding date .
2.7.4.2.2.5. Clinical Laboratory Evaluations (Phase 1, Study C4591001)
Details and outputs regarding clinical laboratory evaluations for Phase 1 of Study C4591001
are in Module 5.3.5.1 C4591001 Efficacy Final Analy sis Interim CSR Section 12.1.5 .
Overall, 1 to 3 days after Dose 1, there were transient decreases in l ymphocy tes
(<0.8 ×LLN), which returned to normal b y 6 to 8 days after Dose 1, in the y ounger and older
BNT162b1 and BNT162b2 groups. Most shifts were from normal or Grade 1 to Grade 1, 2,
or 3 decrease in l ymphocy te counts, which returned to normal by 6 to 8 days after Dose 1 and
were observed in all age and dose groups. The incidence of decreased l ymphocy te counts
was lower for BNT162b2 recipients compared with BNT162b1 recipients. Shifts from
normal to Grade 1 (younger BNT162b1 group) or Grade 2 (older BNT162b2 group)
neutrophil decrease were also observed but were infrequent.
Overall, clinical chemistry and other hematology abnormalities were observed infrequent ly.
None of the laboratory abnormalities were associated with clinical findings.
2.7.4.2.2.6. Physical Examination Findings (Phase 1, Study C4591001)
Overall, there were fewer abnormalities noted during ph ysical examinations after BNT162b2
than after BNT162b1 in both age groups. Full d etails and outputs regarding phy sical
examination findings for Phase 1 of Study C4591001 are in Module 5.3.5.1 C4591001
Efficacy Final Anal ysis Interim CSR Section 12.1.6 .
2.7.4.2.2.7. Narratives (Phase 1, Study C4591001)
Narratives generated for Phase 1 are provided in Module 5.3.5 .1C4591001 6-Month Update
Interim CSR Section 14 .
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Page 562.7.4.2.2.8. Conclusions (Phase 1, Study C4591001)
Based on Phase 1 data from Study C4591001, BNT162b2 was safe and well -tolerated in
younger healthy adults 18 to 55 y ears of age, and in older healthy adults 65 to 85 y ears of
age, with no unanticipated safet y findings. Reactogenicity and AEs were generall y milder
and less frequent in participants in the older group compared with the younger group and
overall tended to increase with increasing BNT162b2 dose. Reactogenicity was mostly mild
to moderate and short -lived after dosing, and the AE profile did not s uggest any safet y
concerns. Clinical laboratory evaluations showed a transient decrease in l ymphocytes that
was observed in all age and dose groups after Dose 1, which resolved within approximately
1week , wasnot associated with any other clinical sequela e,andwasnot considered
clinically relevant.
2.7.4.2.3. Phase 2 (Study C4591001)
Reactogenicit y, AE, and SAE data for the 360 participants in the Phase 2 portion of the study
are presented up to the data cutoff date of 02 September 2020. Adverse event results bey ond
7 day s after Dose 2, as defined in the protocol objectives, are included in Phase 3 anal yses
(see Section 2.7.4.2.4 ).
2.7.4.2.3.1. Reactogenicity (Phase 2, Study C4591001)
Reactogenicit y results are up to 7 day s after Dose 1 and Dose 2.
2.7.4.2.3.1.1. Local Reactions (Phase 2, Study C4591001)
Details and outputs regarding local reactions for Phase 2 of Study C4591001 are in Module
5.3.5.1 C4591001 Efficacy Final Analy sis Interim CSR Section 12.2.1 .
Frequency and Severity of Local Reactions
After the first and second dose of BNT162b2 and in both age groups, the majority of local
reactions were mild or moderate in severit y, and no Grade 4 (potentially life -threatening)
local reactions were reported. In the BNT162b2 group, pain at the injection site was reported
more frequently in the y ounger age group ( N=88 post -dose 1; N= 86post-dose 2 ) than in the
older age group ( N=92post-dose 1; N=91 post -dose 2 ), and frequency was si milar after
Dose 1 compared with Dose 2 of BNT162b2 in the y ounger age group (85.2% vs. 80.2%,
respectivel y) and in the older age group (70.7% vs. 72.5%, respectively ). In the placebo
group, pain at the injection site was reported at similar frequencies ( 7.8% to 10.2%) in the
younger and older age groups after Dose 1 and Dose 2.
In the BNT162b2 group, redness and swelling were similar in the y ounger and older age
group after Dose 1. After Dose 2, the frequency of redness and swelling was slightly higher
in the older age group (7.7% and 12.1%, respectively ) than in the y ounger age group (3.5%
and 3.5%, respectively). In the placebo group, only 1 participant in the older age group
reported redness after Dose 1, and no swelling was reported.
One participant in the BNT162b2 group (older age group) reported severe injection site pain
after Dose 1, and 1 participant in the y ounger age group reported severe injection site pain
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Page 57after Dose 2. One participant in the BNT162b2 group (older age group) reported severe
redness after Dose 2.
Overall, across age groups, pain at the injection site was the most frequent local reaction and
did not increase after Dose 2, and redness and swelling were generally similar in frequency
after Dose 1 and Dose 2.
Onset and Duration
Across age groups, local reactions for the BNT162b2 group after either dose had a median
onset day between Day 1.0 and Day 3.0 (Day 1.0 was the day of vaccination), and ranges
were generally similar in the y ounger and older age groups. Across age groups, after either
dose of BNT162b2, local reactions resolved after a median duration of 1.0 to 3.0 days, which
was generall y similar in the younger and older age groups.
2.7.4.2.3.1.2. Systemic Events (Phase 2, Study C4591001)
Details and outputs regarding s ystemic events for Phase 2 of Study C4591001 are in Module
5.3.5.1 C4591001 Efficacy Final Analy sis Interim CSR Section 12.2.2 .
Frequency and Severity of Systemic Events
In the BNT162b2 group, sy stemic events were generally reported more frequently and were
of higher severity in the y ounger group (N=88 post -dose 1; N= 86post-dose 2) compared
with the older group ( N=92post-dose 1; N= 91post-dose 2) , with frequencies and severity
increasing with number of doses (Dose 1 vs Dose 2). Vomiting and diarrhea were exceptions
with vomiting infrequent and similar in both age groups and vomiting and diarrhea similar
after each dose. Frequencies of s ystemic events in the y ounger and older BNT162b2 groups
(Dose 1 vs Dose 2) are listed below:
Fatigue: younger group (50.0% vs 59.3%) compared to older group (35.9% vs 52.7%)
Headache: younger group (31.8% vs 51.2%) compared to older group (27.2% vs
36.3%)
Muscle pain: y ounger group (23.9% vs 45.3%) compared to older group (14.1% vs
28.6%)
Chills: y ounger group (9.1% vs 40.7%) compared to older group (7.6% vs 20.9%)
Joint pain: y ounger group (9.1% vs 17.4%) compared to older group (4.3% vs 16.5%)
Fever: y ounger group (3.4% vs 17.4%) compared to older group (0.0% vs 11.0%).
Vomiting: simila r in both age groups and after either dose.
Diarrhea: reported less frequently in the older group and was similar after each dose.
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Page 58Systemic events were generall y reported less frequently in the placebo group than in the
BNT162b2 group, for both age groups and doses, with some exceptions. In the y ounger age
group, fever, headache, chills, vomiting, and diarrhea after Dose 1, and vomiting after Dose 2
were reported at similar frequencies in both the placebo and BNT162b2 groups. I n the older
age group, vomit ing, diarrhea, muscle pain, and joint pain after Dose 1, and vomiting and
diarrhea after Dose 2 were reported at similar frequencies in the placebo and BNT162b2
groups.
Use of antip yretic/pain medication was slightly less frequent in the older age group af ter both
doses but increased in both age groups overall after Dose 2 as compared with after Dose 1.
Use of antip yretic/pain medication was less frequent in the placebo group than in the
BNT162b2 group.
After the first and second dose and in both age grou ps, the majority of systemic events were
mild or moderate in severity , and no Grade 4 (potentially life-threatening) sy stemic events
were reported. Across age groups, severe s ystemic events were onl y reported after Dose 2 of
BNT162b2 overall and included fever (1.1%), fatigue (4.0%), headache (2.8%),
chills (2.3%), and muscle pain (1.7%).
Onset and Duration
Across age groups, s ystemic events after both doses of BNT162b2 had a median onset day
between Day 2.0 to Day 3.0 (Day 1.0 was the day of vaccinati on), and ranges were similar in
the y ounger and older age groups. Across age groups, sy stemic events for this group after
either dose resolved with a median duration of 1 day , which was similar in the y ounger and
older age groups. The median duration of f ever and chills after either dose for both age
groups was 1 day. There was no clear difference in the durations of s ystemic events that
occurred after Dose 1 compared to those that occurred after Dose 2.
2.7.4.2.3.2. Summary of Adverse Events (Phase 2, Study C4591001)
Full details and outputs regarding the summary of adverse events for Phase 2 of Study
C4591001 are in Module 5.3.5.1 C4591001 Efficacy Final Analy sis Interim CSR Section
12.2.3.1.
AE reporting for 360 participants evaluated in Phase 2 as of the data cutoff date
(14November 2020) includes at least 2 months of follow -up. The number of participants
who reported at least 1 AE from Dose 1 to 7 day s after Dose 2 was similar in the BNT162b2
group compared with the placebo group, which was generally similar in the 2 vaccine groups
in the y ounger and older age groups. ( 9.1% vs 11.1% and 4.3% vs 8.9% , respectively ).Two
severe events were reported for 2 participants in the BNT162b2 younger ag e group: my algia
(AE) and gastric adenocarcinoma (SAE) (Section 2.7.4.2.3.3.4 and Section 2.7.4.2.3.4.2 ,
respectivel y). The SAE of gastric adenocarcinoma occurred 23 days after receiving Dose 1.
Both events were assessed by the investigator as not related to study intervention.
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Page 592.7.4.2.3.3. Analysis of Ad verse Events (Phase 2, Study C4591001)
Full details and outputs regarding AEs by SOC and PT, related AEs, immediate AEs, and
severe AEs for Phase 2 of Study C4591001 are in Module 5.3.5.1 C4591001 Efficacy Final
Analy sis Interim CSR Section 12.2.3.2 .
2.7.4.2.3.3.1. Adverse Events by System Organ Class and Preferred Te rm(Phase 2,
Study C4591001)
The number of participants who reported at least 1 AE was similar in the BNT162b2 group
compared to the placebo group from Dose 1 to 7 day s after Dose 2.
In the younger age group, 8 (9.1%) and 10 (11.1%) participants reported at least 1 AE in the
BNT162b2 group and the placebo group, respectively .In the older age group, 4 (4.3%) and 8
(8.9%) participants reported at least 1 AE in the BNT162b2 group and the placebo group,
respectivel y.
Overall, most AEs reported up to 7 day s after Dose 2 were in the SOCs of gastrointestinal
disorders (3 [1.7%] in the BNT162b2 group and 2 [1.1%] in the placebo group), general
disorders and administration site conditions (3 [1.7%] in the BNT162b 2 group and
7[3.9%] in the placebo group), and musculoskeletal and connective tissue disorders
(3[1.7%] in the BNT162b2 group and 1 [0.6%] in the placebo group).
The most frequentl y reported AE b y PT was injection site pain (3 [3.4%]) in the younger
BNT1 62b2 group, which all occurred on the day of vaccination with Dose 1 during the
reporting period for local reactions. Two events resolved within 3 day s, and 1 event resolved
11days later. All other AEs by PT were reported in ≤2 participants in each vacc ine group.
One participant in the older BNT162b2 group had an AE of contusion in the upper left arm
deltoid region, which was assessed by the investigator as related to study intervention .
2.7.4.2.3.3.2. Related Adverse Events (Phase 2, Study C4591001)
The number of participants with AEs assessed b y the investigator as related to study
intervention from Dose 1 to 7 day s after Dose 2 were low in frequency and similar in the
BNT162b2 group and placebo group. Within the BNT162b2 group, a similar proportion of
participants in the young and old age groups reported related AEs. Most investigator -
assessed related AEs were reactogenicit y events in the SOC of general disorders and
administration site conditions, and they were reported by a similar proportion of participants
in the BNT162b2 group overall compared with the placebo group, with injection site pain
being the PT reported most frequentl y and exclusively in the BNT162b2 younger age group.
2.7.4.2.3.3.3. Immediate Adverse Events (Phase 2, Study C4591001)
There were no i mmediate AEs after any dose of BNT162b2 30 µg or placebo.
2.7.4.2.3.3.4. Severe or Life-Threatening Adverse Events (Phase 2, Study C4591001)
Two participants (both in the BNT162b2 younger age group) reported severe events of
myalgia (AE) and gastric adenocarcinoma (SAE, discussed in Section 2.7.4.2.3.4.2 ). The
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Page 60participant who reported myalgia had scapular muscle pain, which began 2 day s after Dose 2
andwhich lasted 12days. Both events were assessed by the investigator as not related to
study intervention.
2.7.4.2.3.4. Deaths, Serious Adverse Events, Safety -Related Participant Withdrawals,
and Other Significant Adverse Events (Phase 2, Study C4591001)
Full details and outputs regarding deaths, serious adverse events, safet y-related participant
withdrawals, and other significant adverse events for Phase 2 of Study C4591001 are in
Module 5.3.5.1 C4591001 Efficacy Final Anal ysisInterim CSR Section 12.2.4 .
2.7.4.2.3.4.1. Deaths(Phase 2, Study C4591001)
There were no Phase 2 participants who died through the data cutoff date of
02September 2020 .
2.7.4.2.3.4.2. Serious Adverse Events (Phase 2, Study C4591001)
From Dose 1 to 7 day s after Dose 2, 1 participant (BNT162b2 younger age group )had a n
SAE of gastric adenocarcinoma 23 days after Dose 1, which was assessed by the investigator
as not related to stud y intervention. The SAE was ongoing at the time of the data cutoff, and
the participant was withdrawn from the study because of the SAE .
2.7.4.2.3.4.3. Safety-Related Participant Withdrawals (Phase 2, Study C4591001)
The participant in the BNT162b2 y ounger age group who reported an SAE of gastric
adenocarcinoma (Section 2.7.4.2.3.4.2 )was discontinued from the study on Day 23 after
Dose 1 of BNT162b2.
2.7.4.2.3.4.4. Other Significant Adverse Events(Phase 2, Study C4591001)
AEs of special interest were not defined for Phase 2 of this study ; however, targeted medical
events were monitored throughout the stud y(see Section 2.7.4.2.4.3.4 ).
2.7.4.2.3.5. Narratives (Phase 2, Study C4591001)
Narratives for the Phase 2 participants who w erewithdrawn from the study because of an
SAE through the data cutoff date (14 November 2020) are provided in Module 5.3.5.1
C4591001 Efficacy Final Analy sis Interim CSR Section 14.
2.7.4.2.3.6. Conclusions (Phase 2, Study C4591001)
Based on Phase 2 data from 360 participants in Study C4591001, BNT162b2 at 30 µg was
safe and well -tolerated in adults 18 to 85 y ears of age. Reactogenicit y and AEs were
generall y milder and less frequent in participants in the older group ( ≥56years of age)
compared with the younger group ( ≤55 y ears of age). Reactogenicity was mostly mild to
moderate and short -lived after dosing, and the AE profile did not suggest any serious safet y
concerns. No treatment -related SAEs were reported, and incidence of discon tinuations due to
AEs up to the data cutoff date (representing at least 2 months of follow -up after Dose 2) was
low. There were no deaths as of the data cutoff date (02 September 2020) . Phase 2 safety
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Page 61data were concordant with safet y data in the Phase 1 po rtion of the study , both overall and
with regard to younger and older participants.
2.7.4.2.4. Phase 3 (Study C4591001)
Safety data are available up to the data cutoff date of 13 March 2021. Reactogenicity data are
from the 9839 participants in the reactogenicity subset (Section 2.7.4.2.4.1 ). Adverse Event
data are provided for ~ 44,000 participants as described in Section 2.7.4.2.4.2 .
2.7.4.2.4.1. Reactogenicity (Phase 3, Study C4591001)
The reactogenicit y data were collected b y participants’ e -diary for reporting prompted local
reactions and s ystemic events for 7 day s after each dose.
Reactogenicit y results are up to 7 day s after Dose 1 and Dose 2.
2.7.4.2.4.1.1. Local Reactions (Phase 3, Study C4591001)
Details and outputs regarding local reactions for Phase 3of Study C4591001 are in Module
5.3.5.1 C4591001 6- Month Update CSR Section 12.2.1.
Frequency and Severity of Local Reactions
In the BNT162b2 group, pain at the injection site was reported more frequently in the
younger age group (N=2899 post-Dose 1; N= 2682 post-Dose 2)than in the older age group
(N=2008 post-Dose 1; N= 1860 post-Dose 2),and frequency was similar after Dose 1
compared with Dose 2 of BNT162b2 in the younger age group ( 83.7% vs 78.3%) and in the
older group ( 70.1% vs 66.1%) (Figure 1and Figure 2, respectivel y). In the placebo group,
pain at the injection site after Doses 1 and 2 was reported at slightly high er frequencies in the
younger age group ( 14.2% and 11.6%, respectively ) than in the older age group ( 9.3% and
7.8%, respectively ).
In the BNT162b2 group, frequencies of redness and swelling were similar in the y ounger and
older age group after Doses 1 and 2. Frequencies of redness were similar after Dose 1
compared with Dose 2 of BNT162b2 in the younger age group ( 5.4% vs 5.6 %) and in the
older age group ( 5.3% vs 7.2%). Frequencies of swelling were similar after Dose 1 compared
with Dose 2 of BNT162b2 in t he younger age group ( 6.3% vs 6.8%, respectively ) and in the
older age group ( 7.0% vs 7.8%). In the placebo group, redness and swelling were reported
infrequentl y in the younger ( ≤1.0%) and older ( ≤1.2%) groups after Doses 1 and 2.
Overall, across age grou ps, pain at the injection site did not increase after Dose 2, and
redness and swelling were generally similar in frequency after Dose 1 and Dose 2. Severe
redness and swelling were reported infrequently and were similar between the y ounger and
older age g roups ( ≤0.7% ) after any dose. Severe pain at the injection site occurred more
frequentl y in the younger age group compared to the older age group (2.5% vs 0.7%) . After
the first and second dose and in both age groups, the majority of local reactions were m ild or
moderate in severity , and no Grade 4 local reactions were reported.
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Page 62Subgroup Analyses
There were 177 BNT162b2 and 187 placebo participants with baseline positive
SARS -CoV -2 status, and 4701 BNT162b2 and 4690 placebo participants with baseline
negative SARS -CoV -2 status, respectivel y. For local reactions the frequency of redness,
swelling, and pain at the injection site after any dose of BNT162b2 was 8.5%, 10.2%, and
80.2% compared with 9.9%, 11.1%, and 84.5% for those positive and negative at base line,
respectivel y. While the frequency of local reactions was numerically higher in those negative
at baseline, these differences are not clinicall y meaningful .
Onset and Duration
The median onset for local reactions after either dose of BNT162b2 was between Day 1.0
and Day 2.0 (Day 1.0 was the day of vaccination) in the y ounger age group and between
Day 1.0 and Day 3.0 in the older age group. Local reactions resolved with median durations
between 1.0 and 2.0 day s in both age groups.
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Page 63Figure1.Subjects Reporting Local Reactions, by Maximum Severity, Within 7 Days After Each Dose, by Age Group
(Reactogenicity Subset) –Phase 2/3 Subjects ≥16 Years of Age –Safety Population
Age Group : 16 Through 55 Years of Age – Safety Population
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Page 64Figure 2.Subjects Reporting Local Reactions, by Maximum Severity, Within 7 Days After Each Dose, by Age Group
(Reactogenicity Subset) –Phase 2/3 Subjects ≥16 Years of Age –Safety Population
Age Group : >55 Years o f Age
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Page 652.7.4.2.4.1.1.1. Participants with Confirmed Stable HIV Disease (Phase 3, Study
C4591001, Local Reactions)
Local reactions in participants with confirmed stable HIV disease were similar to those
observed for all participants ≥16years of age b y severit y (Figure 3), onset day , and median
duration. The frequency of pain at the injection site was similar after Dose 1 compared with
Dose 2 of BNT162b2 (63.0% vs 53.3%). The frequency of redness and swelling was similar
after Dose 1 compared with Dose 2 of BNT162b2 (redness: 3.7% vs 6.7%; swelling: 5.6% vs
8.3%, respectively ). There was 1 (1.7%) severe reaction (pain at the injection site) reported
after Dose 2 of BNT162b2 and no Grade 4 reactions were reported.
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Page 66Figure 3.Subjects Reporting Local Reactions, by Maximum Severity, Within 7 Days After Each Dose (Reactogenicity
Subset) – Blinded Placebo -Controlled Follow -up Period –Phase 2/3 HIV -Positive Subjects ≥16 Years of Age –
Safety Population
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Page 672.7.4.2.4.1.2. Systemic Events (Phase 3, Study C4591001)
Details and outputs regarding s ystemic events for Phase 3 of Study C4591001 are in Module
5.3.5.1 C4591001 6- Month Update CSR Section 12. 2.2.
Frequency and Severity of Local Reactions
Systemic events were generall y increased in frequency and severit y in the younger group
(Figure 4) compared with the older group ( Figure 5), with frequencies and severit y increasing
with number of doses (Dose 1 vs Dose 2). Vomiting and diarrhea were exceptions, which
were reported similarl y infrequentl y in both age groups and at similar incidences after each
dose.
Systemic events in the younger group compared with the older group, with frequencies
increasing with number of doses (Dose 1 vs Dose 2), were:
fatigue: y ounger group (49.4% vs 61.5%) compared to older group (33.7% vs 51.0%)
headache: younger group (43.5% vs 54.0%) compared to ol der group (25.0% vs 39.4%)
muscle pain: y ounger group (22.9% vs 39.3%) compared to older group (13.6% vs
28.9%)
chills: y ounger group (16.5% vs 37.8%) compared to older group (6.5% vs 23.4%)
joint pain: y ounger group (11.8% vs 23.8%) compared to older grou p (8.7% vs 19.0%)
fever: younger group (4.1% vs 16.4%) compared to older group (1.3% vs 11.8%)
vomiting: younger group (1.2% vs 2.2%) compared to the older group (0.5% vs 0.7%)
diarrhea: y ounger group (10.7% vs 10.0%) compared to the older group (8.4% vs 8 .2%).
Systemic events were generall y reported less frequently in the placebo group than in the
BNT162b2 group, for both age groups and doses, with some exceptions. I n the y ounger age
group, vomiting and diarrhea (after Dose 1 and Dose 2) were reported at s imilar frequencies
in the placebo group and the BNT162b2 group ( Figure 4). In the older age group, vomiting
and diarrhea (after Dose 1 and Dose 2) were r eported at similar frequencies in the placebo
group and the BNT162b2 group (Figure 5).
Following both Dose 1 and Dose 2, use of antipy retic/pain medication was slightly less
frequent in the older age group ( 19.0% vs 37.0%) than in the y ounger age group ( 27.8% vs
45.2%) after both doses, and medication use increased in both age groups after Dose 2 as
compared with after Dose 1. Use of antipy retic/p ain medication was less frequent in the
placebo group than in the BNT162b2 group and was similar after Dose 1 and Dose 2 in the
younger and older placebo groups ( ranging from 9.3% to 13.7%).
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Page 68Severe fever (>38.9°C to 40.0°C) increased in frequency with the number of doses (Dose 1
versus Dose 2) in younger (0.3% vs 1.5%) and older (0.0% vs 0.4%) participants who
received BNT162b2 and was reported in 0.1% of participants who received placebo in both
age group safter both doses. One participant in the y ounger B NT162b2 group reported fever
of 41.2°C only on Day 2 after Dose 2 and was nonfebrile for all other day s of the reporting
period. Grade 4 fever was not reported in the older BNT162b2 group or in any placebo
participants.
After the first and second dose and in both age groups, the majority of systemic events were
mild or moderate in severity .
Subgroup Analyses
There were 177 BNT162b2 and 187 placebo participants with baseline positive
SARS -CoV -2 status, and 4701 BNT162b2 and 4690 placebo participants with baseline
negative SARS -CoV -2 status. For an y fever after either dose there were 31 (17.5%)
compared to 714 (15.1%) in those positive and negative for SARS- CoV -2 at baseline,
respectivel y. Severe fever (>38.9°C to 40.0°C) was reported in 1 (0.6%) participan t and 49
(1.0%) participants in those positive and negative for SARS -CoV -2 at baseline, respectivel y.
The frequency for other sy stemic events after an y dose was numerically lower for those
positive at baseline: fatigue, headache and chills the frequency was 54.2%, 49.7% and 32.8%
compared with 65%, 57.4%, 34.7% for those positive and negative for SARS -CoV -2 at
baseline, respectivel y. Joint pain was another exception where 27.1% compared to 25.0%
were reported between those positive and negative for SARS -CoV -2 at baseline. Note that
the baseline SARS -CoV -2 positive subgroup included far fewer participants the negative
subgroup, so their results should be interpreted with caution .
Onset and Duration
Systemic events in the younger and older age groups after ei ther dose of BNT162b2 had a
median onset day between Day 2.0 and Day 4.0 (Day 1.0 was the day of vaccination) and
resolved with a median duration of 1 day in both age groups .
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Page 69Figure 4.Subjects Reporting Systemic Events, by Maximum Severity, Within 7 Days After Each Dose, by Age Group
(Reactogenicity Subset) –Phase 2/3 Subjects ≥16 Years of Age –Safety Population
Age Group : 16 Through 55 Years
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Page 70Figure 5.Subjects Reporting Systemic Events, by Maximum Severity, Within 7 Days After Each Dose, Age Group
(Reactogenicity Subset) –Phase 2/3 Subjects ≥16 Years of Age –Safety Population
Age Group: >55 Years
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Page 712.7.4.2.4.1.2.1. Participants with Confirmed Stable HIV Disease (Phase 3, Study
C4591001, Systemic Events)
Systemic events from participants with confirmed stable HIV disease were similar to those
observed for all participants ≥16years of age by severit y (Figure 6), onset day , and duration.
Fever, headache, chills, and joint pain increased in frequency from Dose 1 to Dose 2 while
fatigue, vomiting, diarrhea, and muscle pain were similar after each dose. There were no
severe s ystemic events after Dose 1 of BNT162b2 but after Dose 2, there was 1 (1.7%)
severe fever (>38.9°C to 40.0°C), 3 (5.0%) participants with severe fatigue, 2 (3.3%)
participants with severe headache, 1 (1.7%) participant with severe ch ills, and 1 (1.7%)
participant with severe diarrhea. There were no grade 4 s ystemic events reported after either
dose.
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Page 72Figure 6.Subjects Reporting Systemic Events, by Maximum Severity, Within 7 Days After Each Dose (Reactogenicity
Subset) – Blinded Placebo -Controlled Follow -up Period –Phase 2/3 HIV -Positive Subjects ≥16 Years of Age –
Safety Population
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Page 732.7.4.2.4.2. Adverse Events (Phase 3, Study C4591001)
AEsafet y data are from either the blinded placebo- controlled follow -up period, the open-
label observational follow- up period, or both. The time periods and safet y anal ysis groups are
presented below and in Figure 7.
Blinded placebo -controlled follow -up period from Dose 1 to 1 month after Dose 2
(frequencies) (Section 2.7.4.2.4.2.1 )
Blinded placebo -controlled follow -up period from Dose 1 to the unblinding date (IRs)
(Section 2.7.4.2.4.2.2 )
Open -label follow -up period –original BNT162b2 participants (IRs)
(Section 2.7.4.2.4.2.3 )
Blinded placebo -controlled and open -label follow -up periods from Dose 1 to 6
months after Dose 2 – original BNT162b2 participants (frequencies)
(Section 2.7.4.2.4.2.4 )
Open -label follow -up period –original placebo participants who then received
BNT162b2 (I Rs) (Section 2.7.4.2.4.2.5 )
For AEanalyses bey ond 1 month after Dose 2, and for AEs after unblinding, incidence rates
(IRs) per 100 Person -Years are reported (as opposed to frequencies) to account for the
variable exposure since unblinding began for individual participants.
In this ongoing stud y, tables summarizing participant withdrawals may include some
participants who were reported as withdrawn but remain in the study and are continuing to be
evaluated. These participants are documented in Module 5.3.5.1 C4591001 6- Month Update
Interim CSR E rrata.
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Page 74Figure 7Study C4591001 Phase 3 Safety Analyses: Time Periods and Analysis
Groups
Full details and outputs regarding adverse events for Phase 3 of Study C4591001 are in
Module 5.3.5.1 C4591001 6- Month Update CSR Section 12.2.3.
2.7.4.2.4.2.1. Blinded Placebo -Controlled Follow -Up Period From Dose 1 to 1 Month
After Dose 2 (Phase 3, Study C4591001)
2.7.4.2.4.2.1.1. Summary of Adverse Events : Blinded Placebo -Controlled Follow -Up
Period From Dose 1 to 1 Month After Dose 2 (Phase 3, Study C4591001)
An overv iew of AEs from Dose 1 to 1 month after Dose 2 for the 43,847 participants during
the blinded placebo -controlled follow -up period (including those anal yzed in Phase 2) is
presented in Table 5.The numbers of overall participants who reported at least 1 AE and at
least 1 related AE were higher in the BNT162b2 group (30.2% and 23.9%, respectivel y) as
compared with the placebo group (13.9% and 6.0%, respectively ). The higher frequencies in
the BNT162b2 group was due to terms consistent with reactogenicity reported at greater
frequency in the BNT162b2 group vs the placebo group. This pattern is further described in
Section 2.7.4.2.4.2.1.2.1 .Severe AEs were reported by 1.2% and 0.7% in in the BNT162b2
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Page 75and placebo groups respectively , and life -threatening AEs were similar (0.1% in bo th
groups).
SAEs and AEs leading to withdrawal were reported by ≤0.6% and ≤0.2%, respectivel y, in
both groups. Discontinuations due to related AEs were reported in 13 participants in the
BNT162b2 group and 11 participants in the placebo group (0.1% in both groups) .
From Dose 1 to 1 month after Dose 2, there were 3 deaths in the BNT162b2 group and 5
deaths in the placebo group during the blinded follow- up period ( Section 2.7.4.2.4.3.1 ).
In the younger age group, the number of participants who reported at least 1 AE from Dose 1
to 1 month after Dose 2 was 4233 (32.6 %) and 1871 (14.4 %) in the BNT162b2 and placebo
groups, res pectively . In the older age group, the number of participants who reported at least
1 AE from Dose 1 to 1 month after Dose 2 was 2384 (26.7 %) and 1177 ( 13.2%) in the
BNT162b2 and placebo groups, respectively.
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Page 76Table5. Number (%) of Subjects Reporting at Least 1 Adverse Event From Dose 1
to 1 Month After Dose 2 –Blinded Placebo -Controlled Follow -up Period
–Phase 2/3 Subjects ≥ 16 Years of Age – Safety Population
Vaccine Group (as Administered)
BNT162b2 (30 μg)
(Na=21926)Placebo
(Na=21921)
Adverse Event nb(%) nb(%)
Any event 6617 (30.2) 3048 (13.9)
Relatedc5241 (23.9) 1311 (6.0)
Severe 262(1.2) 150(0.7)
Life-threatening 21(0.1) 26(0.1)
Any serious adverse event 127(0.6) 116(0.5)
Relatedc3(0.0) 0
Severe 71(0.3) 66(0.3)
Life-threatening 21(0.1) 26(0.1)
Any adverse event leading to withdrawal 32(0.1) 36(0.2)
Relatedc13(0.1) 11(0.1)
Severe 10(0.0) 10(0.0)
Life-threatening 3(0.0) 7(0.0)
Death 3(0.0) 5(0.0)
a. N = number of subjects in the specified group. This value is the denominator for the percentage calculations.
b. n = Number of subjects reporting at least 1 occurrence of the specified event category. For "any event," n = number of
subjects reporting at least 1 occurrence of any event.
c. Assessed by the investigator as related to investigational product.
PFIZER CONFIDENTIAL SDTM Creation: 25MAR2021 (20:15) Source Data: adae Table Generation: 27MAR2021
(02:09)
(Cutoff Date: 13MAR2021, Snapshot Date: 25MAR2021) Output File:
./nda2_unblinded/C4591001_BLA/adae_s091_all_pd2_p3_saf1
2.7.4.2.4.2.1.1.1. Participants with Confirmed Stable HIV Disease: Blinded Placebo-
Controlled Follow -Up Period From Dose 1 to 1 Month After Dose 2 (Phase 3, Study
C4591001, Summary of Adverse Events )
From Dose 1 to 1 month after Dose 2, the subset of 200 HIV- positive participants during the
blinded placebo -controlled follow -up period showed generall y similar trends as the overall
population (likewise attributed to reactogenicity reported in the BNT162b2 group). The
numbers of HIV -positive participants who reported at least 1 AE and at lea st 1 related AE
were higher in the BNT162b2 group (26.0% and 19.0%, respectively ) as compared with the
placebo group (13.0% and 3.0%, respectively ). In this group, there was 1 severe AE and 1
AE leading to withdrawal (both were in the BNT162b2 group), and there were no SAEs or
deaths.
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Page 772.7.4.2.4.2.1.2. Analysis of Adverse Events : Blinded Placebo-Controlled Follow -Up
Period From Dose 1 to 1 Month After Dose 2 (Phase 3, Study C4591001)
2.7.4.2.4.2.1.2.1. AdverseEvents by System Organ Class and Preferred Term : Blinded
Placebo-Controlled Follow-Up Period From Dose 1 to 1 Month After Dose 2 (Phase 3,
Study C4591001)
There are no Tier 1 AEs identified for this program.
Tier 2 AEs (defined as an event rate ≥1.0% in any vaccine group [PT level]) reported from
Dose 1 to 1 month after Dose 2 are presented inFigure 8.
Most Tier 2 AEs were reactogenicit y events and all were reported in 4 SOCs: general
disorders and administration site conditions, musculoskelet al and connective tissue disorders,
nervous s ystem disorders, and gastrointestinal disorders. The proportions of participants
reporting Tier 2 AEs were generally higher in the BNT162b2 group (N= 21,926 ; ranging from
1.1% to 13.3%) than in the placebo group (N=21,921 ; ranging from 0.3% to 1.9%). Most of
the PTs were in the SOC of general disorders and administration site conditions:
injection site pain (2915 [13.3%] BNT162b2 vs 397 [1.8%] placebo)
pyrexia (1517 [6.9%] BNT162b2 vs 77 [0.4%] placebo)
fatigue (1463 [6.7%] BNT162b2 vs 379 [1.7%] placebo)
chills (1365 [6.2%] BNT162b2 vs 120 [0.5%] placebo)
pain (628 [2.9%] BNT162b2 vs 61 [0.3%] placebo).
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Page 78Figure 8.Forest Plot of Tier 2 Adverse Events Reported From Dose 1 to 1 Month After Dose 2 –Blinded Placebo -
Controlled Follow -up Period –Phase 2/3 Subjects ≥16 Years of Age –Safety Population
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Page 79From Dose 1 to 1 month af ter Dose 2 during the blinded placebo- controlled follow -up
period, 6617 (30.2%) BNT162b2 participants and 3048 (13.9%) placebo participants
reported at least 1 AE .Most reported AEs were in SOCs with reactogenicity events.
(Table 6).
general disorders and administration site conditions (4725 [21.5%] BNT162b2 vs
993[4.5%] placebo)
musculoskeletal and connective tissue disorders (1804 [8.2%] BNT162b2 vs 527
[2.4%] placebo)
nervous s ystem disorders (1565 [7.1%] BNT162b2 vs 600 [2.7%] placebo)
gastrointestinal disorders ( 699 [3.2%] BNT162b2 vs 464 [2.1 %]placebo).
The number of BNT162b2 participants who reported at least 1 AE from Dose 1 to 1month
after Dose 2 was 4233 ( 32.6%) and 2384 (26.7 %) in the younger and older groups,
respectivel y. In the younger versus older BNT162b2 age groups, AE frequencies in above
SOCs were:
general disorders and administration site conditions (3161 [24.3%] vs 1564 [17.5%])
musculoskeletal and connective tissue disorders (1201 [9.2%] vs 603 [6.8%])
nervous s ystem disorders (1067 [8.2%] vs 498 [5.6%])
gastrointestinal disorders (440 [3.4%] vs 259 [2.9 %])
As shown in Table 6, the most frequently reported AEs in the BNT162b2 group by PT
overall were injection site pain (2 915 [13.3 %]), py rexia ( 1517 [6.9 %]), fatigue ( 1463
[6.7%]), chills ( 1365 [6.2 %]), headache ( 1339 [6 .1%]), and my algia ( 1239 [5.7 %]). During
this time period from Dose 1 to 1 month after Dose 2, most of these AEs were reported
during the e-diary 7-day reporting period.
The frequency of AEs in the SOC of investigations was higher in the BNT162b2 group
(0.8%) as compared with the placebo group (0.2%) mainly due to the higher frequency of the
PT B ody Temperature increased (120 in the BNT162b2 group and 12 in the placebo group).
In the skin and subcutaneous tissue disorders SOC, there were 17 participants who reported
night sweats in the BNT162b2 group (compared to 3 in the placebo group), and all but 1 of
these participants reported the AE within the first 7 day s after Dose 1 or 2, respectivel y,and
there were 31 participants who reported h yperhidrosis in the BNT162b2 group (compared to
9 in the placebo group), and all but 3 of these participants reported the AE within the first 7
days after Dose 1 or 2.
Nineteen study participants reported events in the Hepatobiliary Disorders SOC
(14BNT162b2 recipients and 5 placebo recipients) ( Table 6). Of the 19 total participants,
3participants had hepatic events :
One participant in the placebo group reported hepatic cirrhosis
One participant in the placebo group report ed nonalcoholic fatt y liver disease
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Page 80One participant in the BNT162b2 group reported alcoholic cirrhosis
The remaining 16 participants reported biliary events (cholecy stitis/cholecystitis acute ,
biliary colic, bile duct stone, and biliary dyskinesia): 13 participants in the BNT162b2 group
and 3 participants in the placebo group.
In the BNT162b2 group, 8 participants reported cholelithiasis (1 reported an event each
of cholelithiasis and cholecy stitis), 1 participant reported cholecy stitis acute,
2participants reported biliary colic, and 1 participant each reported bile duct stone/biliary
dyskinesia.
In the placebo group, there were 3 participants who reported the following: 1 participant
repor ted an event each of cholecy stitis acute and cholelithiasis, 1 participant reported
cholecy stitis acute, and 1 participant reported cholelithiasis.
In the nervous s ystems disorder SOC, there were 3 participants who reported facial paral ysis
in the BNT162b2 group (compared to none in the placebo group). More details are presented
in Section 2.7.4.2.4. 3.4.1.2 .
For l ymphadenopathy the frequ ency in the BNT162b2 group was 0.4 % compared to the
frequency of 0.0% on the placebo group. Most AEs of ly mphadenopathy in the BNT162b2
group were judged b y the investigator as related to study intervention (further discussed in
Section 2.7.4.2.4.3.4.1.3 .
Other events of clinical interest that were identified by the sponsor are discussed in
Section 2.7.4.2.4.3.4 .
Post Hoc Analysis
Beyond the 9839 participants in the Phase 2/3 reactogenicit y subset, events related to
reactoge nicity are no longer reported using an e- diary but are instead reported as AEs. As
previously described in the final anal ysis interim CSR dated 03 December 2020, ananalysis
was conducted to evaluate if the imbalance in AEs observed from Dose 1 to 1 month after
Dose 2 was attributed to reactogenicity events. The anal ysis examined the AEs reported
within 7 days after each dose, which represented the reactogenicit y reporting period. The
time period was chosen because man y AEs were reported in the SOCs of gene ral disorders
and administration site conditions, musculoskeletal and connective tissue disorders, and
nervous s ystem disorders, which includes AEs consistent with reactogenicity events , and
could only be attributed to reactogenicity if they occurred durin g this time period as opposed
to occurring up to 1 month from each dose.
PTs reported from Dose 1 to 7 day s after Dose 1 and from Dose 2 to 7 days after Dose 2 in
the SOCs of general disorders and administration site conditions (injection site pain, chill s,
fatigue , and p yrexia), musculoskeletal and connective tissue disorders (m yalgia), and nervous
system disorders (headache) represented the majority of PTs reported in those SOC s.AEs
reported from Dose 1 to 7 day s after Dose 1 and from Dose 2 to 7 day s after Dose 2 were
largel y attributable to reactogenicity events. This observation provides a reasonable
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Page 81explanation for the greater rates of AEs observed overall in the BNT162b2 gro up compared
with the placebo group, consistent with results previously described in the final anal ysis
interim CSR dated 03 December 2020.
In addition to analy sis of AEs corresponding to e -diary terms that were reported within
7days after Dose 1 or Dose 2 that are attributable to reactogenicity , additional consideration
was given to AE terms that are reported at higher frequency in the BNT162b2 group
compared to placebo. The following additional AEs were identified: pain in extremity ,
decreased appetite, l ethargy , asthenia, malaise, night sweats, and hy perhidrosis. Careful
examination of these terms after either dose of BNT162b2 shows that these events are
clustered within the 7 -day period when reactogenicity events are known to occur. Since the
majority ofthe participants did not have an e -diary and reported reactogenicity as AEs, there
is considerable leeway in how sy mptoms are described by participants from multiple
countries, interpreted b y investigators and reported as AEs. As these events are occurrin g
when reactogenicit y is being reported, these events are considered to be attributable to the
experience of reactogenicity events and are plausibly associated with local reactions and
systemic events.
These PTs were reported more frequently in the younger age group.
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Page 82Table6. Number (%) of Subjects Reporting at Least 1 Adverse Event From Dose 1
to 1 Month After Dose 2, by System Organ Class and Preferred Term –
Blinded Placebo -Controlled Follow -up Period – Phase 2/3 Subjects ≥ 16
Years of Age –Safety Population
Vaccine Group (as Administered)
BNT162b2 (30 μg)
(Na=21926)Placebo
(Na=21921)
System Organ Class
Preferred Termnb(%)(95%CIc)nb(%)(95%CIc)
Any event 6617 (30.2) (29.6, 30.8) 3048 (13.9) (13.4, 14.4)
BLOOD AND LYMPHATIC SYSTEM DISORDERS 105 (0.5) (0.4, 0.6) 19 (0.1) (0.1, 0.1)
Lymphadenopathy 83 (0.4) (0.3, 0.5) 7 (0.0) (0.0, 0.1)
Iron deficiency anaemia 8 (0.0) (0.0, 0.1) 1 (0.0) (0.0, 0.0)
Anaemia 4 (0.0) (0.0, 0.0) 4 (0.0) (0.0, 0.0)
Lymph node pain 7 (0.0) (0.0, 0.1) 1 (0.0) (0.0, 0.0)
Blood loss anaemia 1 (0.0) (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Leukocytosis 0 (0.0, 0.0) 2 (0.0) (0.0, 0.0)
Neutropenia 1 (0.0) (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Thrombocytopenia 1 (0.0) (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Thrombocytosis 0 (0.0, 0.0) 2 (0.0) (0.0, 0.0)
Hypochromic anaemia 1 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Leukopenia 1 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Lymphadenitis 1 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Lymphadenopathy mediastinal 1 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Lymphopenia 1 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Splenomegaly 0 (0.0, 0.0) 1 (0.0) (0.0, 0.0)
CARDIAC DISORDERS 56 (0.3) (0.2, 0.3) 50 (0.2) (0.2, 0.3)
Palpitations 6 (0.0) (0.0, 0.1) 14 (0.1) (0.0, 0.1)
Tachycardia 13 (0.1) (0.0, 0.1) 6 (0.0) (0.0, 0.1)
Atrial fibrillation 7 (0.0) (0.0, 0.1) 9 (0.0) (0.0, 0.1)
Coronary artery disease 3 (0.0) (0.0, 0.0) 3 (0.0) (0.0, 0.0)
Acute myocardial infarction 3 (0.0) (0.0, 0.0) 2 (0.0) (0.0, 0.0)
Acute coronary syndrome 1 (0.0) (0.0, 0.0) 3 (0.0) (0.0, 0.0)
Cardiac failure congestive 2 (0.0) (0.0, 0.0) 2 (0.0) (0.0, 0.0)
Myocardial infarction 0 (0.0, 0.0) 4 (0.0) (0.0, 0.0)
Angina unstable 1 (0.0) (0.0, 0.0) 2 (0.0) (0.0, 0.0)
Bradycardia 1 (0.0) (0.0, 0.0) 2 (0.0) (0.0, 0.0)
Left ventricular hypertrophy 2 (0.0) (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Mitral valve incompetence 1 (0.0) (0.0, 0.0) 2 (0.0) (0.0, 0.0)
Angina pectoris 1 (0.0) (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Aortic valve incompetence 0 (0.0, 0.0) 2 (0.0) (0.0, 0.0)
Arrhythmia 1 (0.0) (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Arteriospasm coronary 1 (0.0) (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Atrial flutter 0 (0.0, 0.0) 2 (0.0) (0.0, 0.0)
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Page 83Table6. Number (%) of Subjects Reporting at Least 1 Adverse Event From Dose 1
to 1 Month After Dose 2, by System Organ Class and Preferred Term –
Blinded Placebo -Controlled Follow -up Period – Phase 2/3 Subjects ≥ 16
Years of Age –Safety Population
Vaccine Group (as Administered)
BNT162b2 (30 μg)
(Na=21926)Placebo
(Na=21921)
System Organ Class
Preferred Termnb(%)(95%CIc)nb(%)(95%CIc)
Cardiac arrest 2 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Mitral valve prolapse 1 (0.0) (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Myocardial ischaemia 2 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Sinus tachycardia 1 (0.0) (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Supraventricular tachycardia 1 (0.0) (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Tricuspid valve incompetence 1 (0.0) (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Ventricular extrasystoles 2 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Acute left ventricular failure 1 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Arrhythmia supraventricular 1 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Atrioventricular block complete 0 (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Atrioventricular block first degree 1 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Bundle branch block left 0 (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Bundle branch block right 1 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Cardiac disorder 1 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Cardiac failure acute 0 (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Cardiovascular disorder 1 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Coronary artery dissection 1 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Coronary artery occlusion 0 (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Junctional ectopic tachycardia 0 (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Left atrial enlargement 0 (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Left ventricular dysfunction 1 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Myocarditis 0 (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Pericardial effusion 0 (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Pericarditis 1 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Tachyarrhythmia 0 (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Ventricular arrhythmia 1 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Ventricular tachycardia 1 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
CONGENITAL, FAMILIAL AND GENETIC DISORDERS 2 (0.0) (0.0, 0.0) 2 (0.0) (0.0, 0.0)
Congenital bladder neck obstruction 0 (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Congenital cystic kidney disease 1 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Heart disease congenital 1 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Type V hyperlipidaemia 0 (0.0, 0.0) 1 (0.0) (0.0, 0.0)
EAR AND LABYRINTH DISORDERS 65 (0.3) (0.2, 0.4) 43 (0.2) (0.1, 0.3)
Vertigo 25 (0.1) (0.1, 0.2) 20 (0.1) (0.1, 0.1)
Ear pain 11 (0.1) (0.0, 0.1) 6 (0.0) (0.0, 0.1)
Tinnitus 9 (0.0) (0.0, 0.1) 8 (0.0) (0.0, 0.1)
Vertigo positional 8 (0.0) (0.0, 0.1) 3 (0.0) (0.0, 0.0)
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Page 84Table6. Number (%) of Subjects Reporting at Least 1 Adverse Event From Dose 1
to 1 Month After Dose 2, by System Organ Class and Preferred Term –
Blinded Placebo -Controlled Follow -up Period – Phase 2/3 Subjects ≥ 16
Years of Age –Safety Population
Vaccine Group (as Administered)
BNT162b2 (30 μg)
(Na=21926)Placebo
(Na=21921)
System Organ Class
Preferred Termnb(%)(95%CIc)nb(%)(95%CIc)
Deafness unilateral 3 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Ear discomfort 3 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Cerumen impaction 1 (0.0) (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Ear disorder 0 (0.0, 0.0) 2 (0.0) (0.0, 0.0)
Meniere's disease 1 (0.0) (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Allergic otitis media 0 (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Deafness 0 (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Deafness neurosensory 1 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Ear pruritus 0 (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Eustachian tube dysfunction 1 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Hyperacusis 1 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Hypoacusis 0 (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Otorrhoea 1 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Sudden hearing loss 1 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Tympanic membrane perforation 0 (0.0, 0.0) 1 (0.0) (0.0, 0.0)
ENDOCRINE DISORDERS 13 (0.1) (0.0, 0.1) 5 (0.0) (0.0, 0.1)
Hypothyroidism 6 (0.0) (0.0, 0.1) 4 (0.0) (0.0, 0.0)
Hypogonadism 2 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Thyroid mass 2 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Autoimmune thyroiditis 1 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Goitre 1 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Hyperprolactinaemia 1 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Thyroid cyst 0 (0.0, 0.0) 1 (0.0) (0.0, 0.0)
EYE DISORDERS 60 (0.3) (0.2, 0.4) 50 (0.2) (0.2, 0.3)
Cataract 6 (0.0) (0.0, 0.1) 5 (0.0) (0.0, 0.1)
Eye pain 7 (0.0) (0.0, 0.1) 4 (0.0) (0.0, 0.0)
Eye irritation 6 (0.0) (0.0, 0.1) 3 (0.0) (0.0, 0.0)
Vision blurred 7 (0.0) (0.0, 0.1) 2 (0.0) (0.0, 0.0)
Chalazion 3 (0.0) (0.0, 0.0) 2 (0.0) (0.0, 0.0)
Vitreous detachment 4 (0.0) (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Blepharitis 2 (0.0) (0.0, 0.0) 2 (0.0) (0.0, 0.0)
Conjunctival haemorrhage 1 (0.0) (0.0, 0.0) 3 (0.0) (0.0, 0.0)
Conjunctivitis allergic 3 (0.0) (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Dry eye 1 (0.0) (0.0, 0.0) 3 (0.0) (0.0, 0.0)
Keratitis 1 (0.0) (0.0, 0.0) 3 (0.0) (0.0, 0.0)
Ocular hyperaemia 2 (0.0) (0.0, 0.0) 2 (0.0) (0.0, 0.0)
Glaucoma 1 (0.0) (0.0, 0.0) 2 (0.0) (0.0, 0.0)
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Page 85Table6. Number (%) of Subjects Reporting at Least 1 Adverse Event From Dose 1
to 1 Month After Dose 2, by System Organ Class and Preferred Term –
Blinded Placebo -Controlled Follow -up Period – Phase 2/3 Subjects ≥ 16
Years of Age –Safety Population
Vaccine Group (as Administered)
BNT162b2 (30 μg)
(Na=21926)Placebo
(Na=21921)
System Organ Class
Preferred Termnb(%)(95%CIc)nb(%)(95%CIc)
Lacrimation increased 2 (0.0) (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Photophobia 2 (0.0) (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Retinal detachment 2 (0.0) (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Vitreous floaters 1 (0.0) (0.0, 0.0) 2 (0.0) (0.0, 0.0)
Asthenopia 1 (0.0) (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Blepharospasm 0 (0.0, 0.0) 2 (0.0) (0.0, 0.0)
Diplopia 2 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Eye pruritus 1 (0.0) (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Amaurosis fugax 0 (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Choroidal neovascularisation 1 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Conjunctival hyperaemia 0 (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Conjunctival oedema 0 (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Corneal irritation 1 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Dacryostenosis acquired 0 (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Diabetic retinopathy 0 (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Episcleritis 1 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Eye allergy 0 (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Eye inflammation 0 (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Eye swelling 0 (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Eyelid haematoma 0 (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Eyelid oedema 1 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Eyelid pain 1 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Eyelids pruritus 1 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Iritis 0 (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Ocular discomfort 0 (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Retinal artery occlusion 0 (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Scleral discolouration 1 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Swelling of eyelid 1 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Ulcerative keratitis 1 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Visual acuity reduced 1 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Visual impairment 0 (0.0, 0.0) 1 (0.0) (0.0, 0.0)
GASTROINTESTINAL DISORDERS 699 (3.2) (3.0, 3.4) 464 (2.1) (1.9, 2.3)
Diarrhoea 248 (1.1) (1.0, 1.3) 188 (0.9) (0.7, 1.0)
Nausea 274 (1.2) (1.1, 1.4) 87 (0.4) (0.3, 0.5)
Vomiting 66 (0.3) (0.2, 0.4) 32 (0.1) (0.1, 0.2)
Toothache 24 (0.1) (0.1, 0.2) 27 (0.1) (0.1, 0.2)
Abdominal pain upper 25 (0.1) (0.1, 0.2) 15 (0.1) (0.0, 0.1)
090177e196f5180a\Approved\Approved On: 05-May-2021 14:36 (GMT)
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Page 86Table6. Number (%) of Subjects Reporting at Least 1 Adverse Event From Dose 1
to 1 Month After Dose 2, by System Organ Class and Preferred Term –
Blinded Placebo -Controlled Follow -up Period – Phase 2/3 Subjects ≥ 16
Years of Age –Safety Population
Vaccine Group (as Administered)
BNT162b2 (30 μg)
(Na=21926)Placebo
(Na=21921)
System Organ Class
Preferred Termnb(%)(95%CIc)nb(%)(95%CIc)
Abdominal pain 19 (0.1) (0.1, 0.1) 19 (0.1) (0.1, 0.1)
Gastrooesophageal reflux disease 12 (0.1) (0.0, 0.1) 16 (0.1) (0.0, 0.1)
Dyspepsia 12 (0.1) (0.0, 0.1) 11 (0.1) (0.0, 0.1)
Odynophagia 13 (0.1) (0.0, 0.1) 8 (0.0) (0.0, 0.1)
Constipation 7 (0.0) (0.0, 0.1) 11 (0.1) (0.0, 0.1)
Dental caries 8 (0.0) (0.0, 0.1) 6 (0.0) (0.0, 0.1)
Gastritis 3 (0.0) (0.0, 0.0) 10 (0.0) (0.0, 0.1)
Haemorrhoids 3 (0.0) (0.0, 0.0) 10 (0.0) (0.0, 0.1)
Aphthous ulcer 8 (0.0) (0.0, 0.1) 3 (0.0) (0.0, 0.0)
Abdominal discomfort 5 (0.0) (0.0, 0.1) 5 (0.0) (0.0, 0.1)
Abdominal distension 6 (0.0) (0.0, 0.1) 1 (0.0) (0.0, 0.0)
Flatulence 4 (0.0) (0.0, 0.0) 3 (0.0) (0.0, 0.0)
Irritable bowel syndrome 4 (0.0) (0.0, 0.0) 3 (0.0) (0.0, 0.0)
Dry mouth 2 (0.0) (0.0, 0.0) 4 (0.0) (0.0, 0.0)
Large intestine polyp 2 (0.0) (0.0, 0.0) 4 (0.0) (0.0, 0.0)
Abdominal pain lower 2 (0.0) (0.0, 0.0) 3 (0.0) (0.0, 0.0)
Dysphagia 3 (0.0) (0.0, 0.0) 2 (0.0) (0.0, 0.0)
Inguinal hernia 1(0.0) (0.0, 0.0) 4 (0.0) (0.0, 0.0)
Stomatitis 2 (0.0) (0.0, 0.0) 3 (0.0) (0.0, 0.0)
Diverticulum 3 (0.0) (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Gastrointestinal disorder 3 (0.0) (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Hiatus hernia 3 (0.0) (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Paraesthesia oral 2 (0.0) (0.0, 0.0) 2 (0.0) (0.0, 0.0)
Retching 3 (0.0) (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Small intestinal obstruction 2 (0.0) (0.0, 0.0) 2 (0.0) (0.0, 0.0)
Cheilitis 1 (0.0) (0.0, 0.0) 2 (0.0) (0.0, 0.0)
Faeces soft 1 (0.0) (0.0, 0.0) 2 (0.0) (0.0, 0.0)
Food poisoning 2 (0.0) (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Gingival pain 3 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Hypoaesthesia oral 1 (0.0) (0.0, 0.0) 2 (0.0) (0.0, 0.0)
Lip swelling 2 (0.0) (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Rectal haemorrhage 2 (0.0) (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Swollen tongue 2 (0.0) (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Tooth impacted 1 (0.0) (0.0, 0.0) 2 (0.0) (0.0, 0.0)
Umbilical hernia 1 (0.0) (0.0, 0.0) 2 (0.0) (0.0, 0.0)
Colitis microscopic 2 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Diverticulum intestinal 0 (0.0, 0.0) 2 (0.0) (0.0, 0.0)
090177e196f5180a\Approved\Approved On: 05-May-2021 14:36 (GMT)
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Page 87Table6. Number (%) of Subjects Reporting at Least 1 Adverse Event From Dose 1
to 1 Month After Dose 2, by System Organ Class and Preferred Term –
Blinded Placebo -Controlled Follow -up Period – Phase 2/3 Subjects ≥ 16
Years of Age –Safety Population
Vaccine Group (as Administered)
BNT162b2 (30 μg)
(Na=21926)Placebo
(Na=21921)
System Organ Class
Preferred Termnb(%)(95%CIc)nb(%)(95%CIc)
Eructation 1 (0.0) (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Gingival discomfort 1 (0.0) (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Glossodynia 2 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Haematochezia 2 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Mouth ulceration 0 (0.0, 0.0) 2 (0.0) (0.0, 0.0)
Noninfective gingivitis 2 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Oral pain 2 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Pancreatitis 1 (0.0) (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Pancreatitis acute 0 (0.0, 0.0) 2 (0.0) (0.0, 0.0)
Parotid duct obstruction 1 (0.0) (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Salivary gland calculus 0 (0.0, 0.0) 2 (0.0) (0.0, 0.0)
Abdominal adhesions 1 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Abdominal hernia 0 (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Abdominal rigidity 1 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Abnormal faeces 0 (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Acute abdomen 0 (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Anal pruritus 0 (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Angular cheilitis 1 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Appendix disorder 0 (0.0, 0.0) 1(0.0) (0.0, 0.0)
Chronic gastritis 0 (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Colitis 1 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Colitis ulcerative 1 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Diverticular perforation 0 (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Diverticulum intestinal haemorrhagic 1 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Epiploic appendagitis 1 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Femoral hernia 1 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Frequent bowel movements 0 (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Gastric polyps 0 (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Gastric ulcer 1 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Gastric ulcer haemorrhage 1 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Gastritis erosive 1 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Gastrointestinal haemorrhage 1 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Gastrointestinal mucosa hyperaemia 0 (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Gastrointestinal pain 1 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Gastrointestinal sounds abnormal 0 (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Gingival bleeding 0 (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Gingival swelling 0 (0.0, 0.0) 1 (0.0) (0.0, 0.0)
090177e196f5180a\Approved\Approved On: 05-May-2021 14:36 (GMT)
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Page 88Table6. Number (%) of Subjects Reporting at Least 1 Adverse Event From Dose 1
to 1 Month After Dose 2, by System Organ Class and Preferred Term –
Blinded Placebo -Controlled Follow -up Period – Phase 2/3 Subjects ≥ 16
Years of Age –Safety Population
Vaccine Group (as Administered)
BNT162b2 (30 μg)
(Na=21926)Placebo
(Na=21921)
System Organ Class
Preferred Termnb(%)(95%CIc)nb(%)(95%CIc)
Glossitis 1 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Haemorrhoidal haemorrhage 1 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Hypoaesthesia teeth 1 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Impaired gastric emptying 1 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Incarcerated inguinal hernia 1 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Intestinal obstruction 0 (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Lip oedema 1 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Loose tooth 0 (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Obstructive pancreatitis 1 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Oesophageal food impaction 0 (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Oesophageal spasm 1 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Oesophageal ulcer 1 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Oesophageal varices haemorrhage 0 (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Oesophagitis 0 (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Oral discomfort 1 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Oral lichenoid reaction 1 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Oral mucosa haematoma 0 (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Palatal disorder 0 (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Pancreatic failure 0 (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Peptic ulcer 1 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Proctalgia 1 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Salivary gland mucocoele 0 (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Teething 0 (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Tongue discolouration 0 (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Tongue discomfort 0 (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Tongue oedema 1 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Tongue pruritus 1 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Tongue ulceration 1 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Tooth disorder 0 (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Varices oesophageal 1 (0.0) (0.0, 0.0) 0 (0.0, 0.0)
Volvulus 0 (0.0, 0.0) 1 (0.0) (0.0, 0.0)
GENERAL DISORDERS AND ADMINISTRATION SITE
CONDITIONS4725 (21.5) (21.0, 22.1) 993 (4.5) (4.3, 4.8)
Injection site pain 2915 (13.3) (12.8, 13.8) 397 (1.8) (1.6, 2.0)
Fatigue 1463 (6.7) (6.3, 7.0) 379 (1.7) (1.6, 1.9)
Pyrexia 1517 (6.9) (6.6, 7.3) 77 (0.4) (0.3, 0.4)
Chills 1365 (6.2) (5.9, 6.6) 120 (0.5) (0.5, 0.7)
090177e196f5180a\Approved\Approved On: 05-May-2021 14:36 (GMT)
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CONFIDENTIAL
Page 89Table6. Number (%) of Subjects Reporting at Least 1 Adverse Event From Dose 1
to 1 Month After Dose 2, by System Organ Class and Preferred Term –
Blinded Placebo -Controlled Follow -up Period – Phase 2/3 Subjects ≥ 16
Years of Age –Safety Population
Vaccine Group (as Administered)
BNT162b2 (30 μg)
(Na=21926)Placebo
(Na=21921)
System Organ Class
Preferred Termnb(%)(95%CIc)nb(%)(95%CIc)
Pain 628 (2.9) (2.6, 3.1) 61 (0.3) (0.2, 0.4)
Injection site erythema 185 (0.8) (0.7, 1.0) 28 (0.1) (0.1, 0.2)
Injection site swelling 140 (0.6) (0.5, 0.8) 23 (0.1) (0.1, 0.2)
Malaise 130 (0.6) (0.5, 0.7) 22 (0.1) (0.1, 0.2)
Asthenia 76 (0.3) (0.3, 0.4) 25 (0.1) (0.1, 0.2)
Injection site pruritus 38 (0.2) (0.1, 0.2) 5 (0.0) (0.0, 0.1)
Injection site bruising 13 (0.1) (0.0,
…[truncated]