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BNT162b2
1.16 Risk Management Plan (Non-REMS) for Biologic License Application # 125742
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PHARMACOVIGILANCE PLAN FOR
BIOLOGIC LICENSE APPLICATION #125742
OF
COMIRNATY® ( PFIZER-BIONTECH COVID-19 VACCINE , mRNA, BNT162b2,
PF-07302048 )
Date of Report: 14 December 202129 April 2022
Version 1.4.1
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TABLE OF CONTENTS
LIST OF TABLES ..............................................................................................................3
LIST OF FIGURES ............................................................................................................6
LIST OF ABBREVIATIONS ..............................................................................................7
1. INTRODUCTION ........................................................................................................10
1.1. Product Details ..................................................................................................10
2. SAFETY SPECIFICATION ..........................................................................................12
2.1. Elements of the Safety Specification ..................................................................12
2.1.1. Non-Clinical .........................................................................................12
2.1.2. Clinical ................................................................................................. 15
2.1.2.a. Limitations of the Human Safety Database .............................15
2.1.2.b. Populations Not Studied in the Pre -Approval Phase ................55
2.1.2.c. Adverse Events / Adverse Reactions ......................................57
2.1.2.d. Identified and Potential Interactions, Including Food-
Biologic Product and Drug -Biologic Product Interactions ..............71
2.1.2.e. Epidemiology of Indication and Target Population .................72
2.1.2.f. Pharmacological Class Effects ...............................................87
3. PHARMACOVIGILANCE PLAN ................................................................................88
3.1. Structure of the Pharmacovigilance Plan ............................................................88
3.1.1. Summary of Ongoing Safety Concerns ...................................................88
3.1.2. Routine Pharmacovigilance Practices .....................................................88
3.1.3. Action Plan for Safety Issues ................................................................. 91
3.1.4. Summary of Actions to be Completed, Including Milestones ................109
3.2. Pharmacovigilance Methods ............................................................................123
3.2.1. List of Studies Included in the Pharmacovigilance Plan ........................123
REFERENCES ...............................................................................................................124
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LIST OF TABLES
Table 1. Product Details ....................................................................................10
Table 2. Key Safety Findings and Rel evance to Human Usage ...........................14
Table 3. Exposure to BNT162b2 by Age Group and Dose (C4591001) –
Blinded Placebo-Controlled Follow -up Period ......................................20
Table 4. Exposure to BNT162b2 by Age Group and Dose (C4591001) –
Open-Label Follow -up Period – Subjects Who Originally Received
BNT162b2 ..........................................................................................21
Table 5. Exposure to BNT162b2 by Age Group and Dose (C4591001) –
Open-Label Follow -up Period – Subjects Who Originally Received
Placebo and Then Received BNT162b2 After Unblinding .....................22
Table 6. Exposure to BNT162b2 by Age Group and Dose (BNT162-01) ............23
Table 7. Exposure to BNT162b2 by Dose (Totals) (C4591001) – Blinded
Placebo-Controlled Follow-up Period ...................................................26
Table 8. Exposure to BNT162b2 by Dose (Totals) (C4591001) – Open-
Label Follow -up Period – Subjects Who Originally Received
BNT162b2 ..........................................................................................26
Table 9. Exposure to BNT162b2 by Dose (Totals) (C4591001) – Open-
Label Follow -up Period – Subjects Who Originally Received
Placebo and Then Received BNT162b2 After Unblinding .....................26
Table 10. Exposure to BNT162b2 by Dose (Totals) (BNT162-01 )........................27
Table 11. Exposure to BNT162b2 by Dose, Age Group, and Gender
(C4591001) – Blinded Placebo -Controlled Follow -up Period ................28
Table 12. Exposure to BNT162b2 by Dose, Age Group, and Gender (C4591001) – Open-Label Follow -up Period – Subjects Who
Originally Received BNT162b2 ...........................................................29
Table 13. Exposure to BNT162b2 by Dose, Age Group, and Gender (C4591001) – Open-Label Follow -up Period – Subjects Who
Originally Received Plac ebo and Then Received BNT162b2 After
Unblinding ..........................................................................................29
Table 14. Exposure to BNT162b2 by Dose, Age Group, and Gender
(BNT162-01) .......................................................................................30
Table 15. Exposure to BNT162b2 by Age Group, Dose, and Race/Ethnic Origin (C4591001) – Blinded Placebo -Controlled Follow -up Period .....31
Table 16. Exposure to BNT162b2 by Age Group, Dose, and Race/Ethnic Origin (C4591001) – Open-Label Follow -up Period – Subjects
Who Originally Received BNT162b2 ...................................................35
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Table 17. Exposure to BNT162b2 by Age Group, Dose, and Race/Ethnic
Origin (C4591001) – Open-Label Fo llow-up Period – Subjects
Who Originally Received Placebo and Then Received BNT162b2
After Unblinding .................................................................................37
Table 18. Exposure to BNT162b2 by Dose and Race/Ethnic Origin (C4591001) – Blinded Placebo -Controlled Follow -up Period ................39
Table 19. Exposure to BNT162b2 by Dose and Race/Ethnic Origin (C4591001) – Open-Label Follow -up Period – Subjects Who
Originally Received BNT162b2 ...........................................................41
Table 20. Exposure to BNT162b2 by Dose and Race/Ethnic Origin
(C4591001) – Open-Label Follow -up Period – Subjects Who
Originally Received Placebo and Then Received BNT162b2 After Unblinding ..........................................................................................41
Table 21. Exposure to BNT162b2 by Dose and Race/Ethnic Origin (BNT162 -
01) ......................................................................................................42
Table 22. Exposure to BNT162b2 (30 μg) by Special Population (C4591001) – Blinded Placebo -Controlled Follow -up Period ...................................43
Table 23. Exposure to BNT162b2 (30 μg) by Special Population (C4591001) – Open-Label Follow -up Period – Subjects Who Originally
Received Placebo and Then Received BNT162b2 After Unblinding ......44
Table 24. Exposure to BNT162b2 by Dose (Totals) (C4591001) – 12-15
Years – Blinded Placebo -Controlled Follow -up Period .........................45
Table 25. Exposure to BNT162b2 by Dose (Totals) (C4591001) – 12-15
Years – Open-Label Follow -up Period – Subjects Who Originally
Received Placebo and Then Received BNT162b2 After Unblinding ......45
Table 26. Exposure to BNT162b2 by Gender (C4591001) – 12-15 Years –
Blinded Placebo-Controlled Follow -up Period ......................................46
Table 27. Exposure to BNT162b2 by Gender (C4591001) – 12-15 Years –
Open-Label Follow -up Period – Subjects Who Originally Received
Placebo and Then Received BNT162b2 After Unblinding .....................46
Table 28. Exposure to BNT162b2 by Race/Ethnic Origin (C4591001) – 12-15
Years – Blinded Placebo -Controlled Follow -up Period .........................47
Table 29. Exposure to BNT162b2 by Race/Ethnic Origin (C4591001) – 12-15
Years – Open-Label Follow -up Period – Subjects Who Originally
Received Placebo and Then Received BNT162b2 After Unblinding ......48
Table 30. Exposure to BNT162b2 (30 μg) by Special Population (C4591001) – 12-15 Years – Blinded Placebo -Controlled Follow -up Period .............49
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Table 31. Exposure to BNT162b2 (30 μg) by Special Population (C4591001)
– 12-15 Years – Open-Label Follow -up Period – Subjects Who
Originally Received Placebo and Then Received BNT162b2 After
Unblinding ..........................................................................................50
Table 32. Cumulative Estimated Shipped/Administered Dose s of BNT162b2
by Region Worldwide ..........................................................................53
Table 33. Exposure of Special Populations Included or not in Clinical Trial Development Programs ........................................................................55
Table 34. Myocarditis and Pericarditis ................................................................. 57
Table 35. Anaphylaxis ........................................................................................62
Table 36. Vaccine-Associated Enhanced Disease (VAED), including
Vaccine-Associated Enhanced Respirator y Disease (VAERD) ..............63
Table 37. Use in Pregnancy and Lactation ...........................................................67
Table 38. Vaccine Effectiveness ..........................................................................69
Table 39. Use in Paediatric Individuals <5 Years of Age§.....................................71
Table 40. Incidence, Prevalence, and Mortality of COVID -19 as of 15 August
202115 ................................................................................................. 73
Table 41. Distribution of Cases (n=29,346,352) by Age, Sex, Race, and Cross-Tabulated Age and Sex -- United States a s of 14 August
2021
20 ................................................................................................76
Table 42. Distribution of Deaths (n=513,204) by Age, Sex, Race, and
Cross-Tabulated Age and Sex -- United States as of 14 August
2021 20 ................................................................................................76
Table 43. COVID-19 incidence and rate ratios, by age group among persons
aged <25 years across three periods of 2020 in 16 U.S.
jurisdictions32 ......................................................................................78
Table 44. Demographics of 135,794 US individuals under age 25 tested for COVID-19 by 08 September 2020
33 .....................................................79
Table 45. Risk for COVID -19 infection, Hospitalisation, and Death by Age
Group and by Race/Ethnici ty39 .............................................................80
Table 46. Hazard Ratios and 95% Confidence Intervals for COVID -19-related
Death46................................................................................................81
Table 47. Signs and symptoms among 291 pediatric (age <18 years) and 10,944 adult (age 18– 64 years) patients with laboratory confirmed
COVID-19 — United States, 12 February – 2April 2020
59 ....................83
Table 48. Preconditions among COVID -19 Patients in EU/EEA, by Severity
of Disease. Case -based Data from TESSy Reported 12 August
202191 ................................................................................................. 86
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Table 49. Comorbidities in individuals tested for COVID -19 in the
Providence St. Joseph Health System – States of California,
Oregon, and Washington, 01 March–31 December 2020 40 ...................87
Table 50. Ongoing Safety Concerns ....................................................................88
Table 51. Action Plan for Important Identified Risk “Myocarditis and
Pericarditis” ........................................................................................91
Table 52. Action Plan for Important Identified Risk “Anaphylaxis” ......................95
Table 53. Action Plan for Important Potential Risk “Vaccine -associated
enhanced disease (VAED) including Vaccine -associated enhanced
respiratory disease (VAERD)” .............................................................98
Table 54. Action Plan for Missing Information “Use in Pregnancy and Lactation” .........................................................................................100
Table 55. Action Plan for Missing Information “Vaccine Effectiveness” ............103
Table 56. Action Plan for Missing Information “Use in Paediatric Individuals <5 Years of Age” ...............................................................................104
Table 57. Summary of Safety Concerns and Action Plans ..................................110
LIST OF FIGURES
Figure 1. Age-Sex distribution of COVID -19 Cases as Different Levels of
Severity, Pooled Data for EU/EEA Countries. Case -based Data
from TESSy produced on 12 August 2021a...........................................75
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LIST OF ABBREVIATIONS
Abbreviation Definition of Term
AE adverse event
AESI adverse event of special interest
A:G albumin:globulin
ALC-0315 ((4-hydroxybutyl)azanediyl)bis(hexane -6,1-diyl)bis(2-
hexyldecanoate )
ALC-0159 2-[(polyethylene glycol) -2000]-N,N-
ditetradecylacetamide
ARDS acute respiratory distress syndrome
BALB/c bagg albino
BC Brighton Collaboration
BEST biologics effectiveness and safety
BLA biologics license application
BMI body mass index
BP blood pressure
CD4, CD8 cluster of differentiation -4, 8
CDC Centers for Disease Control and Prevention
CI confidence interval
COPD chronic obstructive pulmonary disease
COVID-19 coronavirus disease 2019
CSR clinical study report
CT clinical trial
DART developmental and reproductive toxicology
DCA data capture aid
DLP data-lock point
DoD Department of Defense
DSPC 1,2-distearoyl -sn-glycero-3-phosphocholine
ECDC European Center for Disease Control
EEA European Economic Area
eGFR estimated glomerular filtration rate
EU European Union
EUA emergency use authorization
FDA (US) Food and Drug Administration
GLP good laboratory practice
HbA1c glycated hemoglobin
HBV hepatitis b virus
HCV hepatitis c virus
HIV human immunodeficiency virus
IA interim analysis
ICU intensive care unit
IFN Interferon
IL-4 interleukin -4
IM intramuscular(ly)
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Abbreviation Definition of Term
IMD index of multiple deprivation
IND investigational new drug
LNP lipid nanoparticle
LOE lack of efficacy
MAH marketing authorization holder
MedDRA Medical Dictionary for Regulatory Activities
MERS-CoV Middle East respiratory syndrome –coronavirus
MHS Military Health System
MIS-C multisystem inflammatory syndrome in children
MOA mechanism of action
modRNA nucleoside -modified messenger ribonucleic acid
mRNA messenger ribonucleic acid
NCMD National child mortality database
NDA new drug application
NDS new drug submission
NHP nonhuman primate
NHS National Health Service
NICE National Institute for Health and Care Excellence
OCS oral corticosteroids
OTIS Organization of Teratology Information Specialists
PHN Pediatric Heart Network
PK pharmacokinetic
PRAC pharmacovigilance risk assessment committee
PT Preferred Term
PVP pharmacovigilance plan
RBC red blood cell
RMP Risk Management Plan
RNA ribonucleic acid
RR relative risk
RSV respiratory syncytial virus
SAE serious adverse event
SARS severe acute respiratory syndrome
SARS-CoV-1 severe acute respiratory syndrome coronavirus 1
SARS-CoV-2 severe acute respiratory syndrome coronavirus 2
siRNA small-interfering RNA
SMSR summary monthly safety report
Tdap tetanus, diphtheria, and acellular pertussis
TESSy The European Surveillance System
Th1 T helper cell type 1
Th2 T helper cell type 2
UK United Kingdom
US United States
USP United States pharmacopeia
V8 variant 8
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Abbreviation Definition of Term
V9 variant 9
VAED vaccine-associated enhanced disease
VAERD vaccine-associated enhanced respiratory disease
WBC white blood cells
WHO World Health Organization
WOCBP women of childbearing potential
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1. INTRODUCTION
1.1. Product Details
Table 1. Product Detailsa
Product COVID-19 Vaccine, mRNA, herein after referred to as BNT162b2 is a
nucleoside -modified messenger RNA ( modRNA ) encoding the viral spike (S)
glycoprotein of severe acute res piratory syndrome coronavirus 2 (SARS-CoV-
2).
Brief description of the
product Chemical class:
modRNA formulated in lipid particles .
Mechanism of Action:
The modRNA in the BNT162b2 is formulated in lipid particles, which enable
delivery of the mRNA into host cells to allow expression of the SARS -CoV-2
S antigen. The vaccine elicits an immune response to the S antigen, which
protects against COVID -19.
Important information about its composition :
1. PBS Sucrose Formulation with purple cap
The BNT162b2 is a sterile suspension for injection.
The BNT162b2 is supplied as a frozen suspension in multiple dose vials .
Each vial must be diluted with 1.8 mL of sterile 0.9% Sodium Chloride
Injection, USP prior to use to form the vaccine.
Each dose of the BNT162b2 contains 30 mcg of a nucleoside -modified
messenger RNA (modRNA) encoding the viral spike (S) glycoprotein of
SARS-CoV-2.
Each 0.3 mL dose of the BNT162b2 also includes the following
ingredients:
lipids (0.43 mg ( (4-hydroxybutyl)azanediyl)bis(hexane -6,1-diyl)bis(2 -
hexyldecanoate), 0.05 mg 2 -(polyethylene glycol 2000)-N,N-
ditetradecylacetamide, 0.09 mg 1,2 -distearoyl -sn-glycero-3-
phosphocholine, and 0.2 mg cholesterol), 0.01 mg potassium chloride,
0.01 mg monobasic potassium phosphate, 0.36 mg sodium chloride,
0.07 mg dibasic sodium phosphate dihydrate, and 6 mg sucros e. The
diluent (0.9% Sodium Chloride Injection, USP) contributes an additional
2.16 mg sodium chloride per dose.
The BNT162b2 does not contain preservative.
The vial stoppers are not made with natural rubber latex.
2. Tris Sucrose Formulation with gray cap
The drug product formulation is based on the current approved vaccine
except that the formulation buffer has been changed from phosphate
buffered saline to Tris buffer without sodium chloride and potassium
chloride while maintaining the same target pH. Excipients for 30
micrograms (mcg)/dose dispersion for injection: ALC -0315, ALC -0159,
DSPC, cholesterol, trometamol, trometamol hydrochloride, and sucrose.
The label for Tris/Sucrose – 30 mcg (for ages 12 years and older) states
“Do Not Dilute” in prominent placement, as well as having a wide gray
border, in contrast to the purple PBS/Sucrose border .
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Table 1. Product Detailsa
Indication Current: Active immunization to prevent COVID -19 caused by SARS -CoV-2
in individuals 16 years of age and older.
Proposed : Active immunization to prevent COVID -19 caused by SAR S-CoV-
2 in individuals 12 years of age and older.
Dosage and route of
administration Current:
BNT162b2 is administered intramuscularly as a series of two doses (0.3 mL
each) 3 weeks apart .
There are no data available on the interchangeability of BNT162b2 with other
COVID-19 vaccines to complete the vaccination series. Individuals who have
received 1 dose of BNT162b2 should receive a second dose of BNT162b2 to
complete the vaccination series.
a. COVID-19 Vaccine, mRNA US Prescribing Information
Data Lock
Point / Data
cut-off: 16 years and older 13 March 2021 (Pfizer Clinical Database)
23 October 2020 (BioNTech Clinical Database)
18 June 2021 (Pfizer Safety Database)
12 to 15 years older 02 September 2021 (Pfizer Clinical Database)
30 September 2021 (Pfizer Safety Database)
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2. SAFETY SPECIFICATION
2.1. Elements of the Safety Specification
2.1.1. Non-Clinical
Nonclinical evaluation of BNT162b2 included pharmacology (mouse immunogenicity and
NHP immunogenicity and challenge studies), pharmacokinetic (series of biodistribution,
metabolism and pharmacokinetic studies), and toxicity (2 GLP rat repeat -dose toxicity and a
GLP DART) studies in vitro and in vivo. No additional toxicity studies are planned for
BNT162b2.
Nonclinical studies in mice and NHP for BNT162b2 demonstrated both a strong neutralizing
antibody response and a Th1-type CD4+ and an IFN γ+ CD8+ T-cell response. The Th1
profile is characterized by a strong IFNγ, but not IL -4, response indicating the absence of a
potentially deleterious Th2 immune response and is a pattern favored for vaccine safety and
efficacy.1 Rhesus macaques (Study VR -VRT-10671) t hat had received two IM
immunizations with 100 µg BNT162b2 or saline 21 days apart were challenged with 1.05 ×
106 plaque forming units of SARS -CoV-2 (strain USA -WA1/2020), split equally between the
intranasal and intratracheal routes.2 BNT162b2 provided complete protection from the
presence of detectable viral RNA in the lungs compared to the saline control with no clinical,
radiological or histopathological evidence of vaccine -elicited disease enhancement.
An intravenous rat PK study, using an LNP wit h the identical lipid composition as
BNT162b2, demonstrated that the novel lipid excipients in the LNP formulation, ALC -0315
and ALC-0159, distribute from the plasma to the liver. While there was no detectable
excretion of either lipid in the urine, the percent of dose excreted unchanged in feces was ~1% for ALC -0315 and ~50% for ALC -0159. Further studies indicated metabolism played a
role in the elimination of ALC -0315. Biodistribution was assessed using luciferase
expression as a surrogate reporter for mulated like BNT162b2, with the identical lipid
composition. After IM injection of the LNP -formulated RNA encoding luciferase in
BALB/c mice, luciferase protein expression was demonstrated at the site of injection 6 hours
post dose and expression decreased over time to almost reach background levels after 9 days.
Luciferase was detected to a lesser extent in the liver; expression was present at 6 hours after
injection and was not detected by 48 hours after injection. After IM administration of a
radiolabeled LNP -mRNA formulation containing ALC -0315 and ALC -0159 to rats, the
percent of administe red dose was also greatest at the injection site. Outside of the injection
site, total recovery of radioactivity was greatest in the liver and much lower in the spleen,
with very little recovery in the adrenal glands and ovaries. The metabolism of ALC -0315
and ALC-0159 was evaluated in blood, liver microsomes, S9 fractions, and hepatocytes from
mice, rats, monkeys, and humans. The in vivo metabolism was examined in rat plasma,
urine, feces, and liver samples from the PK study. ALC -0315 and ALC -0159 are
metabolized by hydrolytic metabolism of the ester and amide functionalities, respectively,
and this hydrolytic metabolism is observed across the species evaluated.
In GLP toxicity studies, two variants of the BNT162b2 candidate were tested, designated
“variant 8” and “variant 9” (V8 and V9, respectively). The variants differ only in their codon
optimization sequences which are designed to improve antigen expression, otherwise the
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amino acid sequences of the encoded antigens are identical. BNT162b2 (V9) was evaluated
clinically and submitted for application. Two GLP-compliant repeat -dose toxicity studies
were performed in Wistar Han rats; one with each variant. Both studies were 17 days in
duration with a 3-week recovery period. A GLP -compliant DART study in Wistar Han rats
has also been completed. Safety pharmacology, genotoxicity and carcinogenicity studies
have not been conducted, in accordance with the 2005 WHO vaccine guideline.3
The IM route of exposure was selected for nonclinical investigations a s it is the clinical route
of administration. Rats were selected as the toxicology test species as they demonstrated an antigen-specific immune response to the vaccine and are routinely used for regulatory
toxicity studies with an extensive historical saf ety database.
Administration of up to 100 µg BNT162b2 by IM injection to male and female Wistar Han
rats once every week, for a total of 3 doses, was tolerated without evidence of systemic
toxicity. Expected inflammatory responses to the vaccine were evident such as edema and erythema at the injection sites, transient elevation in body temperature, elevations in WBC count and acute phase reactants, and lower A:G ratios. Injection site reactions were common
in all vaccine -administered animals and were greater after boost immunizations. Changes
secondary to inflammation included slight and transient reduction in body weights and transient reduction in reticulocytes, platelets and RBC mass parameters. Decreased
reticulocytes were reported in rats treated wi th the licensed LNP -siRNA pharmaceutical
Onpattro™ (NDA # 210922) but have not been observed in humans treated with this biotherapeutic
4 suggesting this is a species -specific effect. Decreased platelet counts were
noted after repeat administration, but were small in magnitude of change, likely related to inflammation -related platelet activation and consumption, and unassociated with other
alterations in hemostasis. Elevated levels of gamma -glutamyl transferase were observed in
the first repeat -dose toxi city study with BNT162b2 (V8) without evidence of cholestasis or
hepatobiliary injury but was not recapitulated in the second repeat dose -toxicity study with
BNT162b2 (V9), the final clinical candidate. All changes in clinical pathology parameters
and acute phase proteins were reversed at the end of the recovery phase for BNT162b2 , with
the exception of low magnitude higher red cell distribution width (consistent with a regenerative erythroid response) and lower A:G ratios (resulting from acute phase respo nse)
in animals administered BNT162b2. Macroscopic pathology and organ weight changes were
also consistent with immune activation and inflammatory response and included increased size and/or weight of draining iliac lymph nodes and spleen. Vaccine -related microscopic
findings at the end of the dosing phase consisted of edema and inflammation in injection sites and surrounding tissues, increased cellularity in the draining iliac lymph nodes, bone marrow
and spleen and hepatocyte vacuolation in the liver. Vacuolation of periportal hepatocytes,
the only test article -related liver microscopic finding, was not associated with any
microscopic evidence of hepatic injury or hepatic functional effects (i.e., liver functional
enzymes were not elevated) and may be associated with hepatocyte uptake of the LNP
lipids.
5 Microscopic findings at the end of the dosing phase were partially or completely
recovered in all animals at the end of the 3 -week recovery period for BNT162b2. A robust
immune response was elicited to the BNT162b2 antigen.
Administration of BNT162b2 to female rats twice before the start of mating and twice during
gestation at the human clinical dose (30 µg) was associated with non -adverse effects (body
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weight, food consumption and effects localized to the injection site) after each dose
administration. However, there were no effects of BNT162b2 administration on mating
performance, fertility, or any ovarian or uterine parameters in the F0 female rats nor on
embryo-fetal or postnatal survival, growth, or development in the F1 offspring. An immune
response was confirmed in F0 female rats following administration of each vaccine candidate
and these responses were also detectable in the F1 offspring (fetuses and pups).
In summary, the nonclinical safety findings related to BNT162b2 administration primarily
represent an expected immune reaction to vaccine administration and are clinically manageable or acceptable risks in the intended population. The key safety findings regarding BNT162b2 from nonc linical studies and their relevance to human usage are presented in
Table 2. There was no evidence of vaccine -elicited disease enhancement.
Table 2. Key Safety Findings and Relevance to Human Usage
Key Safety findings from Nonclinical Studiesa Relevance to Human Usage
Pharmacology
NHP Challenge Model
• No evidence of vaccine -elicited disease
enhancement.
• Suggests low risk of vaccine -enhanced disease
in humans; being investigated in CTs.
Toxicity
Injection site reactions:
• Injection site reactions were common and
reversible or showed signs of reversibility at the
end of the 3 -week recovery period in nonclinical
studies.
• In common with other vaccines, BNT162b2
administration has the potential to generate
injection site reac tions such as edema and
erythema at the injection sites.
Inflammation and immune activation:
• Evidence of inflammation or immune activation
was common, reversible, and included transiently
higher body temperature, higher circulating
WBCs, and higher acute phase reactants.
Secondarily, transiently lower body weights,
reticulocytes, platelets, and RBC mass parameters
were observed.
• In common with all vaccines, BNT162b2
administration has the potential to generate
inflammation which can lead to increas ed
body temperature, higher circulating WBCs and higher acute phase proteins.
• Decreased reticulocytes have not been observed in humans treated with the LNP-siRNA pharmaceutical Onpattro
4,
suggesting this finding in rats is a species -
specific effect.
• BNT162b2 administration has the potential to
transiently decrease platelets and RBC mass parameters. These slight decreases are not likely to be clinically meaningful due to their
small magnitude.
Developmental and Reproductive Toxicity
• No vaccine -related effects on female fertility or the
development of fetuses or offspring were observed
in a DART study of BNT162b2 in rats.
• No effects are anticipated in WOCBP,
pregnant women or their offspring.
a. Safety pharmacology, genotoxicity, and carcinogenicity studies were not conducted, in accordance with
2005 WHO vaccine guideline, as they are generally not considered necessary to support dev elopment and
licensure of vaccines for infectious diseases.3 In addition, the components of the vaccine construct are lipids
and RNA and are not exp ected to have carcinogenic or genotoxic potential.
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2.1.2. Clinical
2.1.2.a. Limitations of the Human Safety Database
The pivotal study was initially planned to enroll approximately 30,000 participants, which
would have a probability of 78% of detecting an AE with a frequency of 0.01% (1/1000) and
a probability of 95% of detecting an AE with a frequency of 0.02% (1/500). The protocol
was amended to enroll approximately 46,000 participants, which would slightly enhance the
ability to detect AEs. However, rarer events might not be detected.
Participants in the pivotal study were initially planned to be followed for up to 24 months in order to assess the potential for late -occurring adverse reactions, such as the theoretical risk
of VAED. After completing the final efficacy analysis with vaccine efficacy shown to be 95%, and obtaining regulatory authorization to vaccinate in many countries,
Pfizer-BioNTech started to unblind all participants to determine those randomized to placebo
so that they could be offered vaccine in accordance with local authorization. To date, most
placebo subjects have been unblinded to receive act ive vaccine at or prior to 6 months after
the second dose, therefore, a placebo group for comparison of safety data is only available
for up to 6 months post Dose 2.
2.1.2.a.1. Clinical Trial Exposure
Brief Overview of Development
Study BNT162-01
BioNTech is conducting a first-in-human dose level –finding Phase 1/2 study in Germany to
gather safety and immunogenicity data to enable evaluation of 4 vaccines candidates
individually to inform the overall clinical development of a BNT162b2.
BNT162-01 is not conducted under the US IND application but is being conducted under a
German Clinical Trial Application.
Four vaccine candidates were evaluated in Study BNT162 -01. Based on safety and
immunogenicity results from this study, 2 vaccine candidates, BNT162b1 and BNT162b2,
were selected for evaluation in Study C4591001, which is a Phase 1/2/3 randomized, placebo-controlled, observer -blind, dose -finding, vaccine candidate-selection, and efficacy
study in healthy adults (conducted under IND 019736).
Study C4591001
Phase 1: comprised dose -level–finding evaluations of the 2 selected vaccine candidates;
multiple dose levels (some corresponding to those evaluated in Study BNT162-01) were
evaluated. Study vaccine was administered using the same 2-dose schedule as in Study
BNT162-01 (21 days apart). Dose levels were administered first to an 18- to 55-year age
cohort, then to a 65- to 85-year age cohort.
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Both vaccine candidate constructs were safe and well tolerated. BNT162b2 at the 30-µg
dose level was selected and advanced to t he Phase 2/3 expanded cohort and efficacy
evaluation primarily because:
• the reactogenicity profile for BNT162b2 was more favorable than BNT162b1 in both
younger and older adults with similar immunogenicity results;
• in the NHP challenge study (VR -VTR-10671, see Section 2.1.1), a trend toward
earlier clearance of BNT162b2 was observed in the nose.
Phase 2 (enrollment has completed) comprised the evaluation of safety and
immunogenicity data for the first 360 participants (180 from the active vaccine group and
180 from the placebo group, with each group divided between the younger and older age
cohorts) entering the study after completion of Phase 1.
Phase 3 part of the study (which is ongoing) evaluates the efficacy and safety in all
participants (including the first 360 participants from Phase 2). Phase 3 introduced:
• enrollment of participants 16 to 17 years of age to be evaluated with the 18- to 55-
year-old cohort,
• enrollment of a 12- to 15-year-old cohort ,
• immunogenicity data from the 12- to 15-year-old cohort (Table 3, Table 5, Table 11,
Table 13, Table 15, and Table 17), anticipated to bridge to the 16- to 25-year-old
cohort.
Participants in the pivotal study were initially planned to be followed for up to 24 months in
order to assess the potential for late -occurring adverse reactions, such as the theoretical risk
of VAED including VAERD . After completing the final efficacy analysis with vaccine
efficacy shown to be 95% and obtaining regulatory authori zation to vaccinate in many
countries, Pfizer -BioNTech started to unblind all participants to determine those participants
randomised to placebo so that they could be offered vaccine in accordance with local
authorization. To d ate, most placebo subjects have been unblinded to receive active vaccine
at or prior to 6 months after the second dose, therefore, a placebo group for comparison of
safety data is only available for up to 6 months post Dose 2.
The initial efficacy analysis on the 16 years and older population was event-driven, with
prespecified interim analyses after accrual of at least 62, 92, and 120 cases and a final
analysis at 164 cases.
A further efficacy analysis has been conducted on 12- to ≤15-year -old cohort participants and
on 16 years and older participants cohort pa rticipants reported by 13 March 2021.
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Other ongoing1 BNT162b2 interventional studies at the cut-off of the clinical d atabase (02
September 2021) also include:
• C4591005: A phase 1/2 study , placebo-controlled, randomized, and observer -blind study
to evaluate the safety, tolerability, and immunogenicity of a SARS-CoV-2 RNA vaccine
candidate against COVID -19 in healthy Japanese adults.
One hundred sixty participants were randomly assigned in a 3:1 ratio to study
intervention (candidate vaccine: 120, placebo: 40).
• PASS: C4591015: A phase 2/3 study, placebo -controlled, ra ndomized, observer -blind
study to evaluate the safety, tolerability, and immunogenicity of SARS -CoV-2 RNA
vaccine candidate (BNT162b2) against COVID -19 in healthy pregnant women 18 years
of age and older.
• C4591007: A phase 1, open-label dose -finding study to evaluate safety, tolerability, and
immunogenicity and phase 2/3 placebo-controlled, observer -blinded safety, tolerability,
and immunogenicity study of a SARS-CoV-2 RNA vaccine candidate against COVID -19
in healthy children <12 years of age .
Phase 1 is an open-label dose -finding study that consist s of up to 3 different dos e levels
in each age group, with 16 participants per dose level (total of 144 participants). Phase 2/3 will evaluate the safety, tolerability, and immunogenicity of the selected dose level in
each age group from Phase 1, with a total of approximately 4500 participants.
Participants will be randomized in a 2:1 ratio to receive active vaccine or placebo.
• C4591020: A phase 3, randomized, observer -blind study to evaluate the safety,
tolerability, and immunogenicity of multiple formulations of the vaccine candidate BNT -
162B2 against C OVID-19 in healthy adults 18 through 55 years of age .
• C4591031 A phase 3 master protocol to evaluate additional dose(s) of BNT162B2 in
healthy individuals previously vaccinated with BNT162B2.
• BNT162-01 A multi-site, phase I/II, 2 -Part, dose -escalation trial investigating the safety
and immunogenicity of four prophylactic SARS-CoV -2 RNA vaccines against COVID -19
using different dosing regimens in healthy and immunocompromised adults.
• BNT162-03
2 Safety and immunogenicity of SARS -CoV-2 mRNA vaccine (BNT162b1) in
Chinese healthy subjects: A phase I, randomized, placebo - controlled, observer -blind
study.
1 Study C4591017 was completed and therefore is removed from this list.
2 This study is conducted by Shanghai Fosun Pharmaceutical Development, Inc. and sponsored by
BioNTech SE.
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• BNT162-04 A multi-site, phase I/II, 2 -part, dose e scalation trial investigating the safety
and immunogenicity of a prophylactic SARS-CoV-2 RNA vaccine (BNT162b3) against
COVID-19 using different dosing regimens in healthy adults .
• BNT162-062 Safety and immunogenicity of SARS-CoV-2 mRNA vaccine (BNT162b2) in
Chinese healthy population: A phase II, randomized, placebo-controlled, obser ver-blind
study
• BNT162-14 A Phase II, open-label, rollover trial to evaluate the safety and
immunogenicity of one or two boosting doses of Comirnaty or one dose of BNT162b2s01
in BNT162-01 trial subjects, or two boosting doses of Comirnaty in BNT162-04 tri al
subjects
• BNT162-17 A Phase II trial to evaluate the safety and immunogenicity of a SARS -CoV-2
multivalent RNA vaccine in healthy subjects.
Clinical Trial Exposure
Population for analysis of CTs data in this US Pharmacovigilance Plan includes the following 2 studies:
C4591001: Phase 1/2/3, placebo-controlled, randomized, observer -blind, dose finding, study
to evaluate the safety, tolerability, immunogenicity, and efficacy of SARS -CoV-2 RNA
vaccine candidates against COVID -19 in healthy individuals .
BNT162-01: A multi-site, phase I/II, 2 -part, dose -escalation trial investigating the safety and
immunogenicity of four prophylactic SARS-CoV -2 RNA vaccines against COVID -19
using different dosing regimens in healthy adults.
Participants 16 years of age and older
At the cut-off date of 13 March 2021, a total of 46,505 participants were vaccinated in the
BNT162b2 clinical development program:
• 21,745 participants received 2 doses and 360 received 1 dose of BNT162b2
during the blinded follow -up period; 96 participants from study BNT162 -01
received 2 doses of the vaccine.
• 19,647 participants , who originally received placebo, then received 1 dose of
BNT162b2 in the Open-Label Follow -up period after unblinding. (none from
study BNT162-01).
Exposure to BNT162b2 for participants aged 16 years and older in the 2 ongoing studies by
number of doses, and demographic characteristics is shown in Table 3 through Table 21.
In addition, exposure in clinical studies in special populations is provided in Table 22 and
Table 23.
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Participants 12 to 15 years of age
• At the cut-off date of 13 March 2021, a total of 2260 participants 12 to 15 years of
age were vaccinated in the BNT162b2 clinical development program (study
C4591001) .
• At the cut-off date of 02 September 2021, updated clinical study exposure data for the
12- to 15 years of age are provided for the ongoing study C4591001 :
o One thousand one hundred twenty-four (1124) participants received 2 doses and
7 received 1 dose of BNT162b2 in the Blinded -Placebo Controlled Follow-up
period.
o One thousand and ten (1010) participants who originally received placebo, then
received 1 dose of BNT162b2 (18) or 2 doses (992) in the Open-Label Follow-
up period after unblinding.
Exposure to BNT162b2 for participants aged 12- to 15 years of age by number of doses
and demographic c haracteristics is shown in Table 3,Table 5, Table 11, Table 13,
Table 15, Table 17 (at the cut -off date of 13 March 2021) and in Table 24, Table 25,
Table 26, Table 27, Table 28, and Table 29 (at the cut -off date of 02 September 2021) .
In addition, exposure in clinical studies in special populations is provided in Table 22
and Table 23, Table 30 and Table 31.
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Exposure in participants 12 years of age and older (Studies C4591001 – Cut-off date 13
March 2021 and BNT162-01 – Cut off date 23 October 2020)
Table 3. Exposure to BNT162b2 by Age Group and Dose (C4591001) – Blinded
Placebo-Controlled Follow -up Period
Age Group
Dose
Exposure (Number of Doses Received) Number of Subjects
Exposed to BNT162b2 Total Number of
Vaccine Doses
≥12 years to ≤15 years
Vaccine 30 µg
1 Dose 7 7
2 Doses 1124 2248
Total 1131 2255
≥16 years to ≤17 years
Vaccine 30 µg
1 Dose 4 4
2 Doses 374 748
Total 378 752
≥18 years to ≤55 years
Vaccine 10 µg
2 Doses 12 24
Total 12 24
Vaccine 20 µg
2 Doses 12 24
Total 12 24
Vaccine 30 µg
1 Dose 267 267
2 Doses 12438 24876
Total 12705 25143
>55 years to ≤64 years
Vaccine 30 µg
1 Dose 67 67
2 Doses 4341 8682
Total 4408 8749
≥65 years to ≤74 years
Vaccine 10 µg
2 Doses 12 24
Total 12 24
Vaccine 20 µg
2 Doses 9 18
Total 9 18
Vaccine 30 µg
1 Dose 17 17
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Table 3. Exposure to BNT162b2 by Age Group and Dose (C4591001) – Blinded
Placebo-Controlled Follow -up Period
Age Group
Dose
Exposure (Number of Doses Received) Number of Subjects
Exposed to BNT162b2 Total Number of
Vaccine Doses
2 Doses 3624 7248
Total 3641 7265
≥75 years to ≤84 years
Vaccine 20 µg
2 Doses 3 6
Total 3 6
Vaccine 30 µg
1 Dose 3 3
2 Doses 899 1798
Total 902 1801
≥85 years
Vaccine 30 µg
1 Dose 2 2
2 Doses 21 42
Total 23 44
Note: 30 μg includes data from phase 1 and phase 2/3.
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Table 4. Exposure to BNT162b2 by Age Group and Dose (C4591001) – Open-Label
Follow-up Period – Subjects Who Originally Received BNT162b2
Age Group
Dose
Exposure (Number of Doses Received) Number of Subjects
Exposed to BNT162b2 Total Number of
Vaccine Doses
≥16 years to ≤17 years
Vaccine 30 µg
1 Dose 3 3
≥18 years to ≤55 years
Vaccine 30 µg
1 Dose 58 58
>55 years to ≤64 years
Vaccine 30 µg
1 Dose 17 17
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Table 4. Exposure to BNT162b2 by Age Group and Dose (C4591001) – Open-Label
Follow-up Period – Subjects Who Originally Received BNT162b2
Age Group
Dose
Exposure (Number of Doses Received) Number of Subjects
Exposed to BNT162b2 Total Number of
Vaccine Doses
≥65 years to ≤74 years
Vaccine 30 µg
1 Dose 8 8
≥75 years to ≤84 years
Vaccine 30 µg
1 Dose 1 1
≥85 years
Vaccine 30 µg
1 Dose 2 2
Note: 30 μg includes data from phase 1 and phase 2/3.
Note: Subjects who received 2nd Dose of BNT162b2 after unblinding.
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Table 5. Exposure to BNT162b2 by Age Group and Dose (C4591001) – Open-Label
Follow-up Period – Subjects Who Originally Received Placebo and Then
Received BNT162b2 After Unblinding
Age Group
Dose
Exposure (Number of Doses Received) Number of Subjects
Exposed to BNT162b2 Total Number of
Vaccine Doses
≥12 years to ≤15 yearsa
Vaccine 30 µg
1 Dose 30 30
2 Doses 19 38
Total 49 68
≥16 years to ≤17 years
Vaccine 30 µg
1 Dose 107 107
2 Doses 186 372
Total 293 479
≥18 years to ≤55 years
Vaccine 30 µg
1 Dose 2713 2713
2 Doses 8419 16838
Total 11132 19551
>55 years to ≤64 years
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Table 5. Exposure to BNT162b2 by Age Group and Dose (C4591001) – Open-Label
Follow-up Period – Subjects Who Originally Received Placebo and Then
Received BNT162b2 After Unblinding
Age Group
Dose
Exposure (Number of Doses Received) Number of Subjects
Exposed to BNT162b2 Total Number of
Vaccine Doses
Vaccine 30 µg
1 Dose 655 655
2 Doses 3330 6660
Total 3985 7315
≥65 years to ≤74 years
Vaccine 30 µg
1 Dose 128 128
2 Doses 3286 6572
Total 3414 6700
≥75 years to ≤84 years
Vaccine 30 µg
1 Dose 23 23
2 Doses 783 1566
Total 806 1589
≥85 years
Vaccine 30 µg
1 Dose 1 1
2 Doses 16 32
Total 17 33
Note: 30 μg includes data from phase 1 and phase 2/3.
a. Includes subjects who became eligible for unblinding at 16 years of age, confirmed to have received
placebo originally and then received BNT162b2 post unblinding.
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Table 6. Exposure to BNT162b2 by Age Group and Dose (BNT162-01)
Age Group
Dose
Exposure (Number of Doses
Received) No. of Subjects
Exposed to BNT162b2 Total No. of Vaccine Doses
≥18 years to ≤ 64 years
Vaccine 1 µg
1 Dose 1 1
2 Doses 11 22
Total 12 23
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Table 6. Exposure to BNT162b2 by Age Group and Dose (BNT162-01)
Age Group
Dose
Exposure (Number of Doses
Received) No. of Subjects
Exposed to BNT162b2 Total No. of Vaccine Doses
Vaccine 3 µg
1 Dose 0 0
2 Doses 12 24
Total 12 24
Vaccine 10 µg
1 Dose 1 1
2 Doses 11 22
Total 12 23
Vaccine 20 µg
1 Dose 0 0
2 Doses 17 34
Total 17 34
Vaccine 30 µg
1 Dose 0 0
2 Doses 18 36
Total 18 36
≥65 years to ≤74 years
Vaccine 1 µg
1 Dose 0 0
2 Doses 0 0
Total 0 0
Vaccine 3 µg
1 Dose 0 0
2 Doses 0 0
Total 0 0
Vaccine 10 µg
1 Dose 0 0
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Table 6. Exposure to BNT162b2 by Age Group and Dose (BNT162-01)
Age Group
Dose
Exposure (Number of Doses
Received) No. of Subjects
Exposed to BNT162b2 Total No. of Vaccine Doses
2 Doses 5 10
Total 5 10
Vaccine 20 µg
1 Dose 0 0
2 Doses 6 12
Total 6 12
Vaccine 30 µg
1 Dose 0 0
2 Doses 6 12
Total 6 12
≥75 years to ≤84 years
Vaccine 1 μg
1 Dose 0 0
2 Doses 0 0
Total 0 0
Vaccine 3 μg
1 Dose 0 0
2 Doses 0 0
Total 0 0
Vaccine 10 µg
1 Dose 0 0
2 Doses 1 2
Total 1 2
Vaccine 20 µg
1 Dose 0 0
2 Doses 1 2
Total 1 2
Vaccine 30 µg
1 Dose 0 0
2 Doses 0 0
Total 0 0
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(11:32) (Cutoff date:23OCT2020, Snapshot Date: 23OCT2020)
Output File: ex_b2_age_dose2.rtf
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Table 7. Exposure to BNT162b2 by Dose (Totals) (C4591001) – Blinded Placebo -
Controlled Follow -up Period
Dose
Exposure (Number of
Doses Received) Number of Subjects
Exposed to BNT162b2 Total Number of
Vaccine Doses
Vaccine 10 µg
2 Doses 24 48
Total 24 48
Vaccine 20 µg
2 Doses 24 48
Total 24 48
Vaccine 30 µg
1 Dose 367 367
2 Doses 22821 45642
Total 23188 46009
Note: 30 μg includes data from phase 1 and phase 2/3.
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Table 8. Exposure to BNT162b2 by Dose (Totals) (C4591001) – Open-Label Follow -
up Period – Subjects Who Originally Received BNT162b2
Dose
Exposure (Number of Doses Received) Number of Subjects
Exposed to BNT162b2 Total Number of
Vaccine Doses
Vaccine 30 µg
1 Dose 89 89
Note: 30 μg includes data from phase 1 and phase 2/3.
Note: Subjects who received 2nd Dose of BNT162b2 after unblinding.
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27MAR2021 (12:46)
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Table 9. Exposure to BNT162b2 by Dose (Totals) (C4591001) – Open-Label Follow-
up Period – Subjects Who Originally Received Placebo and Then Received
BNT162b2 After Unblinding
Dose
Exposure (Number of Doses Received) Number of Subjects
Exposed to BNT162b2 Total Number of
Vaccine Doses
Vaccine 30 µg
1 Dose 3657 3657
2 Doses 16039 32078
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Table 9. Exposure to BNT162b2 by Dose (Totals) (C4591001) – Open-Label Follow-
up Period – Subjects Who Originally Received Placebo and Then Received
BNT162b2 After Unblinding
Dose
Exposure (Number of Doses Received) Number of Subjects
Exposed to BNT162b2 Total Number of
Vaccine Doses
Total 19696 35735
Note: 30 μg includes data from phase 1 and phase 2/3.
PFIZER CONFIDENTIAL SDTM Creation: 25MAR2021 (23:24) Source Data: adsl Table Generation:
27MAR2021 (12:46)
(Cutoff Date: 13MAR2021, Snapshot Date: 25MAR2021) Output File:
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Table 10. Exposure to BNT162b2 by Dose (Totals) (BNT162-01)
Dose
Exposure (Number of Doses Received) No. of Subjects
Exposed to
BNT162b2 Total No. of Vaccine Doses
Vaccine 1 µg
1 Dose 1 1
2 Doses 11 22
Total 12 23
Vaccine 3 µg
1 Dose 0 0
2 Doses 12 24
Total 12 24
Vaccine 10 µg
1 Dose 1 1
2 Doses 23 46
Total 24 47
Vaccine 20 µg
1 Dose 0 0
2 Doses 24 48
Total 24 48
Vaccine 30 µg
1 Dose 0 0
2 Doses 24 48
Total 24 48
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Table 10. Exposure to BNT162b2 by Dose (Totals) (BNT162-01)
Dose
Exposure (Number of Doses Received) No. of Subjects
Exposed to
BNT162b2 Total No. of Vaccine Doses
PFIZER CONFIDENTIAL SDTM Creation: 24NOV2020 (15:06) Source Data: adsl Table Generation: 10MAR2021
(11:49) (Cutoff date:23OCT2020, Snapshot Date: 23OCT2020)
Output File: ex_b2_dosertf
Table 11. Exposure to BNT162b2 by Dose, Age Group, and Gender (C4591001) –
Blinded Placebo -Controlled Follow -up Period
Number of Subjects Exposed
to BNT162b2 Total Number of Vaccine
Doses
Dose
Age Group Male Female Male Female
Vaccine 10 µg
≥18 years to ≤55 years 5 7 10 14
≥65 years to ≤74 years 2 10 4 20
Total 7 17 14 34
Vaccine 20 µg
≥18 years to ≤55 years 6 6 12 12
≥65 years to ≤74 years 4 5 8 10
≥75 years to ≤84 years 1 2 2 4
Total 11 13 22 26
Vaccine 30 µg
≥12 years to ≤15 years 567 564 1128 1127
≥16 years to ≤17 years 187 191 373 379
≥18 years to ≤55 years 6456 6249 12770 12373
>55 years to ≤64 years 2231 2177 4421 4328
≥65 years to ≤74 years 1934 1707 3858 3407
≥75 years to ≤84 years 511 391 1020 781
≥85 years 12 11 23 21
Total 11898 11290 23593 22416
Note: 30 μg includes data from phase 1 and phase 2/3.
PFIZER CONFIDENTIAL SDTM Creation: 25MAR2021 (23:24) Source Data: adsl Table Generation:
27MAR2021 (12:46)
(Cutoff Date: 13MAR2021, Snapshot Date: 25MAR2021) Output File:
./nda2_unblinded/C4591001_PVP_BLA/adsl_s932
090177e19a14c996\Final\Final On: 29-Apr-2022 17:55 (GMT)
FDA-CBER-2022-5812-0235836
BNT162b2
1.16 Risk Management Plan (Non-REMS) for Biologic License Application # 125742
CONFIDENTIAL
Page 29
Table 12. Exposure to BNT162b2 by Dose, Age Group, and Gender (C4591001) –
Open-Label Follow -up Period – Subjects Who Originally Received
BNT162b2
Number of Subjects
Exposed to BNT162b2 Total Number of Vaccine
Doses
Dose
Age Group Male Female Male Female
Vaccine 30 µg
≥16 years to ≤17 years 0 3 0 3
≥18 years to ≤55 years 24 34 24 34
>55 years to ≤64 years 12 5 12 5
≥65 years to ≤74 years 4 4 4 4
≥75 years to ≤84 years 0 1 0 1
≥85 years 1 1 1 1
Total 41 48 41 48
Note: 30 μg includes data from phase 1 and phase 2/3.
Note: Subjects who received 2nd Dose of BNT162b2 after unblinding.
PFIZER CONFIDENTIAL SDTM Creation: 25MAR2021 (23:24) Source Data: adsl Table Generation:
27MAR2021 (12:46)
(Cutoff Date: 13MAR2021, Snapshot Date: 25MAR2021) Output File:
./nda2_unblinded/C4591001_PVP_BLA/adsl_s9323
Table 13. Exposure to BNT162b2 by Dose, Age Group, and Gender (C4591001) –
Open-Label Follow -up Period – Subjects Who Originally Received Placebo
and Then Received BNT162b2 After Unblinding
Number of Subjects
Exposed to BNT162b2 Total Number of Vaccine
Doses
Dose
Age Group Male Female Male Female
Vaccine 30 µg
≥12 years to ≤15 yearsa 26 23 36 32
≥16 years to ≤17 years 152 141 250 229
≥18 years to ≤55 years 5424 5708 9450 10101
>55 years to ≤64 years 1973 2012 3602 3713
≥65 years to ≤74 years 1801 1613 3530 3170
≥75 years to ≤84 years 495 311 976 613
≥85 years 13 4 25 8
Total 9884 9812 17869 17866
Note: 30 μg includes data from phase 1 and phase 2/3.
a. Includes subjects who became eligible for unblinding at 16 years of age, confirmed to have received
placebo originally and then received BNT162b2 post unblinding.
PFIZER CONFIDENTIAL SDTM Creation: 25MAR2021 (23:24) Source Data: adsl Table Generation:
27MAR2021 (12:46)
090177e19a14c996\Final\Final On: 29-Apr-2022 17:55 (GMT)
FDA-CBER-2022-5812-0235837
BNT162b2
1.16 Risk Management Plan (Non-REMS) for Biologic License Application # 125742
CONFIDENTIAL
Page 30
Table 13. Exposure to BNT162b2 by Dose, Age Group, and Gender (C4591001) –
Open-Label Follow -up Period – Subjects Who Originally Received Placebo
and Then Received BNT162b2 After Unblinding
Number of Subjects
Exposed to BNT162b2 Total Number of Vaccine
Doses
Dose
Age Group Male Female Male Female
(Cutoff Date: 13MAR2021, Snapshot Date: 25MAR2021) Output File:
./nda2_unblinded/C4591001_PVP_BLA/adsl_s932_open
Table 14. Exposure to BNT162b2 by Dose, Age Group, and Gender (BNT162-01)
No. of Subjects Exposed to
BNT162b2 Total No. of Vaccine Doses
Dose
Age Group Male Female Male Female
Vaccine 1 µg
≥18 years to ≤64 years 7 5 14 9
≥65 years to ≤74 years 0 0 0 0
≥75 years to ≤84 years 0 0 0 0
Total 7 5 14 9
Vaccine 3 µg
≥18 years to ≤64 years 5 7 10 14
≥65 years to ≤74 years 0 0 0 0
≥75 years to ≤84 years 0 0 0 0
Total 5 7 10 14
Vaccine 10 µg
≥18 years to ≤64 years 8 10 16 19
≥65 years to ≤74 years 3 2 6 4
≥75 years to ≤84 years 1 0 2 0
Total 12 12 24 23
Vaccine 20 µg
≥18 years to ≤64 years 7 10 14 20
≥65 years to ≤74 years 1 5 2 10
≥75 years to ≤84 years 0 1 0 2
Total 8 16 16 32
Vaccine 30 µg
≥18 years to ≤64 years 10 8 20 16
≥65 years to ≤74 years 2 4 4 8
≥75 years to ≤84 years 0 0 0 0
090177e19a14c996\Final\Final On: 29-Apr-2022 17:55 (GMT)
FDA-CBER-2022-5812-0235838
BNT162b2
1.16 Risk Management Plan (Non-REMS) for Biologic License Application # 125742
CONFIDENTIAL
Page 31
Table 14. Exposure to BNT162b2 by Dose, Age Group, and Gender (BNT162-01)
No. of Subjects Exposed to
BNT162b2 Total No. of Vaccine Doses
Dose
Age Group Male Female Male Female
Total 12 12 24 24
PFIZER CONFIDENTIAL SDTM Creation: 24NOV2020 (15:06) Source Data: adsl Table Generation: 10MAR2021
(11:53) (Cutoff date:23OCT2020, Snapshot Date: 23OCT2020)
Output File: ex_b2_age_dose_sex.rtf
Table 15. Exposure to BNT162b2 by Age Group, Dose, and Race/Ethnic Origin
(C4591001) – Blinded Placebo -Controlled Follow -up Period
Age Group
Dose
Race/Ethnic Origin Number of Subjects
Exposed to BNT162b2 Total Number of
Vaccine Doses
≥12 years to ≤15 years
Vaccine 30 µg
Racial origin
White 971 1937
Black or African American 52 103
Asian 72 143
American Indian or Alaska Native 4 8
Native Hawaiian or other Pacific Islander 3 6
Multiracial 23 46
Not reported 6 12
Total 1131 2255
Ethnic origin
Hispanic/Latino 132 263
Non-Hispanic/non -Latino 997 1988
Not reported 2 4
Total 1131 2255
≥16 years to ≤17 years
Vaccine 30 µg
Racial origin
White 309 614
Black or African American 30 60
Asian 22 44
American Indian or Alaska Native 4 8
Native Hawaiian or other Pacific Islander 3 6
Multiracial 10 20
Total 378 752
Ethnic origin
Hispanic/Latino 49 98
090177e19a14c996\Final\Final On: 29-Apr-2022 17:55 (GMT)
FDA-CBER-2022-5812-0235839
BNT162b2
1.16 Risk Management Plan (Non-REMS) for Biologic License Application # 125742
CONFIDENTIAL
Page 32
Table 15. Exposure to BNT162b2 by Age Group, Dose, and Race/Ethnic Origin
(C4591001) – Blinded Placebo -Controlled Follow -up Period
Age Group
Dose
Race/Ethnic Origin Number of Subjects
Exposed to BNT162b2 Total Number of
Vaccine Doses
Non-Hispanic/non -Latino 329 654
Total 378 752
≥18 years to ≤55 years
Vaccine 10 µg
Racial origin
White 11 22
Asian 1 2
Total 12 24
Ethnic origin
Hispanic/Latino 1 2
Non-Hispanic/non -Latino 11 22
Total 12 24
Vaccine 20 µg
Racial origin
White 10 20
Black or African American 2 4
Total 12 24
Ethnic origin
Hispanic/Latino 1 2
Non-Hispanic/non -Latino 11 22
Total 12 24
Vaccine 30 µg
Racial origin
White 9923 19637
Black or African American 1400 2764
Asian 683 1358
American Indian or Alaska Native 161 311
Native Hawaiian or other Pacific Islander 40 80
Multiracial 427 851
Not reported 71 142
Total 12705 25143
Ethnic origin
Hispanic/Latino 4000 7874
Non-Hispanic/non -Latino 8650 17160
Not reported 55 109
Total 12705 25143
>55 years to ≤64 years
Vaccine 30 µg
Racial origin
090177e19a14c996\Final\Final On: 29-Apr-2022 17:55 (GMT)
FDA-CBER-2022-5812-0235840
BNT162b2
1.16 Risk Management Plan (Non-REMS) for Biologic License Application # 125742
CONFIDENTIAL
Page 33
Table 15. Exposure to BNT162b2 by Age Group, Dose, and Race/Ethnic Origin
(C4591001) – Blinded Placebo -Controlled Follow -up Period
Age Group
Dose
Race/Ethnic Origin Number of Subjects
Exposed to BNT162b2 Total Number of
Vaccine Doses
White 3719 7388
Black or African American 430 849
Asian 135 267
American Indian or Alaska Native 30 58
Native Hawaiian or other Pacific Islander 8 15
Multiracial 76 152
Not reported 10 20
Total 4408 8749
Ethnic origin
Hispanic/Latino 965 1903
Non-Hispanic/non -Latino 3413 6786
Not reported 30 60
Total 4408 8749
≥65 years to ≤74 years
Vaccine 10 µg
Racial origin
White 12 24
Total 12 24
Ethnic origin
Non-Hispanic/non -Latino 12 24
Total 12 24
Vaccine 20 µg
Racial origin
White 9 18
Total 9 18
Ethnic origin
Non-Hispanic/non -Latino 9 18
Total 9 18
Vaccine 30 µg
Racial origin
White 3272 6528
Black or African American 219 437
Asian 82 164
American Indian or Alaska Native 22 44
Native Hawaiian or other Pacific Islander 6 12
Multiracial 30 60
Not reported 10 20
Total 3641 7265
Ethnic origin
090177e19a14c996\Final\Final On: 29-Apr-2022 17:55 (GMT)
FDA-CBER-2022-5812-0235841
BNT162b2
1.16 Risk Management Plan (Non-REMS) for Biologic License Application # 125742
CONFIDENTIAL
Page 34
Table 15. Exposure to BNT162b2 by Age Group, Dose, and Race/Ethnic Origin
(C4591001) – Blinded Placebo -Controlled Follow -up Period
Age Group
Dose
Race/Ethnic Origin Number of Subjects
Exposed to BNT162b2 Total Number of
Vaccine Doses
Hispanic/Latino 583 1158
Non-Hispanic/non -Latino 3038 6067
Not reported 20 40
Total 3641 7265
≥75 years to ≤84 years
Vaccine 20 µg
Racial origin
White 3 6
Total 3 6
Ethnic origin
Non-Hispanic/non -Latino 3 6
Total 3 6
Vaccine 30 µg
Racial origin
White 838 1673
Black or African American 22 44
Asian 31 62
American Indian or Alaska Native 3 6
Native Hawaiian or other Pacific Islander 1 2
Multiracial 7 14
Total 902 1801
Ethnic origin
Hispanic/Latino 107 213
Non-Hispanic/non -Latino 789 1576
Not reported 6 12
Total 902 1801
≥85 years
Vaccine 30 µg
Racial origin
White 20 38
Asian 1 2
American Indian or Alaska Native 1 2
Multiracial 1 2
Total 23 44
Ethnic origin
Hispanic/Latino 2 4
Non-Hispanic/non -Latino 21 40
Total 23 44
090177e19a14c996\Final\Final On: 29-Apr-2022 17:55 (GMT)
FDA-CBER-2022-5812-0235842
BNT162b2
1.16 Risk Management Plan (Non-REMS) for Biologic License Application # 125742
CONFIDENTIAL
Page 35
Table 15. Exposure to BNT162b2 by Age Group, Dose, and Race/Ethnic Origin
(C4591001) – Blinded Placebo -Controlled Follow -up Period
Age Group
Dose
Race/Ethnic Origin Number of Subjects
Exposed to BNT162b2 Total Number of
Vaccine Doses
Note: 30 μg includes data from phase 1 and phase 2/3.
PFIZER CONFIDENTIAL SDTM Creation: 25MAR2021 (23:24) Source Data: adsl Table Generation:
27MAR2021 (12:46)
(Cutoff Date: 13MAR2021, Snapshot Date: 25MAR2021) Output File:
./nda2_unblinded/C4591001_PVP_BLA/adsl_s942
Table 16. Exposure to BNT162b2 by Age Group, Dose, and Race/Ethnic Origin
(C4591001) – Open-Label Follow -up Period – Subjects Who Originally
Received BNT162b2
Age Group
Dose
Race/Ethnic Origin Number of Subjects
Exposed to BNT162b2 Total Number of
Vaccine Doses
≥16 years to ≤17 years
Vaccine 30 µg
Racial origin
White 3 3
Total 3 3
Ethnic origin
Non-Hispanic/non -Latino 3 3
Total 3 3
≥18 years to ≤55 years
Vaccine 30 µg
Racial origin
White 46 46
Black or African American 2 2
Asian 2 2
American Indian or Alaska Native 8 8
Total 58 58
Ethnic origin
Hispanic/Latino 31 31
Non-Hispanic/non -Latino 27 27
Total 58 58
>55 years to ≤64 years
Vaccine 30 µg
Racial origin
White 14 14
Asian 1 1
American Indian or Alaska Native 2 2
Total 17 17
090177e19a14c996\Final\Final On: 29-Apr-2022 17:55 (GMT)
FDA-CBER-2022-5812-0235843
BNT162b2
1.16 Risk Management Plan (Non-REMS) for Biologic License Application # 125742
CONFIDENTIAL
Page 36
Table 16. Exposure to BNT162b2 by Age Group, Dose, and Race/Ethnic Origin
(C4591001) – Open-Label Follow -up Period – Subjects Who Originally
Received BNT162b2
Age Group
Dose
Race/Ethnic Origin Number of Subjects
Exposed to BNT162b2 Total Number of
Vaccine Doses
Ethnic origin
Hispanic/Latino 10 10
Non-Hispanic/non -Latino 7 7
Total 17 17
≥65 years to ≤74 years
Vaccine 30 µg
Racial origin
White 8 8
Total 8 8
Ethnic origin
Hispanic/Latino 5 5
Non-Hispanic/non -Latino 3 3
Total 8 8
≥75 years to ≤84 years
Vaccine 30 µg
Racial origin
White 1 1
Total 1 1
Ethnic origin
Non-Hispanic/non -Latino 1 1
Total 1 1
≥85 years
Vaccine 30 µg
Racial origin
White 2 2
Total 2 2
Ethnic origin
Non-Hispanic/non -Latino 2 2
Total 2 2
Note: 30 μg includes data from phase 1 and phase 2/3.
Note: Subjects who received 2nd Dose of BNT162b2 after unblinding.
PFIZER CONFIDENTIAL SDTM Creation: 25MAR2021 (23:24) Source Data: adsl Table Generation:
27MAR2021 (12:46)
(Cutoff Date: 13MAR2021, Snapshot Date: 25MAR2021) Output File:
./nda2_unblinded/C4591001_PVP_BLA/adsl_s9423
090177e19a14c996\Final\Final On: 29-Apr-2022 17:55 (GMT)
FDA-CBER-2022-5812-0235844
BNT162b2
1.16 Risk Management Plan (Non-REMS) for Biologic License Application # 125742
CONFIDENTIAL
Page 37
Table 17. Exposure to BNT162b2 by Age Group, Dose, and Race/Ethnic Origin
(C4591001) – Open-Label Follow -up Period – Subjects Who Originally
Received Placebo and Then Received BNT162b2 After Unblinding
Age Group
Dose
Race/Ethnic Origin Number of Subjects
Exposed to BNT162b2 Total Number of
Vaccine Doses
≥12 years to ≤15 yearsa
Vaccine 30 µg
Racial origin
White 45 62
Asian 3 5
Multiracial 1 1
Total 49 68
Ethnic origin
Hispanic/Latino 2 4
Non-Hispanic/non -Latino 47 64
Total 49 68
≥16 years to ≤17 years
Vaccine 30 µg
Racial origin
White 251 410
Black or African American 11 19
Asian 14 25
American Indian or Alaska Native 2 4
Native Hawaiian or other Pacific Islander 1 2
Multiracial 12 16
Not reported 2 3
Total 293 479
Ethnic origin
Hispanic/Latino 26 43
Non-Hispanic/non -Latino 266 434
Not reported 1 2
Total 293 479
≥18 years to ≤55 years
Vaccine 30 µg
Racial origin
White 8806 15340
Black or African American 1087 1899
Asian 619 1136
American Indian or Alaska Native 128 236
Native Hawaiian or other Pacific Islander 17 32
Multiracial 405 781
Not reported 70 127
Total 11132 19551
Ethnic origin
090177e19a14c996\Final\Final On: 29-Apr-2022 17:55 (GMT)
FDA-CBER-2022-5812-0235845
BNT162b2
1.16 Risk Management Plan (Non-REMS) for Biologic License Application # 125742
CONFIDENTIAL
Page 38
Table 17. Exposure to BNT162b2 by Age Group, Dose, and Race/Ethnic Origin
(C4591001) – Open-Label Follow -up Period – Subjects Who Originally
Received Placebo and Then Received BNT162b2 After Unblinding
Age Group
Dose
Race/Ethnic Origin Number of Subjects
Exposed to BNT162b2 Total Number of
Vaccine Doses
Hispanic/Latino 3441 5300
Non-Hispanic/non -Latino 7635 14157
Not reported 56 94
Total 11132 19551
>55 years to ≤64 years
Vaccine 30 µg
Racial origin
White 3416 6271
Black or African American 331 592
Asian 120 227
American Indian or Alaska Native 35 67
Native Hawaiian or other Pacific Islander 4 7
Multiracial 63 120
Not reported 16 31
Total 3985 7315
Ethnic origin
Hispanic/Latino 901 1560
Non-Hispanic/non -Latino 3067 5724
Not reported 17 31
Total 3985 7315
≥65 years to ≤74 years
Vaccine 30 µg
Racial origin
White 3093 6076
Black or African American 187 360
Asian 78 154
American Indian or Alaska Native 20 39
Native Hawaiian or other Pacific Islander 6 12
Multiracial 22 43
Not reported 8 16
Total 3414 6700
Ethnic origin
Hispanic/Latino 547 1060
Non-Hispanic/non -Latino 2842 5590
Not reported 25 50
Total 3414 6700
≥75 years to ≤84 years
Vaccine 30 µg
090177e19a14c996\Final\Final On: 29-Apr-2022 17:55 (GMT)
FDA-CBER-2022-5812-0235846
BNT162b2
1.16 Risk Management Plan (Non-REMS) for Biologic License Application # 125742
CONFIDENTIAL
Page 39
Table 17. Exposure to BNT162b2 by Age Group, Dose, and Race/Ethnic Origin
(C4591001) – Open-Label Follow -up Period – Subjects Who Originally
Received Placebo and Then Received BNT162b2 After Unblinding
Age Group
Dose
Race/Ethnic Origin Number of Subjects
Exposed to BNT162b2 Total Number of
Vaccine Doses
Racial origin
White 752 1483
Black or African American 22 42
Asian 17 34
American Indian or Alaska Native 4 8
Multiracial 6 12
Not reported 5 10
Total 806 1589
Ethnic origin
Hispanic/Latino 89 174
Non-Hispanic/non -Latino 706 1393
Not reported 11 22
Total 806 1589
≥85 years
Vaccine 30 µg
Racial origin
White 15 29
Asian 1 2
Multiracial 1 2
Total 17 33
Ethnic origin
Non-Hispanic/non -Latino 17 33
Total 17 33
Note: 30 μg includes data from phase 1 and phase 2/3.
a. Includes subjects who became eligible for unblinding at 16 years of age, confirmed to have received
placebo originally and then received BNT162b2 post unblinding.
PFIZER CONFIDENTIAL SDTM Creation: 25MAR2021 (23:24) Source Data: adsl Table Generation:
27MAR2021 (12:46)
(Cutoff Date: 13MAR2021, Snapshot Date: 25MAR2021) Out put File:
./nda2_unblinded/C4591001_PVP_BLA/adsl_s942_open
Table 18. Exposure to BNT162b2 by Dose and Race/Ethnic Origin (C4591001) –
Blinded Placebo -Controlled Follow -up Period
Dose
Race/Ethnic Origin Number of Subjects
Exposed to BNT162b2 Total Number of
Vaccine Doses
Vaccine 10 µg
Racial origin
White 23 46
090177e19a14c996\Final\Final On: 29-Apr-2022 17:55 (GMT)
FDA-CBER-2022-5812-0235847
BNT162b2
1.16 Risk Management Plan (Non-REMS) for Biologic License Application # 125742
CONFIDENTIAL
Page 40
Table 18. Exposure to BNT162b2 by Dose and Race/Ethnic Origin (C4591001) –
Blinded Placebo -Controlled Follow -up Period
Dose
Race/Ethnic Origin Number of Subjects
Exposed to BNT162b2 Total Number of
Vaccine Doses
Asian 1 2
Total 24 48
Ethnic origin
Hispanic/Latino 1 2
Non-Hispanic/non -Latino 23 46
Total 24 48
Vaccine 20 µg
Racial origin
White 22 44
Black or African American 2 4
Total 24 48
Ethnic origin
Hispanic/Latino 1 2
Non-Hispanic/non -Latino 23 46
Total 24 48
Vaccine 30 µg
Racial origin
White 19052 37815
Black or African American 2153 4257
Asian 1026 2040
American Indian or Alaska Native 225 437
Native Hawaiian or other Pacific Islander 61 121
Multiracial 574 1145
Not reported 97 194
Total 23188 46009
Ethnic origin
Hispanic/Latino 5838 11513
Non-Hispanic/non -Latino 17237 34271
Not reported 113 225
Total 23188 46009
Note: 30 μg includes data from phase 1 and phase 2/3.
PFIZER CONFIDENTIAL SDTM Creation: 25MAR2021 (23:24) Source Data: adsl Table Generation:
27MAR2021 (12:47)
(Cutoff Date: 13MAR2021, Snapshot Date: 25MAR2021) Output File:
./nda2_unblinded/C4591001_PVP_BLA/adsl_s952
090177e19a14c996\Final\Final On: 29-Apr-2022 17:55 (GMT)
FDA-CBER-2022-5812-0235848
BNT162b2
1.16 Risk Management Plan (Non-REMS) for Biologic License Application # 125742
CONFIDENTIAL
Page 41
Table 19. Exposure to BNT162b2 by Dose and Race/Ethnic Origin (C4591001) –
Open-Label Follow -up Period – Subjects Who Originally Received
BNT162b2
Dose
Race/Ethnic Origin Number of Subjects
Exposed to BNT162b2 Total Number of
Vaccine Doses
Vaccine 30 µg
Racial origin
White 74 74
Black or African American 2 2
Asian 3 3
American Indian or Alaska Native 10 10
Total 89 89
Ethnic origin
Hispanic/Latino 46 46
Non-Hispanic/non -Latino 43 43
Total 89 89
Note: 30 μg includes data from phase 1 and phase 2/3.
Note: Subjects who received 2nd Dose of BNT162b2 after unblinding.
PFIZER CONFIDENTIAL SDTM Creation: 25MAR2021 (23:24) Source Data: adsl Table Generation:
27MAR2021 (12:47)
(Cutoff Date: 13MAR2021, Snapshot Date: 25MAR2021) Output File:
./nda2_unblinded/C4591001_PVP_BLA/adsl_s9523
Table 20. Exposure to BNT162b2 by Dose and Race/Ethnic Origin (C4591001) –
Open-Label Follow -up Period – Subjects Who Originally Received Placebo
and Then Received BNT162b2 After Unblinding
Dose
Race/Ethnic Origin Number of Subjects
Exposed to BNT162b2 Total Number of
Vaccine Doses
Vaccine 30 µg
Racial origin
White 16378 29671
Black or African American 1638 2912
Asian 852 1583
American Indian or Alaska Native 189 354
Native Hawaiian or other Pacific Islander 28 53
Multiracial 510 975
Not reported 101 187
Total 19696 35735
Ethnic origin
Hispanic/Latino 5006 8141
Non-Hispanic/non -Latino 14580 27395
Not reported 110 199
Total 19696 35735
090177e19a14c996\Final\Final On: 29-Apr-2022 17:55 (GMT)
FDA-CBER-2022-5812-0235849
BNT162b2
1.16 Risk Management Plan (Non-REMS) for Biologic License Application # 125742
CONFIDENTIAL
Page 42
Table 20. Exposure to BNT162b2 by Dose and Race/Ethnic Origin (C4591001) –
Open-Label Follow -up Period – Subjects Who Originally Received Placebo
and Then Received BNT162b2 After Unblinding
Dose
Race/Ethnic Origin Number of Subjects
Exposed to BNT162b2 Total Number of
Vaccine Doses
Note: 30 μg includes data from phase 1 and phase 2/3.
PFIZER CONFIDENTIAL SDTM Creation: 25MAR2021 (23:24) Source Data: adsl Table Generation:
27MAR2021 (12:47)
(Cutoff Date: 13MAR2021, Snapshot Date: 25MAR2021) Output File:
./nda2_unblinded/C4591001_PVP_BLA/adsl_s952_open
Table 21. Exposure to BNT162b2 by Dose and Race/Ethnic Origin (BNT162-01)
Dose
Race/Ethnic Origin No. of Subjects Exposed to
BNT162b2 Total No. of Vaccine Doses
Vaccine 1 µg
Racial Origin
White 12 23
Total 12 23
Ethnic Origin
Non-Hispanic/non -Latino 12 23
Total 12 23
Vaccine 3 µg
Racial Origin
White 12 24
Total 12 24
Ethnic Origin
Non-Hispanic/non -Latino 12 24
Total 12 24
Vaccine 10 µg
Racial Origin
White 24 47
Total 24 47
Ethnic Origin
Non-Hispanic/non -Latino 24 47
Total 24 47
Vaccine 20 µg
Racial Origin
White 24 48
Total 24 48
Ethnic Origin
090177e19a14c996\Final\Final On: 29-Apr-2022 17:55 (GMT)
FDA-CBER-2022-5812-0235850
BNT162b2
1.16 Risk Management Plan (Non-REMS) for Biologic License Application # 125742
CONFIDENTIAL
Page 43
Table 21. Exposure to BNT162b2 by Dose and Race/Ethnic Origin (BNT162-01)
Dose
Race/Ethnic Origin No. of Subjects Exposed to
BNT162b2 Total No. of Vaccine Doses
Non-Hispanic/non -Latino 24 48
Total 24 48
Vaccine 30 µg
Racial Origin
White 24 48
Total 24 48
Ethnic Origin
Non-Hispanic/non -Latino 24 48
Total 24 48
Only race, ethnic origins collected on the case report form with a count of at least one in either column are displayed.
PFIZER CONFIDENTIAL SDTM Creation: 24NOV2020 (15:06) Source Data: adsl Table Generation: 10MAR2021
(12:27) (Cutoff date:23OCT2020, Snapshot Date: 23OCT2020)
Output File: ex_b2_dose_racertf
Table 22. Exposure to BNT162b2 (30 μg) by Special Population (C4591001) – Blinded
Placebo-Controlled Follow -up Period
Population Number of Subjects
Exposed
to BNT162b2 (30 μg)
(Na=23188)
nb Total Number
of
Vaccine Doses
Subjects with any baseline comorbidity 10371 26487
AIDS/HIV 100 196
Any Malignancy + Metastatic Solid Tumor + Leukemia +
Lymphoma 852 1696
Chronic Pulmonary Disease 1901 3774
Renal Disease 140 279
Rheumatic Disease 75 147
Mild Liver Disease + Moderate or Severe Liver Disease 154 302
Cerebrovascular Disease + Peripheral Vascular Disease +
Myocardial Infarction + Congestive Heart Failure 651 1298
Dementia 7 14
Diabetes With/Without Chronic Complication 1706 3385
Hemiplegia or Paraplegia 4 8
Peptic Ulcer Disease 63 126
Obese 7689 15262
Note: Comorbidity is based on Charlson Comorbidity Index categories. Participants identified as belonging to
these categories were identified by medical history data collected during the study.
Note: 30 μg includes data from phase 1 and phase 2/3.
Note: Hemiplegia or Paraplegia only includes preferred terms Hemiplegia and Paraplegia.
a. N = number of subjects in the specified group.
090177e19a14c996\Final\Final On: 29-Apr-2022 17:55 (GMT)
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Table 22. Exposure to BNT162b2 (30 μg) by Special Population (C4591001) – Blinded
Placebo-Controlled Follow -up Period
Population Number of Subjects
Exposed
to BNT162b2 (30 μg)
(Na=23188)
nb Total Number
of
Vaccine Doses
b. n = Number of subjects reporting at least 1 occurrence of any comorbidity or obese (BMI ≥30 kg/m2 [≥16
Years of age] or BMI ≥95th percentile [12 -15 Years of age]).
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(Cutoff Date: 13MAR2021, Snapshot Date: 25MAR2021) Output File:
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Table 23. Exposure to BNT162b2 (30 μg) by Special Population (C4591001) – Open-
Label Follow -up Period – Subjects Who Originally Received Placebo and
Then Received BNT162b2 After Unblinding
Population Number of Subjects
Exposed
to BNT162b2 (30 μg)
(Na=19696)
nb Total Number
of
Vaccine Doses
Subjects with any baseline comorbidity 8981 21590
AIDS/HIV 86 161
Any Malignancy + Metastatic Solid Tumor + Leukemia +
Lymphoma 734 1406
Chronic Pulmonary Disease 1590 2953
Renal Disease 139 262
Rheumatic Disease 66 122
Mild Liver Disease + Moderate or Severe Liver Disease 102 193
Cerebrovascular Disease + Peripheral Vascular Disease +
Myocardial Infarction + Congestive Heart Failure 567 1075
Dementia 9 17
Diabetes With/Without Chronic Complication 1555 2928
Hemiplegia or Paraplegia 4 8
Peptic Ulcer Disease 76 145
Obese 6760 12320
Note: Comorbidity is based on Charlson Comorbidity Index categories. Participants identified as belonging to
these categories were identified by medical history data collected during the study.
Note: 30 μg includes data from phase 1 and phase 2/3.
Note: Hemiplegia or Paraplegia only includes preferred terms Hemiplegia and Paraplegia.
a. N = number of subjects in the specified group.
b. n = Number of subjects reporting at least 1 occurrence of any comorbidity or obese (BMI ≥30 kg/m2 [≥16
Years of age] or BMI ≥95th percentile [12 -15 Years of age]).
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Table 23. Exposure to BNT162b2 (30 μg) by Special Population (C4591001) – Open-
Label Follow -up Period – Subjects Who Originally Received Placebo and
Then Received BNT162b2 After Unblinding
Population Number of Subjects
Exposed
to BNT162b2 (30 μg)
(Na=19696)
nb Total Number
of
Vaccine Doses
(Cutoff Date: 13MAR2021, Snapshot Date: 25MAR2021) Output File:
./nda2_unblinded/ C4591001_PVP_BLA/admh_s953_open
Exposure in participants 12-15 years of age – (Study C4591001 -6-month follow -up
period – Cut-off date 02 September 2021)
Table 24. Exposure to BNT162b2 by Dose (Totals) (C4591001) – 12-15 Years –
Blinded Placebo -Controlled Follow -up Period
Dose
Exposure (Number of Doses Received) Number of Subjects
Exposed to BNT162b2 Total Number of
Vaccine Doses
Vaccine 30 µg
1 Dose 7 7
2 Doses 1124 2248
Total 1131 2255
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Table 25. Exposure to BNT162b2 by Dose (Totals) (C4591001) – 12-15 Years – Open-
Label Follow -up Period – Subjects Who Originally Received Placebo and
Then Received BNT162b2 After Unblinding
Dose
Exposure (Number of Doses Received) Number of Subjects
Exposed to BNT162b2 Total Number of
Vaccine Doses
Vaccine 30 µg
1 Dose 18 18
2 Doses 992 1984
Total 1010 2002
Note: Includes subjects who became eligible for unblinding at 16 years of age, confirmed to have received
placebo originally and then received BNT162b2 post unblinding.
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Table 25. Exposure to BNT162b2 by Dose (Totals) (C4591001) – 12-15 Years – Open-
Label Follow -up Period – Subjects Who Originally Received Placebo and
Then Received BNT162b2 After Unblinding
Dose
Exposure (Number of Doses Received) Number of Subjects
Exposed to BNT162b2 Total Number of
Vaccine Doses
04NOV2021 (12:52)
(Data Cutoff Date: 02SEP2021, Database Snapshot Date: 27SEP2021) Output File:
./nda2_unblinded/C4591001_PVP_adl6mpd2/adsl_s9222
Table 26. Exposure to BNT162b2 by Gender (C4591001) – 12-15 Years – Blinded
Placebo-Controlled Follow -up Period
Number of Subjects Exposed to
BNT162b2 Total Number of Vaccine Doses
Dose
Age Groupa Male Female Male Female
Vaccine 30 µg
≥12 years to ≤15
years 567 564 1128 1127
a. Based on age at vaccination.
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Table 27. Exposure to BNT162b2 by Gender (C4591001) – 12-15 Years – Open-
Label Follow -up Period – Subjects Who Originally Received Placebo and
Then Received BNT162b2 After Unblinding
Number of Subjects Exposed to
BNT162b2 Total Number of Vaccine Doses
Dose
Age Groupa Male Female Male Female
Vaccine 30 µg
≥12 years to ≤15
years 518 492 1027 975
a. Based on age at vaccination. Includes subjects who became eligible for unblinding at 16 years of age,
confirmed to have received placebo originally and then received BNT162b2 post unblinding.
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Table 27. Exposure to BNT162b2 by Gender (C4591001) – 12-15 Years – Open-
Label Follow -up Period – Subjects Who Originally Received Placebo and
Then Received BNT162b2 After Unblinding
Number of Subjects Exposed to
BNT162b2 Total Number of Vaccine Doses
Dose
Age Groupa Male Female Male Female
(Data Cutoff Date: 02SEP2021, Database Snapshot Date: 27SEP2021) Output File:
./nda2_unblinded/C4591001_PVP_adl6mpd2/adsl_1215_s932_plac
Table 28. Exposure to BNT162b2 by Race/Ethnic Origin (C4591001) – 12-15 Years
– Blinded Placebo -Controlled Follow -up Period
Age Groupa
Dose
Race/Ethnic Origin Number of Subjects
Exposed to BNT162b2 Total Number of
Vaccine Doses
≥12 years to ≤15 years
Vaccine 30 µg
Racial origin
White 970 1935
Black or African American 52 103
Asian 72 143
American Indian or Alaska
Native 4 8
Native Hawaiian or other Pacific
Islander 3 6
Multiracial 24 48
Not reported 6 12
Total 1131 2255
Ethnic origin
Hispanic/Latino 132 263
Non-Hispanic/non -Latino 997 1988
Not reported 2 4
Total 1131 2255
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Table 28. Exposure to BNT162b2 by Race/Ethnic Origin (C4591001) – 12-15 Years
– Blinded Placebo -Controlled Follow -up Period
Age Groupa
Dose
Race/Ethnic Origin Number of Subjects
Exposed to BNT162b2 Total Number of
Vaccine Doses
a. Based on age at vaccination.
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Table 29. Exposure to BNT162b2 by Race/Ethnic Origin (C4591001) – 12-15 Years
– Open-Label Follow -up Period – Subjects Who Originally Received
Placebo and Then Received BNT162b2 After Unblinding
Age Groupa
Dose
Race/Ethnic Origin Number of Subjects
Exposed to BNT162b2 Total Number of
Vaccine Doses
≥12 years to ≤15 years
Vaccine 30 µg
Racial origin
White 866 1718
Black or African American 48 96
Asian 62 123
American Indian or Alaska
Native 2 3
Multiracial 26 52
Not reported 6 10
Total 1010 2002
Ethnic origin
Hispanic/Latino 115 222
Non-Hispanic/non -Latino 892 1774
Not reported 3 6
Total 1010 2002
a. Based on age at vaccination. Includes subjects who became eligible for unblinding at 16 years of age,
confirmed to have received placebo originally and then received BNT162b2 post unblinding.
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Table 30. Exposure to BNT162b2 (30 μg) by Special Population (C4591001) – 12-15
Years – Blinded Placebo -Controlled Follow -up Period
Population Number of Subjects Exposed
to BNT162b2 (30 μg)
(Na=1131)
nb Total Number of
Vaccine Doses
Subjects with any baseline
comorbidity 249 494
Chronic Pulmonary Disease 119 235
Mild Liver Disease + Moderate or
Severe Liver Disease 2 4
Diabetes With/Without Chronic
Complication 2 4
Obese 143 284
Note: Includes subjects who became eligible for unblinding at 16 years of age.
Note: Comorbidity is based on Charlson Comorbidity Index categories. Participants identified as belonging
to these categories were identified by medical history data collected during the study.
Note: Hemiplegia o r Paraplegia only includes preferred terms Hemiplegia and Paraplegia. No participants
were identified.
a. N = number of subjects in the specified group.
b. n = Number of subjects reporting at least 1 occurrence of any comorbidity or obese (BMI
≥95th percentile [12 -15 Years of age]).
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Table 31. Exposure to BNT162b2 (30 μg) by Special Population (C4591001) – 12-15
Years – Open-Label Follow -up Period – Subjects Who Originally
Received Placebo and Then Received BNT162b2 After Unblinding
Population Number of Subjects Exposed
to BNT162b2 (30 μg)
(Na=1010)
nb Total Number of
Vaccine Doses
Subjects with any baseline
comorbidity 214 425
Chronic Pulmonary Disease 114 226
Rheumatic Disease 2 4
Diabetes With/Without Chronic
Complication 2 4
Obese 116 229
Note: Includes subjects who became eligible for unblinding at 16 years of age.
Note: Includes subjects confirmed to have received placebo originally and then received BNT162b2 post
unblinding.
Note: Comorbidity is based on Charlson Comorbidity Index categories. Participants identified as belonging
to these categories were identified by medical history data collected during the study.
Note: Hemiplegia or Paraplegia only includes prefe rred terms Hemiplegia and Paraplegia. No participants
were identified.
a. N = number of subjects in the specified group.
b. n = Number of subjects reporting at least 1 occurrence of any comorbidity or obese ( BMI
≥95th percentile [12 -15 Years of ag e]).
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2.1.2.a.2. Inclusion and Exclusion Criteria
Detailed descriptions of all inclusion and exclusion criteria for clinical studies are provided
in the individual CSRs which were filed to IND 019736 .
Inclusion criteria
• Healthy participants who are determined by medical history, physical examination
(if required), and clinical judgment of the investigator to be eligible for inclusion in the
study.
• Healthy participants with pre -existing stable disease, defined as disease not requiring
significant change in therap y or hospitalization for worsening disease during the 6 weeks
before enrollment, can be included. In order for the overall Phase 3 study population to
be as representative and diverse as possible, the inclusion of participants with known
chronic stable infection with HIV, HCV, or HBV was permitted as the study progressed.
Specific criteria for these Phase 3 participants can be found in the C4591001 protocol,
Section 10. 8.
• Phase 2/3 only: Participants who, in the judgment of the investigator, are at higher risk
for acquiring COVID -19 (including, but not limited to, use of mass transportation,
relevant demographics, front-line essential workers , and others).
• The participants enrolled were 1 2 years of age and older; the 12- to 15-year -old cohort
was included in the protocol in October 2020.
Exclusion criteria
Phase 1 exclusion criteria were stricter than criteria in Phases 2 and 3 of the study.
Participants were excluded from the studies according to the general criteria listed below :
• Previous vaccination with any coronavirus vaccine
Reason for exclusion: To avoid confounding the assessment of serological or clinic al
immune response in the study population.
Is it considered to be included as missing information ? No.
Rationale: Minimal potential clinical impact on the target population .
• Previous clinical or microbiological diagnosis of COVID -19
Reason for exclusion: Phase 1 excluded participants with a previous clinical or
microbiol ogical diagnosis of COVID -19 because these participants may have some
degree of protection from subsequent infection by SARS -CoV-2 and therefore would
confound the pivotal efficacy endpoint. During Phase 2/3, participants with prior
undiagnosed infection were allowed to be enrolled. Screening for SAR S-CoV-2 with
nucleic acid amplificat ion test by nasal swab or antibodies to non-vaccine SARS -CoV-2
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antigen by serology was not conducted before vaccine administration in Phase 2/3, but
samples were taken to run these assays after vaccination, thus identifying participants
with unidentified prior infection. This group will be assessed to identify whether prior
infection affect s safety.
Is it considered to be included as missing information? No.
Rationale : Safety in study participants with prior infection will be assessed in the pivotal
study.
• Immunocompromised individuals with known or suspected immunodeficiency, as
determined by history and/or laboratory/physical examination .
Reason for exclusion: Immunocompromised participants may have impaired immune
responses to vaccines and would therefore limit the ability to demonstrate efficacy, which is the primary pivotal endpoint.
Is it considered to be included as missing information ? No.
Rationale: Participants with potential immunodeficient status were not specifically
included in the study population. However, since the study population is intended to be
as representative as possible of the vulnerable population to COVI D-19 illness ,
sub-analyses of immunogenicity data in future studies may provide further understanding
of immune responses in this population .
• Receipt of blood/plasma products or immunoglobulin, from 60 days before study intervention administration or planned receipt throughout the study
Reason for exclusion: To avoid confounding the assessment of serological or clinical
immune response in the study population.
Is it considered to be included as missing information? No.
Rationale : No impact on the safety of the target population.
• Women who are pregnant or breastfeeding
Reason for exclusion: To avoid use in a vulnerable population.
Is it considered to be included as missing information? Yes.
Rationale : Maternal vaccination with COVID -19 mRNA vaccine is being studies in
C4591015 to explore unexpected negative consequences to the embryo or foetus .
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• Other medical or psychiatric condition including recent (within the past year) or
active suicidal ideation/behavior or laboratory abnormality that may increase the
risk of study participation or, in the investigator’s judgment, make the participant
inappropriate for the study
Reason for exclus ion: To avoid misleading results deriving from non-compliance to
study procedures .
Is it considered to be included as missing information? No .
Rationale : Safety profile of BNT162b2 is not expected to differ in these subjects when
properly administered.
2.1.2.a.2.1. Non-Study Post -Authorization Exposure
Cumulatively, through 30 September 2021, approximately 1,709,812,866 doses of
BNT162b2 were shipped worldwide, corresponding to approximately 1,402,241,841
estimated administered doses.
The worldwide number of shipped doses may serve as a reasonable indicator of subject exposure, considering that approximately 82% of the shipped doses were administered.
The estimated cumulative number of shipped and administered doses of BNT162b2 by
region based on data provided in the shipment tracker (Order Book),
3 from the receipt of the
first temporary authori zation for emergency supply on 01 December 2020 through 30
September 2021, are summarized in Table 32.
Table 32. Cumulative Estimated Shipped/Administered Doses of BNT162b2 by
Region Worldwide
Region/Country/Other % of Doses Total Number of
Shipped Doses Total Number of
Administered Doses
Europe 41.1% 703267110 571473911
European Uniona (27) 30.0% 513505785 415939686
Additional EEA Countriesa
(3) 0.4% 7006155 5674986
Switzerlanda 0.3% 4500990 3690812
UKb 3.6% 61213230 50194849
Other Countriesc 6.3% 107217045 87917977
Commonwealth of
Independent Statesd 0.6% 9823905 8055602
North Americae 18.5% 316093695 264597240
US 15.8% 270020505 226817224
Canada 2.7% 46073190 37780016
Central and South Americaf 12.5% 213085680 174730258
3 The Order Book is the most accurate tracker of shipment used as data source for all the Regions and
Countries; US shipment data not available in the Order Book were taken from the Order Management
Dashboard and data for Fosun License Partner territories, Hong Kong and Macau, were provided by BioNTech.
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Table 32. Cumulative Estimated Shipped/Administered Doses of BNT162b2 by
Region Worldwide
Region/Country/Other % of Doses Total Number of
Shipped Doses Total Number of
Administered Doses
Asia 23.6% 404077581 331343616
Japana 10.7% 183498120 150468458
Other Countriesg 12.9% 220579461 180875158
Oceania 1.4% 23158980 18990364
Australia/New Zealanda 1.4% 23158980 18990364
Other Countries 0.0% 0 0
Africah 2.9% 50129820 41106452
Total 100.0% 1709812866 1402241841
a. In this Region BNT162b2 was conditionally approved;
b. In the UK, both the authori zation for emergency supply under regulation 174 and the conditional
marketing authori zation approval are currently active for BNT162b2.
c. Includes Albania, Kosovo and North Macedonia where BNT162b2 was conditionally approved , Serbia
where it received authorization for emergency supply, Bosnia where it was shipped for COVAX, Turkey
where it was shipped according to a pharmacovigilance agreement in place by the MAH and the Turkish
government;
d. Includes Georgia and Ukraine where BNT162b2 received authorization for emergency supply and
Moldova where it was conditionally approved; in Azerbaijan BNT162b2 was shipped for COVAX, and
Tajikistan and Uzbekistan are part of US government donations;
e. In this Region BNT162b2 initially received authorization for emergency supply; in the US, a full
approval ( BLA) was also granted on 23 August 2021 and in Canada a full approval (NDS) replacing the
pre-existing authorization for emergency supply was granted during the current reporting period on
16 September 2021 ;
f. Includes Chile, Colombia, Costa Rica, Dominican Republic, Ecuador, El Salvador, Honduras, Mexico,
Panama, Paraguay and Uruguay where BNT162b2 received authori zation for emergency supply, Arge ntina,
Brazil and Peru where BNT162b2 was conditionally approved; Bolivia and Guatemala where BNT162b2 was
shipped for COVAX and Antigua&Barbuda, Bahamas, Barbados, Belize, Dominica, Grenada, Guyana,
Jamaica, St Kitts&Nevis, St. Lucia, StVin&Grenadine, Sur iname and Trinidad&Tobago that are part of US
Government donations;
g. Includes Bahrain, Bhutan, Indonesia, Iraq, Israel, Jordan, Kuwait, Lebanon, Macau, Maldives, Mongolia,
Oman, Pakistan, Palestine, Philippines, Qatar, Saudi Arabia, Singapore, Sri Lanka, United Arab Emirates and
Vietnam where BNT162b2 received authorization for emergency supply ; Hong Kong, Malaysia, South Korea
and Thailand where BNT162b2 was conditionally approved and Bangladesh, Laos and West Bank & Gaza
where BNT162b2 was shipped for COVAX;
h. Includes Angola, Cape Verde, Chad, Ivory Coast, Lybia and Togo where BNT162b2 was shipped for
COVAX; Benin, Congo, Gabon, Namibia, Seychelles, Sierra Leone and Uganda that are parts of US Government donations ; Botswana, Egypt, Eswatini, Kenya, Mauritius, Morocco, Rwanda, South Africa and
Tunisia where BNT162b2 received authori zation for emergency supply.
Method Used to Calculate Exposure
Not applicable.
Exposure
Not applicable.
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2.1.2.a.3. Regulatory Actions Related to Safety
There were no withdrawals for safety reasons up to 30 Septemb er 2021.
2.1.2.b. Populations Not Studied in the Pre -Approval Phase
There has been limited exposure to BNT162b2 in some special populations and no
epidemiologic studies have been conducted in pregnant/lactating women, pediatric
participants (<12 years of age), and specific subpopulations that were initially excluded from
the BNT162b2 program.
Table 33. Exposure of Special Populations Included or not in Clinical Trial
Development Programs
Type of special population Exposure
Pregnant women Available data on BNT162b2 administered to pregnant women are
insufficient to inform on vaccine-associated risks in pregnancy. In a
reproductive and developmental toxicity study, no vaccine -related
adverse effects on female fertility, fetal development, o r postnatal
development were reported.
Participants 16 years of age and older
Through the cut-off date of 13 March 2021, there were 50 cases (52
events) originating from Study C4591001 in participant 16 years of
age and older , and all were unique pregnancies.
Participants 12 -15 years of age
Through the cut -off date of 02 September 2021, there w ere no CT
cases of pregnancies from study C4591001 in participants 12 -15 years
of age.
Breastfeeding women Breastfeeding women were not initially included in the BNT162b2
clinical development program .
Data are not available to assess the effects of BNT162b2 on the
breastfed infant or on milk production/excretion.
The developmental and health benefits of breastfeeding should be
considered along with the mother’s clinical need for BNT162b2 and
any potential adverse effects on the breastfed child from BNT162b2
or from the underlying maternal condition. For preventive vaccines,
the underlying maternal condition is susceptible to disease prevented
by the vaccine.
Participants 16 years of age and older
Through the cut-off date of 13 March 2021, there were no CT cases
indicative of exposure during breastfeeding from study C4591001 in
participants 16 years of age and older .
Participants 12 -15 years of age
Through the cut -off date of 02 September 2021, there were no CT
cases indicative of exposure during breastfeeding from study
C4591001 in participants 12 -15 years of age.
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Table 33. Exposure of Special Populations Included or not in Clinical Trial
Development Programs
Type of special population Exposure
Participants with relevant
comorbidities:
• Participants with hepatic
impairment
• Participants with renal impairment
• Participants with cardiovascular
disease
• Immunocompromised participants
• Participants with a disease
severity different from inclusion
criteria in CTs Healthy participants with pre -existing stable disease, defined as
disease not requiring significant change in therapy or hospitalization
for worsening disease during the 6 weeks before enrollment, were
included. This allowed enrollment of a proportion of participants
with common comorbidities such as cardiovascular diseases including
hypertension, chronic pulmonary diseases , asthma, chronic liver
disease, BMI >30 kg/m2, participants with stage 3 or worse chronic
kidney disease , and participants with varying disease severity .
Participants with potential immunodeficient status were not
specifically included in the study population .
Please refer to Table 22, Table 23, Table 30 and Table 31 for the
exposure of special populations.
Participants of different racial
and/or ethnic origin Please refer to Table 15, Table 16, Table 17, Table 18, Table 19,
Table 20, Table 21, Table 28 and Table 29 for exposure information
by ethnic origin from the studies.
Subpopulations carrying known and
relevant polymorphisms No data available .
Pediatric participants The safety and effectiveness of BNT162b2 in individuals younger
than 5 years of age have not been established.
Participants 16 to 17 years of age
A total of 671 pediatric participants 16 to 17 years of age received
BNT162b2 through the DLP of 13 March 2021 :
• 378 participants in the blinded -placebo controlled follow -up
period (Table 3).
• 293 partic ipants in the open -label follow -up period after the
unblinding ( Table 5).
Participants 12 to 15 years of age
One thousa nd one hundred thirty-one (1131) pediatric participants 12
to 15 years of age received in the blinded controlled follow-up period;
1010 participants , who originally received placebo, then received
BNT162b2 in the Open -Label Follow -up period after unblinding
through the cut-off date of 02 September 2021 (Table 24 and
Table 25).
Elderly (≥ 65 years old) The safety and effectiveness of BNT162b2 in elderly participants was
consistent with that seen in younger adult participants.
Clinical studies of BNT162b2 included a total of 8846 participants 65
years of age and over ; of these, 8827 were from study C4591001 ,
through the cut -off date of 13 March 2021:
• 4590 participants in the blinded-placebo controlled follow -
up period (Table 3)
• 4237 participants in the open -label follow -up period after
unblinding (Table 5).
Nineteen (19) participants 65 years of age and over were from study
BNT162-01 study through the cut -off date of 23 October 2020
(Table 6).
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Table 33. Exposure of Special Populations Included or not in Clinical Trial
Development Programs
Type of special population Exposure
Abbreviations: EUA = emergency use authorization; BMI = body mass index; COVID-19 = coronavirus
disease 2019; CT = clinical trial
2.1.2.c. Adverse Events / Adverse Reactions
2.1.2.c.1. Identification of Safety Concern in the Initial PVP Submission
2.1.2.c.1.1. Risks not Considered Important for Inclusion in the List of Safety Concerns
in the PVP
Not all potential or identified risks for the vaccine are considered to meet the level of
importance neces sitating inclusion in the list of safety concerns in the PVP:
• Risks with minimal and temporary clinical impact on patients (in relation to the severity
of the disease prevented) .
• The following reactogenicity events are identified risks not included in the list of safety
concerns in the PVP: Injection site pain, Fever, Chills, Fatigue, Headache, Muscle pain, and Joint pain.
• Very rare potential ri sks for any medicinal treatment, including vaccines, which are well
known to healthcare professionals are not included in the list of safety concerns.
2.1.2.c.2. Important Identified and Potential Risks and Missing Information
2.1.2.c.2.1. Presentation of Important Identified R isks and Important Potential Risks
Important Identified Risk s
Table 34. Myocarditis and Pericarditis
Potential
mechanisms,
evidence source and
strength of evidence A mechanism of action (MOA) by which the vaccine could cause myocarditis and
pericarditis has not been established. Nonclinical studies, protein sequence
analyses and animal studies in rats and non -human primates have not identified a
MOA. Hypotheses for MOA include an immune stimulated response (including the possibility of molecular mimicry), a general systemic inflammatory response
from vaccination or a hypersensitivity response.
Characterisation of
the risk
Participants 16 years of age and older
Data from the CT dataseta (cut-off date: 18 June 2021)
Two cases were retrieved with the myocarditis and pericarditis search strategyb in
the clinical trial dataset through the cut- off date of 18 June 2021. These cases
originated from Phase 3 clinical study C4591001 and are summarized below:
Myocarditis:
There were no cases reporting myocarditis as SAE.
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Table 34. Myocarditis and Pericarditis
Pericarditis (2 cases):
Two (2) serious adverse events [PT Pericarditis] were reported, both deemed not
related to study treatment by the Investigator.
Data from the safety database (cut-off date: 18 June 2021) :
Since the first temporary authorization for emergency supply under Regu lation 174
in the UK (01 December 2020) and through 18 June 2021, 823 potentially relevant
cases (0.3% of the total post -authorization dataset) were retrieved from the
Myocarditis and Pericarditis search strategy:b 490 cases reported events related to
myocarditis and 371 cases reported events related to pericarditis (in 38 of these
823 cases, the subjects developed both myocardi tis and pericarditis related events).
Myocarditis (490 cases):
These 490 cases were individually reviewed and assessed according to Brighton
Collaboration (BC) Myocarditis Case Definition and Level of Certainty
Classification (version 1.4.2, 30 May 2021), as shown in the Table below:
Brighton Collaboration Level Number of cases
BC 1 41
BC 2 44
BC 3 42
BC 4 337
BC 5 26
Total 490
Level 1 indicates a definitive case with the highest level of diagnostic certainty
of myocarditis, level 2 indicates a probable case, and level 3 indicates a possible
case. Level 4 is defined as “reported event of myocarditis with insufficient
evidence to meet the case definition” and Level 5 as not a case of myocarditis.
There were 464 cases meeting BC Leve l 1 to 4, which are presented below:
Country of incidence: Israel (135), US (78), Germany (76), UK (55), France (21),
Italy, Japan (13 each), Austria (10), Greece, Spain (8 each), Sweden (7), Canada,
Norway (6 each), Ireland (5); the remaining 23 cases originated from 17 different
countries.
Gender: Females (133), Males (325), Unknown (6).
Age (n=443) ranged from 16 to 97 years (mean = 37.2 years, median = 32.0 years).
Reported relevant PTs: Myocarditis (463) and Autoimmune myocarditis (1).
Overall even t seriousness and outcome of these 464 cases are summarized below.
Total Events
N = 464 (%)
Serious events 459 (98.9)
Events with Criterion of Hospitalization 337 (72.6)
Distribution of events by Outcome
Outcome: Death 14 (3.0)
Outcome: Resolved/Resolving 149 (32.1)
Outcome: Not resolved 106 (22.8)
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Table 34. Myocarditis and Pericarditis
Outcome: Resolved with sequelae 10 (2.2)
Outcome: Unknown/No data 185 (39.9)
Pericarditis (371 cases)
Country of incidence: US (68), France (62), Israel (50), UK (38), Italy (33),
Norway, Spain (24 each), Canada (10), Australia (9), Greece (7), Germany (6), Belgium, Denmark, Netherlands, Switzerland (5 each); the remaining 20 cases
originated from 11 different countries.
Gender: Females (185), Males (181), Unknown (5).
Age (n=335) ranged from 16 to 92 years (mean = 51.5 years, median = 51.0 years).
Reported relevant PTs: Pericarditis (360) and Pleuropericarditis (12).
Overall event seriousness and outcome of these 371 cases are summarized below.
Total Events
N = 372 (%)
Serious events 370 (99.5)
Events with Criterion of Hospitalization 206 (55.4)
Distribution of events by Outcome
Outcome: Death 3 (0.8)
Outcome: Resolved/Resolving 213 (57.3)
Outcome: Not resolved 63 (16.9)
Outcome: Resolved with sequelae 7 (1.9)
Outcome: Unknown/No data 86 (23.1)
Participants 12 to 15 years of age
Data from the CT database (cut-off date 02 September 2021) :
One (1) case was retrieved with the Myocarditis and Pericarditis search strategyb in
the CT database through the cut -off date of 02 September 2021. This case
originated from the clinical study C4591001.
Myocarditis (1 case):
One (1) SAE (PT Myocarditis) was reported 3 days after the administration of the
second dose of BNT162b2 ; the participant recovered the following day. The SAE
was deemed not re lated to study treatment by the investigator.
Pericarditis:
There were no cases reporting pericarditis as SAE.
Data from the safety database (cut-off date 30 September 2021) :
Through 30 September 2021, 180 potentially relevant cases (0.03% of the total
post-authorization dataset) were retrieved from the Myocarditis and Pericarditis
search strategy:b 154 cases reported myocarditis and 61 cases reported pericarditis
(in 35 of these 180 cases, the subjects developed both myocarditis and pericarditis).
Myocarditis ( 154 cases)
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Table 34. Myocarditis and Pericarditis
These 154 cases were individually reviewed and assessed according to Brighton
Collaboration (BC) Myocarditis Case Definition and Level of Certainty
Classification, as shown in the Table below:
Brighton Collaboration Level Number of cases
BC 1 14
BC 2 9
BC 3 0
BC 4 130
BC 5 1
Total 154
Level 1 indicates a definitive case with the highest level of diagnostic certainty
of myocarditis, level 2 indicates a probable case, and level 3 indicates a possible
case. Level 4 is defined as “reported event of myocarditis with insufficient
evidence to meet the case definition” and Level 5 as not a case of myocarditis.
The details of 15 3 cases (excluding 1 Level 5 case) are presented below :
Country of incidence: Hong Kong (39), U S (25), Germany (18), France (17), Italy
(8), Israel (7), Austria and Spain (6 each), Denmark and Japan (5 cases); the
remaining 17 cases originated from 13 different countries .
Gender: Females ( 20), Males (130), and not reported (3) .
Age (n=153) ranged from 12 to 15 years (mean = 13.9 years, median = 14.0 years).
Reported relevant PT: Myocarditis ( 153).
Overall event seriousness and outcome of these 153 cases are summarized below.
Total Events
N = 153 (%)
Serious events 153* (100.0)
Events with Criterion of Hospitalization 110 (71.9)
Distribution of events by Outcome
Outcome: Death 0
Outcome: Resolved/Resolving 79 (51.6)
Outcome: Not resolved 17 (11.1)
Outcome: Resolved with sequelae 0
Outcome: Unknown/No data 57 (37.3)
*Includes 1 case where myocarditis was captured as non -serious and upgraded
to serious after the DLP.
Pericarditis ( 61 cases)
These 61 cases were individually reviewed and assessed according to Brighton
Colloboration (BC) Pericarditis Case Definition and Level of Certainty
Classification, as shown in the Table below
Brighton Collaboration Level Number of cases
BC 1 1
BC 2 4
BC 3 0
BC 4 56
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Table 34. Myocarditis and Pericarditis
BC 5 0
Total 61
Level 1 indicates a definitive case with the highest level of diagnostic certainty
of pericarditis, level 2 indicates a probable case, and level 3 indicates a
possible case. Level 4 is defined as “reported event of pericarditis with
insufficient evidence to meet the case definition” and Level 5 as not a case of
pericarditis.
The details of 61 cases are presented below:
Country of incidence: Hong Kong (29), Italy (7), France (6), US (4), Canada (3),
Australia, Belgium, Germany, and Japan (2 each); the remaining 4 cases originated
from 4 different countries .
Gender: Males ( 48) and Females (13) .
Age (n=61) ranged from 12 to 15 years (mean = 14.0 years, median = 14.0 years).
Reported relevant PT: Pericarditis ( 61).
Overall event seriousness and outcome of these 61 cases are summarized below.
Total Events
N = 61 (%)
Serious events 61 (100.0)
Events with Criterion of Hospitalization 17 (27.9)
Distribution of events by Outcome
Outcome: Death 0
Outcome: Resolved/Resolving 18 (29.5)
Outcome: Not resolved 9 (14.8)
Outcome: Resolved with sequelae 1 (1.6)
Outcome: Unknown/No data 33 (54.1)
Risk factors and risk
groups Post-authorization reports have been received for more males than females, over a
wide age range and following dose 1 and dose 2 of the vaccine. Evaluation by the
US CDC has found reports to be most frequent in adolescent and young adult male
patients following the second dose of vaccine.
Preventability Due to an unknown MOA, preventative measures are not clear for individuals with
or without a personal history of myocarditis or pericarditis.
Impact on the risk -
benefit balance of the
biologic product The vaccine continues to have a favorable risk benefit balance
Public health impact Considering the low rates of myocarditis and pericarditis reported following
vaccination, balanced with the risk of death and illn ess (including myocarditis)
caused by SARS -CoV-2, the public health impact of post -vaccination myocarditis
and pericarditis is minimal.
a. Please note that CT dataset from the safety database includes only cases reporting SAEs.
b. Search criteria: the following PTs were used to retrieve cases of Myocarditis and Pericarditis:
Autoimmune myocarditis; Eosinophilic myocarditis; Giant cell myocarditis; Hypersensitivity myocarditis;
Immune-mediated myocarditis; Myocarditis; Autoimmune pericarditis, Pericarditis; Pericarditis adhesive;
Pericarditis constrictive; Pleuropericarditis.
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Table 35. Anaphylaxis
Potential
mechanisms,
evidence source and
strength of evidence Interaction of an allergen with IgE on basophils and mast cells triggers release of
histamine, leukotrienes and other mediators that cause diffuse smooth muscle
contraction and vasodilation with plasma leakage. This can manifest clinically with
dyspnea, hypotension, swelling (sometimes leading to airway compromise), and
rash (including hives).
Characterisation of
the risk
Participants 16 years of age and older
Data from the CT data seta (cut-off date 18 June 2021)
Through 18 June 2021,b there was 1 case from the CT dataset (from Phase 3
clinical study C4591001) of serious Anaphylactoid reaction in a 17 -year-old
participant reported as resolved and deemed related to study treatment by the
Investigator :
Data from the safety database (cut-off date 18 June 2021) :
Through 18 June 2021,b there were 3822 cases (1.2% of the total post authorization
dataset) reporting a total of 3914 events in individuals 16 years and older including:
Anaphylactic reaction (3414)
Anaphylactic shock (420)
Anaphylactoid rection (75)
Anaphylactoid shock (5)
Overall event seriousness and outcome are summarized below:
Total Events
N = 3914 (%)
Serious events 3868 (98.8)
Events with Criterion of Hospitalization 1231 (31.5)
Distribution of events by Outcome *
Outcome: Death 28 (0.7)
Outcome: Resolved/Resolving 2958 (75.6)
Outcome: Not resolved 171 (4.4)
Outcome: Resolved with sequelae 56 (1.4)
Outcome: Unknown 704 (18)
*For the outcome count, the multiple Lowest Level Terms that code to the same PT
within a case are counted and presented individually. Therefore, for selected PTs the
total count of the event outcome may exceed the total number of events.
Participants 12 to 15 years of age
Data from the CT database (cut-off date 02 September 2021)
Through 02 September 2021, there were no casesb reporting Anaphylactic
reaction/shock, Anaphylactoid reaction/shock as SAEs from the CT database.
Data from the safety database (cut-off date 30 September 2021) :
Through 30 Septemb er 2021, there were 43 casesb (41 Anaphylactic reaction , 4
Anaphylactic shock , and 1 Anaphylactoid reaction ) in individuals 12 to 15 years of
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Table 35. Anaphylaxis
age (0.01% of total post -authorization dataset) ; overall event seriousness and
outcome are summarized below:
Total Events
N = 46 (%)
Serious events 46 (100)
Events with Criterion of Hospitalization 15 (32.6)
Distribution of events by Outcome
Outcome: Death 0
Outcome: Resolved/Resolving 32 (69.6)
Outcome: Resolved with sequelae 0
Outcome: Not resolved 2 (4.3)
Outcome: Unknown 12 (26.1)
Conclusion: Evaluation of Anaphylactic reaction/shock, Anaphylactoid
reaction/shock cases through 30 September 2021 did not reveal any significant new
safety information. Anaphylaxis is appropriately described in the product labeling
as are non -anaphylacti c hypersensitivity events. Surveillance will continue.
Risk factors and risk
groups Known hypersensitivity to any components of the vaccine.
Preventability Prevention of anaphylaxis may not be possible, particularly with the 1st dose of a
vaccine; therefore, healthcare professionals administering the vaccine must be
vigilant for early signs and symptoms.
Impact on the risk -
benefit balance of the
biologic product Anaphylactic reaction in an individual can be impactful (medically important)
because it is a potentially life -threatening event requiring medical intervention.
Public health impact Minimal due to rarity of the event. Although the potential clinical consequences of
an anaphylactic reaction are severe, this is a known ri sk of vaccines to healthcare
professionals with negligible public health impact.
a. Please note that CT dataset from the safety database includes only cases reporting SAEs.
b. Updated search criteria starting from the 6th SMSR (see 5th Monthly Safety Update preliminary PRAC
Assessment Report; EMEA/H/C/005735/MEA/002.4): PTs Anaphylactic reaction, Anaphylactic shock, Anaphylactoid reaction, Anaphylactoid shock, without Brighton Collaboration criteria applied.
Important Potential Risks
Table 36. Vaccine-Associated Enhanced Disease (VAED), including Vaccine -
Associated Enhanced Respiratory Disease (VAERD)
Potential
mechanisms, evidence source
and strength of evidence This potential risk is theoretical because it has not been described in association with
the BNT162b2 or it has not been reported from any other late phase clinical trial of
other human vaccine. Animal models of SARS -CoV-2 infection have not shown
evidence of VAED after immunization, whereas cellular immunopathology has been
demonstrated after viral challenge in some animal models administered SARS -CoV-1
(murine, ferret and non -human primate models) or MERS -CoV (mice model)
vaccines.1,6 This potential risk has been included based on these animal data with
these related betacoronaviruses. Historically, disease enhancement in vaccinated
children f ollowing infection with natural virus has been observed with an inactivated
respiratory syncytial virus vaccine.7
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Table 36. Vaccine-Associated Enhanced Disease (VAED), including Vaccine -
Associated Enhanced Respiratory Disease (VAERD)
Potential mechanisms of enhanced disease may include both T cell -mediated [an
immunopathological response favoring T helper cell type 2 (T H2) over T helper cell
type 1 (T H1)] and antibody- mediated activity (antibody responses with insufficient
neutralizing activity leading to formation of immune complexes and activation of
complement or allowing for Fc -mediated increase in viral entry to cells) .8
Characterization
of the risk
Participant 16 years and older
Data from the CT database (cut-off date 13 March 2021)
Confirmed Case of Postvaccination Severe COVID -19 – Blinded Placebo -
Controlled Follow -up Period - Safety Population (C4591001)
BNT162b2 (30 μg)
(Na=23164) Placebo
(Na=23155)
Timing nb (%) (95% CIc) nb (%) (95% CIc)
PD1 Before Dose
2 0 (0.0, 0.0) 6 (0.0) (0.0, 0.1)
Within 7 days
PD1 0 (0.0, 0.0) 0 (0.0, 0.0)
PD2 1 (0.0) (0.0, 0.0) 25 (0.1) (0.1, 0.2)
Within 7 days
PD2 0 (0.0, 0.0) 2 (0.0) (0.0, 0.0)
Totald 1 (0.0) (0.0, 0.0) 31 (0.1) (0.1, 0.2)
Note: This table includes subjects from Phase 2/3 only.
Abbreviations: PD1 = post -dose 1; PD2 = post -dose 2.
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.
c. Exact 2-sided CI based on the Clopper and Pearson method.
d. Total is the sum of PD1 and PD2.
PFIZER CONFIDENTIAL SDTM Creation: 25MAR2021 (23:24) Source Data:
adc19ef Table Generation: 27MAR2021 (12:47) (Cutoff date: 13MAR2021, Snapshot Date:
25MAR2021)
Output File: /nda2 unblinded/C4591001 PVP BLA/adeff s901
If VAED/VAERD were to occur in vaccinated individuals, it may manifest as a
modified and/or more severe clinical presentation of SARS -CoV-2 viral infection
upon subsequent natural infection. This may result in individuals assumed to be at
lower risk for seve re COVID- 19 having more severe disease, for individuals at known
risk for severe COVID -19 (e.g. older or immunocompromised) having higher rates of
fatal outcomes, or for observation of an unfavorable imbalance in severe COVID -19
cases in vaccinated individ uals when compared to those not vaccinated. It is
challenging to assess for VAED/VAERD on an individual case basis, given the lack of
specific clinical or laboratory markers at this time, rather surveillance for this
theoretical risk is best performed at a population level,9 as noted above. The table
above shows a favorable balance of severe COVID -19 cases in participants receiving
BNT162b2 versus those receiving placebo, providing reassurance against the potential
risk of VAED/VAERD at this time.
Data from the CT dataset
a (cut-off date 18 June 2021) :
There were no cases indicative of VAED/VAERD as SAEs in the CT dataset th rough
the DLP of 1 8 June 2021.
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Table 36. Vaccine-Associated Enhanced Disease (VAED), including Vaccine -
Associated Enhanced Respiratory Disease (VAERD)
Data from the safety database (cut-off date 18 June 2021)
No post-authorized AE reports have been identified as cases of VAED/VAERD,
therefore, t here is no observed d ata at this time. An expected rate of VAED is
difficult to establish so a meaningful observed/expected analysis cannot be conducted
at this point based on available data. The feasibility of conducting such an analysis
will be re-evaluated on an ongoing basis as data on the virus grows and the vaccine
safety data continues to accrue.
The search criteria utilised to identify potential cases of VAED for this report includes
PTs indicating a lack of effect of the vaccine and PTs potentially indicative of severe
or atypical COVID -19.
Since the first temporary author ization for emergency supply under Regulation 174 in
the UK (01 December 2020) and through the DLP 18 June 2021, there were 584 cases
(0.2% of the total post -authorization dataset), reporting 1427 potentially relevant
events.
Seriousness criteria for the t otal 584 cases: Medically significant (452, of which 10
also serious for disability), Hospitalization required (non -fatal/non-life threatening)
(115, of which 3 also serious for disability), Life threatening (34, of which 22 were
also serious for hospitali zation), Death (160).
Gender: Females (298), Males (268), Unknown (18);
Age (n=553) ranged from 17 to 103 years (mean = 70.3 years, median = 77.0);
Overall event seriousness and outcome are summarized below:
Total Events
N = 1427 (%)
Serious events 1261 (88.4)
Events with Criterion of
Hospitalization 612 (42.9)
Distribution of events by Outcome *
Outcome: Death 311 (21.8)
Outcome: Resolved/Resolving 375 (26.3)
Outcome: Not resolved 246 (17.2)
Outcome: Resolved with sequelae 14 (1.0)
Outcome: Unknown/No data 484 (33.9)
* For the outcome count, the multiple Lowest Level Terms that code to the
same PT within a case are counted and presented individually. Therefore, for
selected PTs the total count of the event outcome may exceed the tot al
number of events.
The most frequently reported relevant PTs ( ≥2%) were: Drug ineffective ( 390),
Vaccination failure (194), Dyspnoea ( 180), COVID- 19 pneumonia ( 179), Diarrhoea
(111), Respiratory failure (52), Vomiting ( 50), Pulmonary embolism (33).
Conclusion: VAED may present as severe or unusual clinical manifestations of
COVID-19. Overall, there were 425 subjects with confirmed COVID 19 following
one or both doses of the vaccine; 288 of the 425 cases were severe, resulting in
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Table 36. Vaccine-Associated Enhanced Disease (VAED), including Vaccine -
Associated Enhanced Respiratory Disease (VAERD)
hospitalization, disa bility, life threatening consequences or death. None of the 288
cases could be definitively considered as VAED/VAERD.
In this review of subjects with COVID -19 following vaccination, based on the current
evidence, VAED/VAERVAED remains a theoretical risk f or the vaccine.
Surveillance will continue.
Participants 12 to 15 years of age
Data from the CT database (cut-off date 02 September 2021) :
There were no cases reporting VAED/VAERD as SAEs in the CT data base through
the DLP of 02 September 2021.
Data from the safety databaseb (cut-off date 30 September 2021) :
Through the DLP 30 September 2021, there were 2 cases (reporting 6 potentially
relevant events) indicative of VAED or VAERD in the safety database involving
individual s 12 to 15 years of age.
Seriousness criteria for the 2 cases: Life threatening (1 also serious for hospitalization)
and Hospitalization required (non -fatal/non-life threatening) (1).
Gender: Males (2) ;
Age (n=2): 12 years and 15 years (1 case each) ;
Overall event seriousness and outcome are summarized below:
Total Events
N = 6
Serious events 6
Events with Criterion of
Hospitalization 6
Distribution of events by Outcome
Outcome: Death 0
Outcome: Resolved/Resolving 4
Outcome: Unknown/No data 2
The relevant PTs reported in these 2 cases were: Diarrhoea , Drug ineffective,
Multisystem inflammatory syndrome in children, Seizure, Vaccination failure, and
Vomiting (1 each).
Conclusion: VAED may present as severe or unusual clinical manifestations of
COVID-19. In both cases, the subjects had confirmed COVID -19 following 2 doses of
the vaccine. Upon review, t hese 2 cases unlikely represent VAED as the clinical
course was not descriptive of an unusual clinical manifestation of COVID -19
infection.
In this review of subjects with COVID -19 following vaccination, based on the current
evidence, VAED/VAERD remains a theoretical risk for the vaccine. Surveillance will
continue.
Risk factors and
risk groups It is postulated that the potential risk may be increase d in individuals producing lower
neutralizing antibody titers or in those demonstrating waning immunity.8,9
Preventability An effective vaccine against COVID -19 that produces high neutralizing titers and a
TH1 predominant CD4+ T cell response and strong CD8+ T cell response, is expected
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Table 36. Vaccine-Associated Enhanced Disease (VAED), including Vaccine -
Associated Enhanced Respiratory Disease (VAERD)
to mitigate the risk of VAED/VAERD;1,8 that immune profile is elicited by BNT162b2
in clinical and preclinical studies.10,11
Impact on the
risk-benefit
balance of the
biologic product If there were an unfavorable balance in COVID -19 cases, including severe cases, in
the pivotal clinical study between the vaccine and placebo groups, that may signal
VAED/VAERD.
Public health
impact The potential risk of VAED/VAERD could have a pu blic health impact if large
populations of individuals are affected.
a. Please note that CT dataset from the safety database includes only cases reporting SAEs.
b. Search criteria updated to include new PTs introduced in the MedDRA version 24.0. The updated search
criteria is: PTs Vaccine associated enhanced disease OR Vaccine associated enhanced respiratory disease OR
Standard Decreased Therapeutic Response Search AND at least 1 of the following PTs Dyspnoea;
Tachypnoea; Hypoxia; COVID 19 pneumonia; Respiratory Failure; Acute Respiratory Distress Syndrome;
Cardiac Failure; Cardiogenic shock; Acute myocardial infarction; Arrhythmia; Myocarditis; Vomiting;
Diarrhoea; Abdominal pain; J aundice; Acute hepatic failure; Deep vein thrombosis; Pulmonary embolism;
Peripheral Ischaemia; Vasculitis; Shock; Acute kidney injury; Renal failure; Altered state of consciousness;
Seizure; Encephalopathy; Meningitis; Cerebrovascular accident; Thrombocyt openia; Disseminated
intravascular coagulation; Chillblains; Erythema multiforme; Multiple organ dysfunction syndrome;
Multisystem inflammatory syndrome in children. Note: the “Standard Decreased Therapeutic Response”
search includes the Lack of efficacy P Ts (Drug ineffective/Vaccination failure).
2.1.2.c.2.2. Presentation of Missing Information
Table 37. Use in Pregnancy and Lactation
Evidence source:
The safety profile of the vaccine is not known in pregnant or lactating women due to their exclusion from the
pivotal clinical study. There may be pregnant women who choose to be vaccinated despite the lack of safety
data. It will be important to follow these women for pregnancy and birth outcomes. The timing of
vaccination in a pregnan t woman and the subsequent immune response may have varying favorable or
unfavorable impacts on the embryo/fetus. The clinical consequences of SARS -CoV-2 infection to the
woman and fetus during pregnancy is not yet fully understood and the pregnant woman’ s baseline health
status may affect both the clinical course of her pregnancy and the severity of COVID -19 disease. These
factors and the extent to which the pregnant woman may be at risk of exposure to SARS -CoV-2 will
influence the benefit risk considerat ions for use of the vaccine.
Population in need of further characterization:
The lack of data is communicated in product labeling; one clinical study of the safety and immunogenicity of
the BNT162b2 in pregnant and lactating women is ongoing (C4591015); 2 non-interventional studies
(C4591009 and C4591011 ) are planned and 2 non- interventional studies (C4591021, and C4591022 ) are
ongoing to assess use of BNT162b2 in pregnancy (see 3.1.3 – Action plan for safety issues ).
Data from the Safety Databasea (Cut-off date 18 June 2021 )
Since the first temporary authorization for emergency supply under Regulation 174 in the UK
(01 December 2020) and through 18 June 2021, there were 2636 cases (0.8 % of the total P ost-authorization
dataset) reporting use during pregnancy or lactation.
Overall event seriousness and outcome are summarized below:
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Table 37. Use in Pregnancy and Lactation
Total Events
N = 6215 (%)
Serious events 2464 (39.6)
Events with Criterion of Hospitalization 314 (5.1)
Distribution of events by Outcome *
Outcome: Death 61 (1)
Outcome: Resolved/Resolving 1657 (26.7)
Outcome: Not resolved 602 (9.7)
Outcome: Resolved with sequelae 65 (1)
Outcome: Unknown/No data 3864 (62.2)
* For the outcome count, the multiple Lowest Level Terms that code to the same PT within a case are counted and
presented individually. Therefore, for selected PTs the total count of the event outcome may exceed the total number
of events.
The most freque ntly reported relevant PTs (≥2%) were: Maternal exposure during pregnancy (867),
Exposure via breast milk (791), Exposure during pregnancy (402), Off label use (296), Abortion
spontaneous, Product use issue (277 each), Headache (184), Maternal exposure dur ing breast feeding (161),
Fatigue (155), Pyrexia (134), Pain in extremity (119), Vaccination site pain (91), Myalgia (79), Chills (75),
Maternal exposure timing unspecified (73), Nausea, Pain (72 each), and Dizziness (56).
Participants 1 2 to 15 years of a ge
Data from the safety database: (Cut-off date 30 September 2021)
Through 30 September 2021, there was 1 case reporting use of BNT162b2 during pregnancy in the safety
database. The serious case involved a 12 -year-old female who received first dose of BNT162b2 during
pregnancy (trimester of exposure unknown) and had miscarriage after 2 weeks of vaccine administration
(PTs Maternal exposure during pregnancy, Fatigue, and Abortion spontaneous). Patient outcome was
reported as recovered with sequelae. Through 30 September 2021, there were no cases reporting use of
BNT162b2 during lactation.
a. Cumulative RMP tables on Missing information are provided as per previous FDA’s request to include a
cumulative analysis, from post- authorization experience, of the Important Missing Information identified in
the Pharmacovigilance Plan.
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Table 38. Vaccine Effectiveness
Evidence source:
Although vaccine efficacy in a controlled clinical stud y is the objective of the pivotal stud y, real-world
vaccine effectiveness when the BNT162b2 is used in a large and more diverse population is unknown.
Anticipated risk/consequence of missing information:
Efficacy information obtained from clinical study data is communicated in the product labeling. Four post -
authorization effectiveness studies in real-world use are ongoing: 1 interventional study (BNT162 -01 cohort
13), 1 non-interventional study (C4591014) and 2 low -interventional studies (WI235284 and WI255886) to
determine the effectiveness of BNT162b2 when administered outside of the clinical setting (see 3.1.3 –
Action plan for safety issues ).
Data from the Safety Databasea (Cut-off date: 18 June 2021)
Since the first temporary authorization for emergency supply under Regulation 174 in the UK
(01 December 2020) and through 18 June 2021, there were 6373 cases (1.9% of the total P ost-authorization
dataset) reporting lack of efficacy .
Overall event seriousness and outcome are summarized below:
Total Events
N = 6373 (%)
Serious events 6373 (100)*
Events with Criterion of Hospitalization 616 (9.7)
Distribution of events by Outcome
Outcome: Death 334 (5.2)
Outcome: Resolved/Resolving 1253 (19.7)
Outcome: Not resolved 721 (11.3)
Outcome: Resolved with sequelae 21 (0.3)
Outcome: Unknown/No data 4044 (63.5)
*Includes 26 cases where LOE was captured as non -serious and upgraded to serious after the DLP.
The PT Drug ineffective was reported in 4765 cases, Vaccination failure was reported in 1608 cases; the
most frequently co-reported PTs (≥2%) were: COVID-19 (5022), Asymptomatic COVID-19 (502), Pyrexia
(412), Suspected COVID -19 (379), SARS -CoV-2 test positive (359), Headache (327), Fatigue (262), Cough
(227), Dyspnoea (180), COVID -19 pneumonia (179), Myalgia (162), Asthenia (156), Malaise (152), and
Chills (133) .
Participants 1 2 to 15 years of age
Data from the safety database: (Cut-off date 30 September 2021)
Through 30 September 2021, there were 2 9 cases retrieved reporting lack of efficacy . Upon review, 1 case
was not considered to be true lack of efficacy because the subject d eveloped SARS -CoV-2 infection during
the early days from the first dose (days 1 -13); the development of a vaccine preventable disease during this
time is not considered a lack of effect of the vaccine. Therefore, there were 2 8 relevant cases reporting lac k
of efficacy in individuals 12 to 15 years of age; overall event seriousness and outcome are summarized
below:
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Table 38. Vaccine Effectiveness
Total Events
N = 28 (%)
Serious events 28 (100)
Events with Criterion of Hospitalization 2 (7.1)
Distribution of events by Outcome
Outcome: Death 0
Outcome: Resolved/Resolving 4 (14.3)
Outcome: Not resolved 1 (3.6)
Outcome: Unknown/No data 23 (82.1)
The PTs Drug ineffective and Vaccination failure were reported in 19 and 9 cases, respectively ; the
co-reported events reported more than once were coded to the PTs : COVID-19 (24), Pyrexia (5),
Headache (4), Suspected COVID -19 (3), and Fatigue (2).
a. Cumulative RMP tables on Missing information are provided as per previous FDA’s request to include a
cumulative analysis, from post- authorization experience, of the Important Missing I nformation identified in
the Pharmacovigilance Plan.
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Table 39. Use in Paediatric Individuals <5 Years of Age§
Evidence source :
Paediatric individuals may display different reactogenicity and safety profiles compared to adults, due to
lower body mass and differently matured immunological responses.
Population in need of further characterization :
The are no data in individuals less than 5 years of age ; in the pediatric population:
• 3 clinical studies [C4591001 ( ≥12 to ≤15 years of age), C4591007 (<12 years of age) and C4591007
substudy - Troponin group (5 to <12 years of age and 12 to <1 6 years of age ) are ongoing;
• 1 clinical study [C4591023 (<6 months; ≥5 to <12 years of age) is planned;
• 2 non-interventional studies [C4591009 (< 12 years of age) and C4591038 (former C4591021
substudy) (<12 years of age)] are planned;
• 1 low interventional study is planned [C4591036 (<21 years of age, including <12 years of age)]
For details on these studies, see 3.1.3 – Action plan for safety issues .
Data from the Safety Databasea (cut-off date 30 September 2021)
Since the first temporary authorization for emergency supply under Regulation 174 in the UK
(01 December 2020) and through 30 September 2021, there were 56 casesb (0.01% of the total P ost-
authorization dataset) involving individuals below 5 years of age.
Overall event seriousness and outcome are summarized below:
Total Events
N = 172 (%)
Serious events 30 (17.4)
Events with Criterion of Hospitalization 3 (1.7)
Distribution of events by Outcome
Outcome: Death 2 (1.2)
Outcome: Resolved/Resolving 61 (35.5)
Outcome: Not resolved 46 (26.7)
Outcome: Resolved with sequelae 0
Outcome: Unknown/No data 63 (36.6)
The most frequently reported PTs ( >3 occurrences ) were: Product administered to patient of inappropriate
age (21), Off label use ( 17), Product use issue ( 15), Pyrexia (1 1), Fatigue, Headache , Myalgia, and Nausea (4
each).
§ Missing information has been reworded to reflect the current state .
a. Cumulative RMP tables on Missing information are provided as per previous FDA’s request to include a
cumulative analysis, from post- authorization experience, of the Important Missing Information identified in
the Pharmacovigilance Plan.
b. Please note that at the DLP of 18 June 2021 there were 29 additional pediatric ca ses under 5 years of
age; at the DLP of 30 September 2021, follow -up information was received for these cases and they were
identified to refer to adult subjects, rather than to pediatric subjects under 5 years of age.
2.1.2.d. Identified and Potential Interacti ons, Including Food-Biologic Product and
Drug-Biologic Product Interactions
As noted in the WHO Guidelines on Nonclinical Evaluation of Vaccines,3 pharmacokinetics
testing is n ot required for final formulation. No interaction linked to metabolism is expected
with vaccines. The only potential for interaction is with other vaccines administered
concomitantly and with immunosuppressive drugs.
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Co-administration studies with BNT162b2 have not been done, therefore th ere is not
sufficient data to understand the effect o n vaccine effectiveness of BNT162b2 or co-
administered vaccines. A co-administration study with seasonal influenza vaccine is
planned. If BNT162b2 is given at the same time as other injectable vaccine(s), the vaccine(s)
should be administered at different injection sites.
2.1.2.e. Epidemiology of Indication and Target Population
Indication
Active immunization to prevent COVID-19 caused by SARS -CoV-2 virus , in individuals 12
years and older.
Incidence:
The COVID -19 is caused by a novel coronavirus labeled as SARS -CoV-2. The disease first
emerged in December 2019, when a cluster of patients with pneumonia of unknown caus e
was recognized in Wuhan City, Hubei Province, China .12 The number of infected cases
rapidly increased and spread beyond China throughout the world. On 30 January 2020, the
WHO declared COVID-19 a Public Health Emergency of International Concern and thus a
pandemic.13
Estimates of SARS -CoV-2 incidence change rapidly. The MAH obtained incidence and
prevalence estimates using data from Worldometer, a trusted independent organization that
collects COVID -19 data from official reports and publishes current global and
country-specific statistics online.14
As of 15 August 2021, the overall number of people who had been infected with
SARS-CoV-2 was over 207 million worldwide,15 an increase of 92 million in the 5 months
since 03 March 2021.16 Table 40 shows the incidence and prevalence as of 15 August 2021
for the US, UK, and EU -27 countries. In the EU and the UK, by 15 August 2021 the total
number of confirm ed cases had accumulated to 41 million people, or 8,074 per 100,000
people (from 27 million, or 5,226 per 100,000 by 03 March 2021). Across countries in the
EU, the number of confirmed cases ranged from 2,118 to 15,620 cases per 100,000 people.
Finland a nd Germany reported the lowest incidence rates while Czech Republic, Slovenia,
and Luxembourg reported the highest. 15
In the US, the number of confirmed cases had reached over 37 million cases (11,236 per
100,000 people) by 15 August 2021. 15 This is an increase fro m 29 million (8,864 per
100,000) by 03 March 2021. 16
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Table 40. Incidence, Prevalence, and Mortality of COVID -19 as of 15 August 202115
Total
Cases Incidence:
Total
Cases/
100,000 Active
Cases Prevalence:
Active
Cases/
100,000 Total
Deaths Mortality:
Deaths /
100,000 Population
Global 207,731,370 2,665 17,141,537 220 4,371,692 56 7,794,798,124
EU-27 35,243,565 7,910 2,000,178 449 747,450 168 445,541,383
UK 6,241,011 9,140 1,313,343 1,923 130,894 192 68,284,715
EU-27 +
UK 41,484,576 8,074 3,313,521 645 878,344 171 513,826,098
US 37,435,835 11,236 6,653,787 1,997 637,439 191 333,172,543
EU-27 Countries
Austria 668,732 7,378 8,559 94 10,756 119 9,063,848
Belgium 1,149,869 9,873 52,835 454 25,287 217 11,646,025
Bulgaria 432,962 6,284 14,645 213 18,339 266 6,889,852
Croatia 367,022 9,002 1,903 47 8,283 203 4,076,913
Cyprus 108,707 8,931 17,496 1,437 456 38 1,217,182
Czech
Republic 1,676,222 15,620 2,441 23 30,373 283 10,731,206
Denmark 330,777 5,688 12,854 221 2,560 44 5,815,014
Estonia 136,992 10,319 5,131 387 1,279 96 1,327,533
Finland 117,531 2,118 70,536 1,271 995 18 5,550,349
France 6,449,863 9,857 455,926 697 112,612 172 65,435,079
Germany 3,825,039 4,549 53,169 63 92,370 110 84,083,573
Greece 535,237 5,163 37,611 363 13,174 127 10,366,043
Hungary 810,316 8,412 14,326 149 30,038 312 9,632,892
Ireland 322,989 6,461 42,205 844 5,059 101 4,999,386
Italy 4,435,008 7,347 126,466 210 128,413 213 60,362,319
Latvia 140,122 7,522 1,218 65 2,561 138 1,862,827
Lithuania 289,810 10,815 12,355 461 4,451 166 2,679,705
Luxembourg 74,595 11,704 705 111 828 130 637,340
Malta 35,337 7,979 1,043 236 430 97 442,858
Netherlands 1,901,900 11,072 124,498 725 17,909 104 17,177,282
Poland 2,885,333 7,633 154,721 409 75,299 199 37,800,220
Portugal 1,003,335 9,872 45,367 446 17,562 173 10,163,426
Romania 1,087,223 5,694 2,982 16 34,348 180 19,093,951
Slovakia 393,529 7,204 825 15 12,544 230 5,462,601
Slovenia 261,428 12,573 2,150 103 4,433 213 2,079,258
Spain 4,693,540 10,034 722,353 1,544 82,470 176 46,775,041
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Table 40. Incidence, Prevalence, and Mortality of COVID -19 as of 15 August 202115
Total
Cases Incidence:
Total
Cases/
100,000 Active
Cases Prevalence:
Active
Cases/
100,000 Total
Deaths Mortality:
Deaths /
100,000 Population
Sweden 1,110,147 10,916 15,858 156 14,621 144 10,169,660
The reported numbers refer to cases that have been tested and confirmed to be carrying the
virus and sometimes, depending upon the country, also presumptive, suspect, or probable
cases of detected infection . There are large geographic variations in the proportion of the
population tested as well as in the quality of reporting across countries. People who carry the
virus but remain asymptomatic are less likely to be tested and therefore mild cases are likely underreported. The numbers should therefore be interpreted with caution.
17
Prevalence:
The prevalence of SARS-CoV-2 infection is defined as active cases per 100,000 people
including confirmed cases in people who have not recovered or died. On 15 August 2021,
the overall prevalence estimates for the EU and UK were 449 and 1,923 active cases per
100,000, respectively15 compared to approximately 1,500 per 100,000 for both the EU and
UK on 03 March 2021.16 The range of reported prevalence was 15 to 1,544 per 100,000:
Slovakia, Romania, and Czech Republic reported the lowest prevalence while Spain, Cyprus,
and Finland reported the highest ( Table 40).
In the US, the prevalence on 15 August 2021 was similar to the UK, with 1,997 active cases
per 100,000.15 This is a decrease of approximately 700 per 100,000 since 03 March 2021,
when the prevalence was 2,685 per 100,000.16
Demographics of the population in the proposed indication and risk factors for the
disease:
Since the beginning of the pandemic, the ECDC has continuously collected COVID -19
information from all countries who are members of the EU/EEA. In the ECDC’s TESSy
database, COVID -19 case-based data, including age and gender, are available for over 80%
of the official number of cases reported by ECDC epidemic intelligence,18 enabling e stimates
of age and gender distribution representative of the European population. TESSy data on age
and sex distributions by severity of symptoms as posted on 12 August 2021 are shown in
Figure 1.19
The top half of the figure represents data ending on 31 July 2020 and the bottom half
presents data from 01 August 2020 to 08 August 2021 (Figure 1). In general, the age-sex
patterns before 01 August 2020 have remained the same since then. The gender distribution
of persons testing positive for SARS -CoV-2 in the European population is simi lar for most
age groups. Cases reported in TESSy have been older than the general population
throughout the pandemic, with few cases observed in people aged younger than 20 years.
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This likely reflects the age distribution of people who met the requirements for being tested
and is unlikely to reflect the actual distribution of infections in the population. Those with
severe outcomes (hospitalized, severely hospitalized [admitted to intensive care and/or
required respiratory support] , or fatal) have been di sproportionately older and male compared
to COVID -19 cases overall. While age-sex patterns have remained consistent throughout the
pandemic, a notable difference between the periods before and since 01 August 2020 is that
the absolute numbers of cases have increased dramatically in the latter period compared to
the earlier one.
Figure 1. Age-Sex distribution of COVID -19 Cases as Different Levels of Severity,
Pooled Data for EU/EEA Countries . Case-based Data from TESSy produced
on 12 August 2021a
Note: “mild” = a case that has not been reported as hospitalized or a case that resulted in death.
a. Data from ECDC. COVID -19 Surveillance report. Week 31, 2021. 12 August 2021. “2.2 Age -sex pyramids” Accessed
15 August 202119
US distributions of COVID cases and deaths by age, sex, and race, as well as the
cross-tabulation of age and sex, are shown in Table 41 as of 14 August 2021.20 At that time,
the CDC reported that the US had recorded a total of 36,556,516 cases of COVID and 618,591 deaths attributable to the disease. However, because demographic data were not
available for all US COVID cases and deaths, the numbers in
Table 41 and Table 42 are
drawn, respectively, from 29,346,352 cases and 513,204 deaths. Those under age 50 account
for roughly 67% of cases but approximately 5% of deaths. For ages 18-74, males account for
less than half of cases but over 60% of deaths. Among the pediatric population, there is close
to a 50-50 case distribution between males and females across ages 0 -17. However, the
pediatric mortality distribution is highly irregular between the sexes, with males being 51.5%
of COVID deaths among 0-4 year olds, 55.9% among 5-11 year olds, 46.7% among 12-15 year olds, and 68.7% among 16-17 year olds.
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Table 41. Distribution of Cases (n=29,346,352) by Age, Sex, Race, and Cross -
Tabulated Age and Sex -- United States as of 14 August 2021a 20
Event Age
Group Age
% Sex Sex % Raceb Race
% Age
Group Males
% Females
%
Cases 0-4 2.2 Males 47.7 H/L 28.3 0-4 51.7 48.3
5-11 4.2 Females 52.3 AI/AN 1 5-11 50.8 49.1
12-15 3.8 Asian 3.2 12-15 49.6 50.4
16-17 2.6 Black 11.6 16-17 48.3 51.7
18-29 22.7 NH/PI 0.3 18-29 46.9 53.1
30-39 16.6 White 50.3 30-39 47.9 52.1
40-49 14.8 M/O 5.3 40-49 47.7 52.3
50-64 20 50-64 48.6 51.4
65-74 7.3 65-74 48.7 51.3
75-84 3.7 75-84 45.7 54.3
85+ 2.1 85+ 34.4 65.6
a. Percentage of missing demographic data varied by types of event and demographic.
b. Except for Hispanics/Latinos, all categories refer to non -Hispanics
Abbreviations: AI/AN=American Indian/Alaska Native, H/L=Hispanic/Latino, M/O=Multiple/Other,
NH/PI=Native Hawaiian/Other Pacific Islander
Table 42. Distribution of Deaths (n=513,204) by Age, Sex, Race, and
Cross-Tabulated Age and Sex -- United States as of 14 August 2021a 20
Event Age
Group Age % Sex Sex % Raceb Race
% Age
Group Males
% Females
%
Deaths 0-4 <0.1 Males 54.2 H/L 18.5 0-4 51.5 48.5
5-11 <0.1 Females 45.8 AI/AN 1.2 5-11 55.9 44.1
12-15 <0.1 Asian 3.8 12-15 46.7 53.3
16-17 <0.1 Black 13.8 16-17 68.7 31.3
18-29 0.6 NH/PI 0.2 18-29 64 36
30-39 1.3 White 58.7 30-39 65.1 34.9
40-49 3.1 M/O 3.8 40-49 65.3 34.7
50-64 15.4 50-64 64 36
65-74 21.6 65-74 60.6 39.4
75-84 27.3 75-84 55.5 44.5
85+ 30.7 85+ 41.8 58.2
a. Percentage of missing demographic data varied by types of event and demographic.
b. Except for Hispanics/Latinos, all categories refer to non -Hispanics
Abbreviations: AI/AN=American Indian/Alaska Native, H/L=Hispanic/Latino, M/O=Multiple/Other, NH/PI=Native
Hawaiian/Other Pacific Islander
In general, disease has been much less severe among ages 0 -24 compared to ages ≥25 years,
with 2.5% hospitalized, 0.8% admitted to an intensive care unit, and <0.1% dying among
ages 0-24, versus 16.6% hospitalized, 8.6% intensive care, and 5% dying among ages
≥25 years.21 Among hospitalized cases with COVID -19 in the US, approximately 90% are
over 40 years old, and between 58% to 66% are at least 60 years old.22 The majority
(approximately 60%) of COVID -19 patients admitte d to hospitals in the US have been
male.22,23,24,25,26
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African American COVID -19 patients have been reported to have an increased risk of
hospitalization23,27 and mortality,28 compared to white patients in the United States. A CDC
report examined demographic trends among US COVID -19 deaths from May to August of
2020.29 During the observation period, the percentage of US COVID -19 deaths that were
Hispanic increased from 16.3% in May to 26.4% in August, the only racial or ethnic group
among whom the percentage of deaths increased during that time. In terms of setting, 6 4.3%
of deaths occurred in inpatient hospitals and 21.5% in nursing homes or long -term care
facilities.
The most recent CDC estimate of the total number of excess deaths (as opposed to overall
deaths in the preceding paragraph) across the US from 26 January 2020 to 27 February 2021
from all causes (COVID -19 and otherwise) ranged from 545,600-660,200, with an estimated
75-88% of excess deaths being associated with COVID -19.30 An earlier CDC report on
excess deaths covering 26 January 2020 through 3 October 2020 broke down excess deaths by demographics
30: by age during that period, the largest increase in deaths compared to
average expected deaths occurred among adults aged 25-44 (26.5% increase). By race,
increases in deaths compared to expectation were largest among Hispanics (53.6% increase), Asian Americans (36.6% increase), African Americans (32.9% increase), and Native Americans and Native Alaskans (28.9% increas e), all compared to an excess 11.9% deaths
among non-Hispanic whites.
While research earlier in the pandemic tended to focus on adults, more recent data have given greater attention to children and adolescents. For the period January 1-March 31 2021 across
14 states (the most recently available data), the CDC’s COVID -NET database recorded 204
adolescents aged 12 -17 who were hospitalized for likely primarily COVID -19-related
reasons.
31 The 204 adolescents were 47.5% male—consistent with the COVID case sex
distribution across all ages —and disproportionately from minorities, with 31.4% Hispanic
and 35.8% non -Hispanic African Americans.31
Another recent CDC report described demographic trends in US COVID -19 incidence
among 15,068 cases aged 0-24 years across 16 jurisdictions during the period 01 January 2020 through 31 December 2020.
32 The report broke down incidence by age groups and
2020 sub-perio ds that are presented in Table 43. The table shows that early in 2020, 5-9 year
olds were experiencing less COVID -19 than 0-4 year olds, but by the end of the year this
pattern had reversed. Compared to 5-9 year olds, the age categories 10 -14, 15-19, and 20-24
years old showed progressively greater incidence rates, a pattern that held throughout 2020.
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Table 43. COVID-19 incidence and rate ratios, by age group among persons aged
<25 years across three periods of 2020 in 16 U.S. jurisdictions32
2020
Sub-Period Age Group
(years) Number
of Cases Cases per 100,000 population
(95% CI) Rate Ratio
(95% CI)
Jan 1-Apr 30 0-4 956 21 (20-23) 1.28 (1.17 -1.41)
5-9 772 17 (16-18) Referencea
10-14 1,184 25 (23-26) 1.49 (1.36 -1.63)
15-19 3,267 67 (65-70) 4.03 (3.72 -4.36)
20-24 8,889 175 (171-178) 10.47 (9.72 -11.26)
May 1-Aug 31 0-4 14,017 314 (309-319) 1.01 (0.98 –1.03)
5-9 14,406 312 (307-317) Referencea
10-14 20,490 430 (424-436) 1.38 (1.35 –1.41)
15-19 50,210 1,034 (1,025 -1,043) 3.32 (3.26 –3.38)
20-24 78,655 1,547 (1,536 -1,557) 4.96 (4.88 –5.05)
Sep 1-Dec 31 0-4 33,595 752 (744–760) 0.71 (0.70 –0.72)
5-9 48,824 1,056 (1,047 –1,066) Referencea
10-14 76,922 1,615 (1,604 –1,627) 1.53 (1.51 –1.55)
15-19 149,660 3,083 (3,067 –3,098) 2.92 (2.89 –2.95)
20-24 187,825 3,693 (3,677 –3,710) 3.50 (3.46 –3.53)
a. Reference to imply that incidence rate in 5 -9 year-old age group is used as comparison to calculate rate ratios for
other age groups
Other US pediatric data are generally consistent with the CDC findings. Table 44
summarizes demographic results for a retrospective cohort of 135,794 individuals under the
age of 25 who were tested for COVID -19 by 08 September 2020 within the PEDSnet
network of US pediatric health systems.33 The Table 44 shows that, among the pediat ric
population, children age 12-17 were more frequently infected than those under age 12.
African Americans and Hispanics had elevated frequencies of testing positive relative to their proportion of the cohort.
A study of 1,945,831 individuals aged 0-18 recorded in the Premier Healthcare Database
between March and October 2020 included 20,714 pediatric cases of COVID -19; the authors
reported similar patterns to what is shown in
Table 43, with the additional observation that
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COVID-19 cases aged 0 -1 and 12-18 years were more likely to develop serious illness than
those aged 2 -11.34
Table 44. Demographics of 135,794 US individuals under age 25 tested for
COVID-19 by 08 September 202033
Characteristic Patients, n (%)
COVID-19 negative
(n=130,420) COVID-19 positive,
Asymptomatic or mild
illness (n=5,015) COVID-19 positive,
Severe illness (n=359)
Age, years
<1 17,431 (13) 494 (10) 72 (20)
1-4 32,619 (25) 808 (16) 40 (11)
5-11 35,617 (27) 1,029 (21) 72 (20)
12-17 32,362 (25) 1,521 (30) 117 (33)
18-24 12,391 (10) 1,163 (23) 58 (16)
Sex
Female 61,637 (47) 2,527 (50) 172 (48)
Male 68,701 (53) 2,485 (50) 187 (52)
Other or Unknown 82 (0.06) 3 (0.06) 0
Race/ethnicity
Hispanic 14,156 (11) 918 (18) 108 (30)
API 4,471 (3) 151 (3) 9 (3)
Black or AA 18,646 (14) 1,424 (28) 119 (33)
White 77,540 (60) 1,988 (40) 97 (27)
Multiple 3,883 (3) 126 (3) 5 (1)
Other or Unknown 11,724 (9) 408 (8) 21 (6)
AA=African American, API=Asian or Pacific Islander
Risk Factors
While anyone can become infected with SARS -CoV-2, COVID -19 disease can range from
very mild (or no symptoms) to severe or fatal. A person’s risk of initial infection increases
through spending time in close physical proximity to others, especially in indoor spaces with
poor ventilation.35 People living in long -term care facilities or high -density apartment
homes, or working in occupations with close proximity to others (e.g. healthcare,
transportation), have a higher risk of infection. 35,36 Among children, the primary source of
infection is an infected adult living in the same household.37 According to the CDC, some
ethnic minority groups have a higher risk of infection, but age is not associated with risk of
initial infection among people aged 5 and older ( Table 45).38, 39
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Table 45. Risk for COVID-19 infection, Hospitalisation, and Death by Age Group and by
Race/Ethnicity39
Rate ratiosa
Age Group (years) Casesc Hospitali sationd Deathe
0-4 <1 <1 <1
5-17 1 <1 <1
18-29b 1 1 1
30-39 1 2 4
40-49 1 2 10
50-64 1 4 35
65-74 1 6 95
75-84 1 9 230
85+ 1 15 600
Race/Ethnicity
Non-Hispanic White f 1 1 1
American Indian or Alaska Native, non -Hispanic 1.7 3.4 2.4
Asian, non -Hispanic 0.7 1.0 1.0
Black or African American, non -Hispanic 1.1 2.8 2.0
Hispanic or Latino 1.9 2.8 2.3
a. Rates are expressed as whole numbers, with values less than 10 rounded to the nearest integer, two -digit
numbers rounded to nearest multiple of five, and numbers greater than 100 rounded to two significant
digits.
b. Rate ratios for each age group are relative to the 18 -29-year age category. This group was selected as the
reference group because it has accounted for the larges t cumulative number of COVID -19 cases
compared to other age groups.
c. Includes all cases reported by state and territorial jurisdictions (accessed on July 12, 2021). The
denominators used to calculate rates were based on the 2019 Vintage population
(https://www.census.gov/newsroom/press -releases/2019/popest -nation html).
d. Includes all hospitalizations reported through CO VID-NET (from March 1, 2020 through July 3, 2021,
accessed on July 12, 2021). Rates were standardized to the 2020 US standard COVID -NET catchment
population (https://www.cdc.gov/coronavirus/2019 -ncov/covid -data/covid -net/purpose -methods.html).
e. Includes all deaths in National Center for Health Statistics (NCHS) provisional death counts (accessed
on July 12, 2021). The denominators used to calculate rates were based on the 2019 Vintage pop ulation
(https://data.cdc.gov/NCHS/Provisional -COVID-19-Deaths-by-Sex-and-Age/9bhg -hcku).
f. Rate ratios for each race/ethnicity group are relative to the Non -Hispanic White category.
Risk for severe or fatal COVID -19 disease has been shown to increase with older age, male
sex, or ethnic minority status. 38,39, 40 41, 42,43 Children aged 5 -17 typically experience a
milder disease course and have lower risk of hospitalization or death.38,44,45Among adults,
these risks increase for every 10-year age group above age 39 (Table 42).38, 46 Table 45 also
gives estimated rate ratios for COVID -19 hospitali sation and death by race/ethnicity relative
to white, non-Hispanic persons in the US. The highest risks of hospitalis ation and death
were observed among American Indian or Alaska native persons (RR = 3. 4 for
hospitalis ation and 2.4 for death) and Hispanic or Latino persons (RR = 2.8 for
hospitalis ation and 2.3 for death). These differences in risk among ethnic groups may be
attributed to differences in underlying factors that are correlated with race/ethnicity including
socioeconomic status, access to health care, and occupation -related virus exposure .39
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Risk of severe or fatal COVID -19 disease is higher among persons who are current or former
smokers, have lower socioeconomic status, have no or public insurance, or live in
neighborhoods with higher rates of limited English proficiency. 40,42,46 The CDC has also
recognized other socio -demographic groups who may need to take extra precautions against
COVID-19 due to increased risk for severe illness: pregnant women; breastfeeding mothers; people with disabil ities; people with developmental , behavioural, or substance abuse
disorders; and newly resettled refugee populations.
47
Among adults, r isk for severe or fatal COVID -19 disease increases with the presence of
chronic medical conditions, including obesity, chronic lung diseases (e.g., COPD or asthma),
cardiovascular disease, diabetes, cancer, liver disease, neurological diseases (e.g., stroke or dementia), chronic kidney disease, sickle cell disease, immunosuppression, HIV, higher
scores on the WHO Clinical Progression Scale and Charlson Comorbidity Index.
41, 46, 48, 40, 42.
Table 46 shows the estimated hazard ratios of COVID -19 mortality associated with these
chronic conditions and socio-demographics from a cohort study of 17 million adults (with
17,000 COVID -19-related deaths) in England.46
The presence of one or more underlying medical conditions also increases risk of severe or fatal disease among children aged 5 -17.
49,50,51, 52 In particular, childhood obesity has been
consistently associated with two to three times the risk of severe disease or hospitalization .49,
52, 53, 54,. For many other individual comorbid conditions, pediatric sample sizes are very
small and different studies produce conflicting results, so it is difficult to estimate precise risk ratios based on current literature.
37, 51
Table 46. Hazard Ratios and 95% Confidence Intervals for COVID -19-related
Death46
Characteristic Category COVID-19 death Hazard Ratio
Adjusted for
age, sex, and NHS
administrative region Fully adjusted
Age 18-39 0.05 (0.04 -0.06) 0.06 (0.04 -0.07)
40-49 0.32 (0.28-0.38) 0.34 (0.29 -0.39)
50-59 1.00 (ref) 1.00 (ref)
60-69 2.93 (2.69 -3.20) 2.57 (2.35 -2.80)
70-79 9.17 (8.48 -9.93) 6.74 (6.21 -7.31)
80+ 43.16 (40.03 -46.53) 24.10 (22.23 -26.13)
Sex Female 1.00 (ref) 1.00 (ref)
Male 1.73 (1.68-1.78) 1.55 (1.50 -1.60)
BMI (kg/m2) Not obese 1.00 (ref) 1.00 (ref)
30-34.9 (obese class I) 1.23 (1.18 -1.28) 1.07 (1.03 -1.12)
35-39.9 (obese class II) 1.79 (1.68 -1.90) 1.44 (1.36 -1.54)
40+ (obese class III) 2.76 (2.54 -3.00) 2.11 (1.93-2.29)
Smoking Never 1.00 (ref) 1.00 (ref)
Former 1.44 (1.40 -1.49) 1.26 (1.22 -1.30)
Current 1.17 (1.10 -1.25) 0.97 (0.91 -1.04)
Ethnicity White 1.00 (ref) 1.00 (ref)
Mixed 1.59 (1.28 -1.97) 1.43 (1.15 -1.78)
South Asian 1.97 (1.82-2.14) 1.70 (1.55 -1.85)
Black 1.82 (1.61 -2.05) 1.44 (1.27 -1.63)
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Table 46. Hazard Ratios and 95% Confidence Intervals for COVID -19-related
Death46
Characteristic Category COVID-19 death Hazard Ratio
Adjusted for
age, sex, and NHS
administrative region Fully adjusted
Other 1.38 (1.17 -1.63) 1.38 (1.16 -1.63)
IMD quintilea 1 (least deprived) 1.00 (ref) 1.00 (ref)
2 1.17 (1.11 -1.23) 1.13 (1.07 -1.19)
3 1.37 (1.30 -1.44) 1.25 (1.19 -1.32)
4 1.77 (1.68 -1.86) 1.53 (1.46 -1.61)
5 (most deprived) 2.11 (2.01 -2.22) 1.71 (1.62 -1.80)
Blood pressure Normal 1.00 (ref) 1.00 (ref)
High BP or diagnosed
hypertension 1.09 (1.06 -1.13) 0.90 (0.87 -0.94)
Respiratory disease excluding asthma 1.95 (1.86 –2.04) 1.66 (1.59 -1.73)
Asthma (vs. none) With no recent OCS use 1.15 (1.10 -1.21) 1.00 (0.95 -1.05)
With recent OCS use 1.61 (1.47 -1.75) 1.15 (1.05 -1.26)
Chronic heart disease 1.57 (1.51 –1.64)
Diabetesb (vs. none) With HbA1c < 58 mmol/mol 1.53 (1.47 -1.59) 1.20 (1.16 -1.25)
With HbA1c ≥ 58 mmol/mol 2.57 (2.45-2.70) 1.83 (1.74 -1.93)
With no recent HbA1c
measure 2.19 (2.02 -2.37) 1.71 (1.58 -1.86)
Cancer (non -
hematological, vs. none) Diagnosed <1 year ago 1.47 (1.31 -1.65) 1.44 (1.28 -1.62)
Diagnosed 1 -4.9 years ago 1.13 (1.04 -1.22) 1.11 (1.03-1.20)
Diagnosed ≥ 5 years ago 0.99 (0.95 -1.04) 2.41 (1.86 -3.13)
Hematological
malignancy (vs. none) Diagnosed <1 year ago 2.54 (1.96 -3.29) 2.80 (2.08 –3.78)
Diagnosed 1 -4.9 years ago 2.28 (1.95 -2.66) 2.25 (1.92 -2.62)
Diagnosed ≥ 5 years ago 1.71 (1.51 -1.93) 1.65 (1.46 -1.87)
Reduced kidney
functionc (vs. none) eGFR 30-60 1.50 (1.45 -1.55) 1.30 (1.25 -1.35)
eGFR 15-< 30 2.74 (2.56 -2.93) 2.52 (2.33 –2.72)
eGFR <15 or dialysis 6.40 (5.75 -7.12) 4.42 (3.93 -4.98)
Liver disease
2.27 (2.01 -2.57) 1.75 (1.54 -1.98)
Dementia 4.59 (4.33 -4.87) 3.62 (3.41 -3.84)
Stroke 2.03 (1.95 -2.12) 1.53 (1.46 -1.59)
Other neurological disease 3.15 (2.96 -3.36) 2.72 (2.55 -2.90)
Organ transplant
5.54 (4.51 -6.81) 1.61 (1.28 -2.02)
Asplenia
1.50 (1.16 -1.95) 1.26 (0.97 -1.64)
Rheumatoid arthritis, lupus, or psoriasis 1.30 (1.21 –1.38) 1.23 (1.17 -1.30)
Other immunosuppressive condition 2.75 (2.10 –3.62) 2.00 (1.57 -2.54)
a. Classification by HbA1c is based on the most recent measurement within 15 months of baseline.
b. eGFR is measured in m L min−1 per 1.73 m2 and derived from the most recent serum creatinine
measurement.
c. Index of Multiple Deprivation (derived from the patient’s postcode)
Models were adjusted for age using a four-knot cubic spline for age, except for estimation of age- group hazard ratios.
Ref, reference group; 95% CI, 95% confidence interval.
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The main existing treatment options:
Through 30 September 2021, other COVID -19 vaccines were authorized and recommended
for use in the United States including vaccines from Moderna (NCT04470427), and Johnson
& Johnson/ Janssen (NCT04505722) . Others may subsequently be approved.
Natural history of the indicated condition in the untreated population, including
mortality and morbidity:
Symptoms of COVID -19
The clinical manifestations of COVID -19 vary widely, from asymptomatic infection in
17-45% across age groups , 55, 56 57, 58 to critical illness and death. The rate of asymptomatic
infection decreases with increasing age and long -term care facilities are associated with a
lower rate of asymptomatic infection when compared to household transmission or other
healthcare facilities.58 A recent meta-analysis has estimated that 46.7% of infections in
children are asymptomatic.58 The most common symptoms of COVID -19 are fever, cough,
and shortness of breath for both children and adults ( Table 47).59, 60 .
Table 47. Signs and symptoms among 291 pediatric (age <18 years) and 10,944 adult
(age 18–64 years) patientsa with laboratory confirmed COVID -19 —
United States, 12 February – 2April 2020 59
No. (%) with sign/symptom
Sign/Symptom Pediatric Adult
Fever, cough, or shortness of breathb 213 (73) 10,167 (93)
Feverd 163 (56) 7,794 (71)
Cough 158 (54) 8,775 (80)
Shortness of breath 39 (13) 4,674 (43)
Myalgia 66 (23) 6,713 (61)
Runny nosec 21 (7.2) 757 (6.9)
Sore throat 71 (24) 3,795 (35)
Headache 81 (28) 6,335 (58)
Nausea/Vomiting 31 (11) 1,746 (16)
Abdominal painc 17 (5.8) 1,329 (12)
Diarrhea 37 (13) 3,353 (31)
a. Cases were included in the denominator if they had a known symptom status for fever, cough, s hortness
of breath, nausea/vomiting, and diarrhea. Total number of patients by age group: <18 years (N = 2,572), 18 –
64 years (N = 113,985).
b. Includes all cases with one or more of these symptoms.
c. Runny nose and abdominal pain were less frequently completed than other symptoms; ther efore,
percentages with these symptoms are likely underestimates.
d. Patients were included if they had information for eith er measured or subjective fever variables and were considered
to have a fever if “yes” was indicated for either variable.
Progression and Timeline of Mild to Moderate Disease
Mild to moderate disease is defined as the absence of viral pneumonia and hypoxia. For those
who develop symptoms, the incubation period is usually 4 to 5 days, with 97.5% experiencing symptoms within 11 days of exposure.
61,62 Those with mild COVID -19 recover
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at home with supportive care and guidance to self -isolate. Those with moderate disease are
monitored at home and are sometimes recommended to be hospitalized if conditions
worsen. 62 Data on rates of re-infection are limited but variants that are not neutralized b y
immune antisera, such as the recent beta ( South African ) variant, may lead to increased risk
of re-infection in the future. 61
Progression and Timeline of Severe Disease Requiring Hospitalization
Those with severe disease will require hospitalization to manage their illness. Based on data
that have been systematically collected for the US by the CDC between 01 August 2020 and
05 September 2021, there were 2,816,280 new hospital admissions for patients with
confirmed COVID -19 in the US.63 For the week ending 22 August 2021, 3.5 patients per
100,000 population were hospitalised due to COVID -19 in 21 countries of the EU/EEA with
available data.64 Based on data from 23 states and New York City, as of August 19, 2021,
1.6%-3.6% of children with COVID -19 have been hospitalised and 0.0-0.03% of children
with COVID-19 have died.65
The most common symptoms in patients are fever (42-80%), shortness of breath (35-71%),
fatigue (33 -62%), cough (77-84%), chills (63%), myalgias (63%), headache (59%), and
diarrhea (33%) .66,67,68,69 COVID-19 patients also commonly experience gustatory disorders
(44%) and olfactory disorders (53%).70 Among unhospitalised children < 18 years of age,
89% experienced one or more typical symptoms of COVID, including fever, cough, shortness of breath, and 22% experienced all three.
67Approximately 17% to 40% of those
hospitalised with COVID -19 experience severe symptoms necessitating intensive care ,22,27,66
with 31% of children hospitalised experiencing severe COVID -19 that necessitates intensive
care or invasive ventilation or ends in death. Risk factors for severe COVID -19 in
hospitalised children include presence of a comorbid condition, younger age, and male sex.34
More than 75% of patients hospitali sed with COVID-19 require supplemental oxygen.71
Studies early in the pandemic demonstrated that time from onset of illness to ARDS was
8-12 days and time from onset of illness to IC U admission was 9.5 –12 days. 61 In 17
countries of the EU/EEA with available data, 1.8 patients per 100,000 population were in the ICU due to COVID -19 for the week ending 28 February 2021.
72 A recent meta-analysis
found that, of patients <19 years of age, 11% went to the ICU, non-invasive ventilation was administered among 12%, and 4% required mechanical ventilation.
56
Mortality
As of 17 August 2021, there were 620,493 deaths reported in the US for all age groups
among 36,951,181 cases (1.7% of cases).73 As of 17 August 2021 there were 746,566 deaths
reported for all age groups in the EU/EEA among 35,381,520 cases (2.1% of cases).74 As of
17 August 2021, the UK has seen 131,466 deaths from COVID -19 in all age groups among
6,352,224 cases (2.1% of cases) .75 According to a recent meta-analysis of paediatric studies
published through October 2020, the mortality for paediatric patients is 0.1-2%.56, 21 In a
study from January through June 2020 using the National Child Mortality Database (NCMD)
in England, 5.7% of 437 children 0-17 years of age who died were SARS -CoV-2
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PCR-positive and those who died of COVID -19 were older and were more likely to be
non-White ethnicity .76
Mortality data are also presented from Worldometer, an independent organi sation that
publishes current, reliable COVID -19 statistics online.14 The mortality of SARS -CoV-2
infection is defined as the cumulative number of deaths among detected cases.
As of 15 August 2021, the overall SARS -CoV-2 mortality for the EU + UK w as
878,344 deaths, or 171 per 100,000 people. Reported mortality among EU countries and the
UK ranged from 18 to 312 deaths per 100,000 ( Table 40). Finland and Cyprus reported the
lowest mortality; Hungary, Czech Republic, and Bulgaria reported the highest.15
In the US, as of 15 August 2021, the mortality was 637,439 deaths (191 per 100,000 people).
Mortality in the US was very similar to that of the UK (192 per 100,000) . 15
Overall reported mortality among hospitalis ed COVID-19 patients varies from 12.8% to 26%
in the EU, UK, and US .27,29, 77,78. Mortality rates are declining over time, presumably due to
an improved understanding of COVID -19 and its management.79
Complications of COVID -19 and Long-COVID
Complications of COVID -19 include impaired function of the heart, brain, lung, liver,
kidney, and coagulation system. 22,25, 80 Based on a meta-analysis of 42 studies, the risk of
thromboembolism was 21% overall and 31% in the ICU, with the pooled odds of mortality
being 74% higher among those who experienced thromboembolism compared to those who
did not.81
COVID-19 symptoms can persist weeks or months beyond the acute infection.82,83 The
NICE guideline scope published on 30 October 2020 defined “Long COVID” signs and
symptoms that continue or develop after acute COVID‑19. It includes both ongoing symptomatic COVID‑19 (from 4 to 12 weeks) and post‑COVID‑19 syndrome (12 weeks or
more and for which signs and symptoms are not explained by an alternative diagnosis).
84
A meta analysis of 31 studies among patients between 18 to 49 years of age found that
COVID-19 symptoms were experienced for 14 days to 3 months post -infection, including
persistent fatigue (39 –73%), breathlessnes s (39–74%), decrease in quality of life (44 –69%),
impaired pulmonary function, abnormal CT findings including pulmonary fibrosis (39 –83%),
evidence of peri -/perimyo -/myocarditis (3 –26%), changes in microstructural and functional
brain integrity with persis tent neurological symptoms (55%), increased incidence of
psychiatric diagnoses (5.8% versus 2.5 –3.4% in controls), and incomplete recovery of
olfactory and gustatory dysfunction (33 –36%).85 Post-acute COVID symptoms in children
with asymptomatic or mild d isease appear to be less severe than in adults, with the most
common symptoms being a post -viral cough (4%), fatigue (2%), or both symptoms (1%)
with the duration of symptoms lasting 3 to 8 weeks.86
Children who are infected with COVID -19 are at risk of subsequent multisystem
inflammatory syndrome (MIS -C) and often develop a rash following resolution of COVID -
19.56,87,88 As of August 19, 2021 there were 4,403 case s of MIS-C reported to health
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departments in the U S. 89 Additional symptoms of MIS -C include abdominal pain, bloodshot
eyes, chest tightness or pain, diarrhea, lethargy, headache, low blood pressure, neck pain, and
vomiting.90
Important co-morbidities:
Important comorbidities in hospitalized COVID -19 patients include hypertension, diabetes,
obesity, cardiovascular disease, chronic pulmonary disease or asthma, chronic kidney disease, cancer, and chronic liver disease.
23, 24, 25, 66, 69 Prevalence of these conditions have
been reported to be lower in mild cases and higher among fatal cases, as shown as for EU/EEA countries in Table 48 below using TESSy data posted on 12 August 2021 .
91
Table 48. Preconditions among COVID -19 Patients in EU/EEA, by Severity of
Disease. Case -based Data from TESSy Reported 12 August 202191
EU/EEA, reported on 12 August 2021
Mild Hospitalised Severe Fatal
Total N 1,948,252 356,472 52,365 109,878
Asplenia (%) 0 0 0 0
Asthma (%) 0.6 1.2 1.3 1.2
Cancer, malignancy (%) 3.1 9.1 10 11.1
Cardiac disorder, excluding hypertension (%) 9.1 23.7 22.8 29.4
Chronic lung disease, excluding asthma (%) 1.8 3.6 4.4 3.6
Current smoking (%) 0.9 0.1 0.2 0
Diabetes (%) 5 17.1 20.5 19.2
Haematological disorders (%) 0 0.2 0.1 0.1
HIV/other immune deficiency (%) 0.2 0.7 0.7 0.5
Hypertension (%) 0.8 2.9 3.2 3.8
Kidney-related condition, renal disease (%) 0.3 1.8 1.9 2.7
Liver-related condition, liver disease (%) 0.3 0.7 0.7 0.6
Neuromuscular disorder, chronic neurological (%) 0.7 1.8 1.4 2.4
Obesity (%) 0.1 0.2 0.5 0.2
Other endocrine disorder, excluding diabetes (%) 0.3 0.2 0.1 0.1
Rheumatic diseases including arthritis (%) 0 0 0 0
Tuberculosis (%) 0 0 0 0
None (%) 76.7 36.7 32.3 25
Table 49 below summarizes comorbidities among US COVID-19 patients in a retrospective
cohort study conducted among 629,953 individuals tested for COVID -19 in a large health
system in the US Northwest between 01 March and 31 December 2020.40 The most common
comorbidities were similar in the full cohort and among those who tested positive: obesity,
hypertension, diabetes, and asthma. Among those hospitalized for COVID -19, a large
number of comorbidities had elevated prevalence compared to th e full cohort and those who
tested positive: obesity, hypertension, diabetes, kidney disease, congestive heart failure, coronary artery disease, and chronic obstructive pulmonary disease.
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Table 49. Comorbidities in individuals teste d for COVID-19 in the Providence St.
Joseph Health System – States of California, Oregon, and Washington,
01 March–31 December 2020 40
Comorbidity Tested
(N= 629,953)
% Positive
(N= 54,645)
% Hospitalized
(N= 8,536)
%
Hypertension 23.3 19.8 40.2
Diabetes 9.4 10.9 28.3
Weight
Underweight 2.1 1.7 3.1
Normal 29.0 23.9 24.3
Overweight 31.7 32.6 30.3
Class 1 Obesity 19.8 22.3 21.2
Class 2 Obesity 9.6 11.1 10.9
Class 3 Obesity 7.7 8.6 10.3
Asthma 6.5 5.3 6.7
Chronic Obstructive Pulmonary Disease 4.0 2.6 8.3
Coronary Artery Disease 5.5 3.6 9.7
Myocardial Infarction 2.2 1.6 5.5
Congestive Heart Failure 5.3 3.9 13.2
Kidney Disease 5.6 5.3 17.2
Liver Disease 3.1 2.5 4.0
Cancer 6.1 3.0 6.3
In a retrospective cohort of 135,794 individuals under the age of 25 who were tested for
COVID-19 by 08 September 2020 within the PEDSnet network of US pediatric health
systems, the proportion of obese individuals was similar among those who tested negative
(18%) and among mild or asymptomatic COVID -19 cases (19%), but clearly elevated among
severe COVID -19 cases (37%).33 Those with severe cases of COVID -19 more commonly
had chronic conditions in at least two body systems, with 25% of COVID -19 negative
individuals, 17% mild or a symptomatic cases, and 38% of severe cases having multiple
chronic conditions.
More recent data provide insight into comorbidities among the pediatric population. For the
period January 1-March 31 2021 across 14 states, the CDC’s COVID-NET database recor ded
204 adolescents aged 12-17 who were hospitalized for likely primarily COVID -related
reasons.31 Among the 204 adolescents, 70.6% had at least one major underlying medical
condition, the most common conditions being obesity (35.8%), chronic lung diseases including asthma (30.9%), and neurologic disorders (14.2%).
31
2.1.2.f. Pharmacological Class Effects
There are 2 vaccines (including BNT162b2 ) with a mRNA platform authorized for
emergency use in multiple US jurisdictions since 11 December 2020. Theoretical con cerns
in mRNA vaccines have included the risk of the presence of naked extracellular RNA in the
body which may lead to edema or coagulation and concerns about aberrant immune
responses to the RNA or lipid particles. The immunogenicity and efficacy data fr om study
C4591001 are indicative of the vaccine delivery system’s success in transfecting the RNA
090177e19a14c996\Final\Final On: 29-Apr-2022 17:55 (GMT)
FDA-CBER-2022-5812-0235895
BNT162b2
1.16 Risk Management Plan (Non-REMS) for Biologic License Application # 125742
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into the appropriate target cells to stimulate an immune response. The RNA itself cannot
integrate into the DNA genome.92,93 The probability of any sequence s from the vaccine
RNA being integrated into the human genome by a reverse transcription mediated
mechanism is considered remote, no higher than the probability of host RNA sequences
being re-inserted into the genome, especially given the small quantity of RNA in the vaccine,
the barriers to transfected RNA reaching the nucleus, the non -replicating nature of the
vaccine RNA, the limited stability of RNA in a cellular context, and the expected targeting of
transfected cells for elimination by T cells elicite d by the vaccine antigen expressed from the
RNA.
3. PHARMACOVIGILANCE PLAN
3.1. Structure of the Pharmacovigilance Plan
3.1.1. Summary of Ongoing Safety Concerns
Table 50. Ongoing Safety Concerns
Important Identified Risks Anaphylaxis
Myocarditis and Pericarditis
Important Potential Risks Vaccine-associated enhanced disease (VAED) including Vaccine -
associated enha
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