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BNT162b2
1.16 Risk Management Plan (Non -REMS) for Biologic License Application # 125742
CONFIDENTIAL
Page 1PHARMACOVIGILANCE PLAN FOR
BIOLOGIC LICENSE APPLICATION #125742
OF
COMIRNATY® ( PFIZER -BIONTECH COVID -19 VACCINE , mRNA, BNT162b2,
PF-07302048 )
Date of Report: 14December 2021
Version 1.4
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Page 2TABLE OF CONTENTS
LIST OF TABLES ................................ ................................ ................................ ..................... 3
LIST OF FIGURES ................................ ................................ ................................ ................... 6
LIST OF ABBREVIATION S................................ ................................ ................................ ....7
1. INTRODUCTION ................................ ................................ ................................ ............... 10
1.1. Product Details ................................ ................................ ................................ ........ 10
2. SAFETY SPECIFICAT ION................................ ................................ ................................ 12
2.1. Elements of the Safety Specification ................................ ................................ .......12
2.1.1. Non- Clinical ................................ ................................ ............................... 12
2.1.2. Clinical ................................ ................................ ................................ ........ 15
2.1.2.a. L imitatio ns of the Human Safet y 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 I nteractions, 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 ................................ ................................ ......90
3.1.4. Summary of Actions to be Completed, I ncluding Milestones.................. 108
3.2. Pharmacovigilance Methods ................................ ................................ ................. 122
3.2.1. L ist of Studies Included in the Pharmacovigilance Plan .......................... 122
REFERENCES ................................ ................................ ................................ ...................... 123
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Page 3LIST OF TABLES
Table 1. Product Details ................................ ................................ .......................... 10
Table 2. Key Safet y Findings and Relevance 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 Originall y Received
BNT162b2 ................................ ................................ ................................ 21
Table 5. Exposure to BNT162b2 by Age Group and Dose (C4591001) –
Open -Label Follow -up Period –Subjects Who Originall y 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 Af ter 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
Originall y Received BNT162b2 ................................ ............................... 29
Table 13. Exposure to BNT162b2 by Dose, Age Group, and Gender
(C4591001) – Open -Label Follow -up Period – Subjects Who
Originall y 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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Page 4Table 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 ................................ ................................ ....................... 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
Originall y Received BNT162b2 ................................ ............................... 41
Table 20. Exposure to BNT162b2 by Dose and Race/Ethnic Origin
(C4591001) – Open -Label Follow -up Period – Subjects Who
Originall y 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) b y Special Population (C4591001)
–Blinded Placebo -Controlled Follow- up Period ................................ .....43
Table 23. Exposure to BNT162b2 (30 μg) b y Special Population (C4591001)
–Open -Label Follow -up Period –Subjects Who Originall y
Received Placebo and Then Rece ived 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 BNT162 b2 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 Originall y 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) b y Special Population (C4591001)
– 12-15 Years – Blinded Placebo -Controlled Follow -up Period .............. 49
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Page 5Table 31. Exposure to BNT162b2 (30 μg) b y Special Population (C4591001)
– 12-15 Years – Open -Label Follow -up Period – Subjects Who
Originall y Received Placebo and Then Received BNT162b2 After
Unblinding ................................ ................................ ................................ 50
Table 32. Cumulative Estimated Shipped/Administered Doses of BNT162b2
by Region Worldwide ................................ ................................ ............... 53
Table 33. Exposure of Special Populations I ncluded or not in Clinical Trial
Development Programs ................................ ................................ ............ 55
Table 34. Myocarditis and Pericarditis ................................ ................................ .....57
Table 35. Anaph ylaxis................................ ................................ .............................. 62
Table 36. Vaccine -Associated Enhanced Disease (VAED), including
Vaccine -Associated Enhanced Respiratory 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 as of 14 August
2021 20................................ ................................ ................................ .......76
Table 42. Distribution of Deaths (n=513,204) b y 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 202033................................ ......................... 79
Table 45. Risk for COVID -19 infection, Hospitalisation, an d Death b y Age
Group and b y Race/Ethnicity39................................ ................................ .80
Table 46. Hazard Ratios and 95% Confidence Intervals for COVID -19-related
Death46................................ ................................ ................................ ......81
Table 47. Signs and s ymptoms among 291 pediatric (age <18 y ears) 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 Severit y
of Disease. Case -based Data from TESSy Reported 12 August
202191................................ ................................ ................................ ........ 86
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Page 6Table 49. Comorbidities in individuals tested for COVID -19 in the
Providence St. Joseph Health Sy stem – States of California,
Oreg on, and Washington, 01 March –31 December 2020 40..................... 87
Table 50. Ongoing Safet y Concerns ................................ ................................ ......... 88
Table 51. Action Plan for Important I dentified Risk “ Myocarditis and
Pericarditis” ................................ ................................ .............................. 90
Table 52. Action Plan for Important I dentified Risk “Anaphy laxis” ....................... 94
Table 53. Action Plan for Important Potential Risk “Vaccine -associated
enhanced disease (VAED) including Vaccine -associated enhanced
respiratory disease (VAERD)” ................................ ................................ .97
Table 54. Action Plan for Missing Information “Use in Pregnancy and
Lactation” ................................ ................................ ................................ .99
Table 55. Action Plan for Missing Information “Vaccine Effectiveness” ............. 102
Table 56. Action Plan for Missing Information “Use in Paediatric Individuals
<5Years of Age” ................................ ................................ .................... 103
Table 57. Summary of Safet y Concerns and Action Plans ................................ .....109
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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Page 7LIST OF ABBREVIATIONS
Abbreviation Definition of Term
AE adverse event
AESI adverse event of special interest
A:G albumin:globulin
ALC-0315 ((4-hydroxybutyl)azanediy l)bis(hexane -6,1- diyl)bis(2-
hexyldecanoate )
ALC-0159 2-[(polyethylene gl ycol)-2000]-N,N-
ditetradecy lacetamide
ARDS acute respiratory distress sy ndrome
BALB/c bagg albino
BC Brighton Collaboration
BEST biologics effectiveness and safet y
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
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 analy sis
ICU intensive care unit
IFN Interferon
IL-4 interleukin -4
IM intramuscular(l y)
IMD index of multiple deprivation
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Page 8Abbreviation Definition of Term
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 Sy stem
MIS-C multisy stem 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 monthl y safety report
Tdap tetanus, diphtheria, and acellular pertussis
TESSy TheEuropean Surveillance Sy stem
Th1 T helper cell ty pe 1
Th2 T helper cell ty pe 2
UK United Kingdom
US United States
USP United States pharmacopeia
V8 variant 8
V9 variant 9
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Page 9Abbreviation Definition of Term
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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Page 101.INTRODUCTION
1.1.Product Details
Table 1.Product Detailsa
Product COVID -19 Vaccine, mRNA, herein after referred to as BNT162b2 isa
nucleoside- modified messenger RNA ( modRNA )encoding the viral spike (S)
glycoprotein of severe acute respiratory syndrome coronavirus 2 (SARS -CoV -
2).
Brief description of the
productChemical class:
modRNA formu lated in lipid particles .
Mechanism ofAction :
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 :
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 -(poly ethylene 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 sucrose. 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 w ith natural rubber latex.
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
administrationCurrent :
BNT162b2 is administered intramuscularly as a series of two doses (0.3 mL
each) 3 w eeks 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 do se of BNT162b2 to
complete the vaccination series.
a.COVID -19 Vaccine, mRNA US Prescribing Information
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Page 11Data 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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Page 122.SAFETY SPECIFICATION
2.1. Elements of the Safety Specification
2.1.1. Non-Clinical
Nonclinical evaluation of BNT162b2 included pharmacology (mouse immunogenicity and
NHP immunogenicit y 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 a nd 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 +CD8+T-cell response. The Th1
profile is char acterized 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 safet y and
efficacy .1 Rhesus macaques (Study VR-VRT -10671) that had received two IM
immunizatio ns with 100 µg BNT162b2 or saline 21 day s apart were challenged with 1.05 ×
106plaque 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
presen ce 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 with the identical lipid composition as
BNT162b2 , demonstrated that the novel lipid excipients in the L NP formulation, AL C-0315
and AL C-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 AL C-0315. Biodistribution was assessed using luciferase
expression as a surrogate reporter formulated like BNT162b2 , with the iden tical 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 backgrou nd levels after 9 day s.
Luciferase was detected to a lesser extent in the liver; expression was present at 6 hours after
injection and was not detected b y 48 hours after injection. After IM administration of a
radiolabeled LNP -mRNA formulation containing ALC-0315 and ALC -0159 to rats, the
percent of administered 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 th e adrenal glands and ovaries. The metabolism of AL C-0315
and AL C-0159 was evaluated in blood, liver microsomes, S9 fractions, and hepatocy tes from
mice, rats, monkey s, and humans. The in vivo metabolism was examined in rat plasma,
urine, feces, and liver samples from the PK study. AL C-0315 and ALC -0159 are
metabolized by hydrolytic metabolism of the ester and amide functionalities, respectivel y,
and this hy drolytic metabolism is observed across the species evaluated.
In GL P 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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Page 13amino 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 day s in
duration with a 3 -week recovery period. A GL P-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 guide line.3
The IM route of exposure was selected for nonclinical investigations as 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 ro utinel y used for regulatory
toxicity studies with an extensive historical safety 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. I njection 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 reticulocy tes, platelets and R BC mass parameters. Decreased
reticulocy tes were reported in rats treated with the licensed LNP- siRNA pharmaceutical
Onpattro™ (NDA # 210922) but have not been observed in humans treated with this
biotherapeutic4suggesting this is a species -specific eff ect. 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 leve ls of gamma -glutam yl transferase were observed in
the first repeat -dose toxicity 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 fin al 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
regenerativ e ery throid response) and lower A:G ratios (resulting from acute phase response)
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 l ymph 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 l ymph nodes, bone marrow
and spleen and hepatocyte vacuolation in the liver. Vacuolation of periportal hepatocy tes,
the only test article -related liver microscopic finding, was not associated with any
microscopic evidence of hepatic injury or hepatic functi onal effects (i.e., liver functional
enzy mes were not elevated) and may be associated with hepatocy te uptake of the LNP
lipids.5 Microscopic findings at the end of the dosing phase were partially or completel y
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 (bod y
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Page 14weight, 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
embry o-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 nonclinical 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 StudiesaRelevance to Hum an Usage
Pharm acology
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 low er 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 increased
body temperature, higher circulating WBCs
and higher acute phase proteins.
Decreased reticulocytes have not been
observed in humans treated w ith the
LNP -siRNA pharmaceutical Onpattro4,
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 m agnitude.
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 w omen or their offspring.
a.Safety pharmacology, genotoxicity, and carcinogenicity studies were not conducted, in accordance w ith
2005 WHO vaccine guideline, as they are generally not considered necessary to support dev elopm ent 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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Page 152.1.2. 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 analy sis 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 conduct ing a first -in-human dose level –finding Phase 1/2 study in Germany to
gather safet y and immunogenicity data to enable evaluation of 4 vaccines candidates
individually to inform the overall clinical development of a BNT162b2.
BNT162 -01 isnot conducted under the US IND application but is being conducted under a
German Clinical Trial Application.
Four vaccine candidates were evaluated in Stud y BNT162 -01. Based on safet y and
immunogenicit y 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 health y 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 day s 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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Page 16Both 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 primaril y because:
the reactogenicit y 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 safet y and
immunogenicity data for the first 360 participants (180 from the active vaccine group and
180 from theplacebo 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 stud y (which is ongoing) evaluates the efficacy and safety in all
participants (including the first 360 participants from Phase 2). Phase 3 introduced:
enrol lment of participants 16 to 17 y ears of age to be evaluated with the 18 -to 55 -
year-old cohort,
enrollment of a 12-to 15-year-old cohort ,
immunogenicit y data from the12-to15-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 anal ysis with vaccine
efficacy shown to be 95% and obtaining regulatory authori zation to vaccinate in man y
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
authori zation. 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
safet y data is onl y available for up to 6 months post Dose 2.
The initial efficacy analysis on the 16 y ears and older population wasevent -driven, with
prespecified interim analy ses after accrual of at least 62, 92, and 120 cases and a final
analysis at 164 cases.
A further efficacy anal ysis has been conducted on 12- to ≤15-year-old cohort participants and
on 16 years and older participants cohort pa rticipants reported b y 13 March 2021.
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Page 17Other o ngoing1BNT162b2 interventional studies at the cut-offof the clinical database (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-2RNA vaccine
candidate against COVID- 19 in healthy Japanese adults.
One hundred sixty participants were randoml y assigned in a 3:1 ratio to study
intervention (candidate vaccine: 120, placebo: 40).
PASS : C4591015: A phase 2/3 study , placebo- controlled, randomized, 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 -blinde d 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 consists 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 , tolerabilit y, and immunogenicity of the selected dose level in
each age group from Phase 1, with a total of approximately 4500 participants.
Participants wil l 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 in vestigating 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 -032Safety and immunogenicity of SARS -CoV-2 mRNA vaccine (BNT162b1) in
Chinese healthy subjects: A phase I, randomized, placebo - controlled, observer -blind
study .
1Study C4591017 w as com pleted and therefore is removed from this list.
2This study is conducted by Shanghai Fosun Pharmaceutical Development, Inc. and sponsored by
BioNTech SE.
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Page 18BNT162 -04 A multi- site, phase I/II, 2 -part, dose escalation trial investigating the safety
and immunogenicity of a prophylactic SARS- CoV-2 RNA vaccine (BNT162b3) aga inst
COVID -19 using different dosing regimens in healthy adults .
BNT162 -062Safety and immunogenicity of SARS- CoV-2 mRNA vaccine (BNT162b2) in
Chinese healthy population: A phase II, randomized, placebo -controlled, observer- blind
study
BNT162 -14A 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 trial
subjects
BNT162 -17 A P hase II trial to evaluate the safet y and immunogenicit y of a SARS -CoV -2
multivalent RNA vaccine in healthy subjects.
Clinical Trial Exposure
Population for anal ysis of CTs data in this US Pharmacovigilance Plan includes the
following 2 studies:
C4591001: P hase 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 -offdate 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 360received 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 originall y 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 3through Table 21.
In addition, exposure in clinical studies in special populations is provided in Table 22and
Table 23.
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Page 19Participants 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, u pdated c linical study exposure data for the
12-to 15 y ears of age are provided for the ongoing study C4591001:
oOne thousand one hundred twent y-four ( 1124 )participants received 2 doses and
7received 1 dose of BNT162b2 in the Blinded -Placebo Controlled Follow -up
period.
oOne thousand and ten (1010 )participants who originall y received pla cebo, then
received 1 dose of BNT162b2 (18) or 2 doses (992) in the O pen-Label Follow -
up period after unblinding.
Exposure to BNT162b2 for participants aged 12 -to 15 y ears of age by number of doses
and demographic characteristics 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
andTable 23, Table 30and Table 31.
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Page 20Exposure 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 BNT162b2Total 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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Page 21Table 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 BNT162b2Total 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 30µg
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 BNT162b2Total 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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Page 22Table 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 BNT162b2Total 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 2ndDose 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 BNT162b2Total 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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Page 23Table 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 BNT162b2Total Number of
Vaccine Doses
Vaccine 30µg
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 BNT162b2Total No. of Vaccine Doses
≥18 years to ≤ 64years
Vaccine 1 µg
1 Dose 1 1
2 Doses 11 22
Total 12 23
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Page 24Table 6.Exposure to BNT162b2 by Age Group and Dose (BNT162 -01)
Age Group
Dose
Exposure (Number of Doses
Received)No. of Subjects
Exposed to BNT162b2Total 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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Page 25Table 6.Exposure to BNT162b2 by Age Group and Dose (BNT162 -01)
Age Group
Dose
Exposure (Number of Doses
Received)No. of Subjects
Exposed to BNT162b2Total 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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Output File: ex_b2_age_dose2 rtf
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Page 26Table 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 BNT162b2Total 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 BNT162b2Total Number of
Vaccine Doses
Vaccine 30µg
1 Dose 89 89
Note: 30 μg includes data from phase 1 and phase 2/3.
Note: Subjects who received 2ndDose of BNT162b2 after unblinding.
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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 BNT162b2Total Number of
Vaccine Doses
Vaccine 30 µg
1 Dose 3657 3657
2 Doses 16039 32078
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Page 27Table 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 BNT162b2Total Number of
Vaccine Doses
Total 19696 35735
Note: 30 μg includes data from phase 1 and phase 2/3.
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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
BNT162b2Total 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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Page 28Table 10.Exposure to BNT162b2 by Dose (Totals) (BNT162-01)
Dose
Exposure (Number of Doses Received)No. of Subjects
Exposed to
BNT162b2Total No. of Vaccine Doses
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Output File: ex_b2_dose.rtf
Table 11.Exposure to BNT162b2 by Dose, Age Group, and Gender (C4591001) –
Blinded Placebo -Controlled Follow -up Period
Number of Subjects Exposed
to BNT162b2Total Number of Vaccine
Doses
Dose
Age GroupMale Fem ale Male Fem ale
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
090177e198e191a8\Approved\Approved On: 15-Dec-2021 10:11 (GMT)
FDA-CBER-2022-5812-0220571
BNT162b2
1.16 Risk Management Plan (Non -REMS) for Biologic License Application # 125742
CONFIDENTIAL
Page 29Table 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 BNT162b2Total Number of Vaccine
Doses
Dose
Age GroupMale Fem ale Male Fem ale
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 2ndDose 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/ads l_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 BNT162b2Total Number of Vaccine
Doses
Dose
Age GroupMale Fem ale Male Fem ale
Vaccine 30 µg
≥12 years to ≤15 yearsa26 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)
090177e198e191a8\Approved\Approved On: 15-Dec-2021 10:11 (GMT)
FDA-CBER-2022-5812-0220572
BNT162b2
1.16 Risk Management Plan (Non -REMS) for Biologic License Application # 125742
CONFIDENTIAL
Page 30Table 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 BNT162b2Total Number of Vaccine
Doses
Dose
Age GroupMale Fem ale Male Fem ale
(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
BNT162b2Total No. of Vaccine Doses
Dose
Age GroupMale Fem ale Male Fem ale
Vaccine 1µg
≥18 years to ≤64 years7 5 14 9
≥65 years to ≤74 years0 0 0 0
≥75 years to ≤84 years0 0 0 0
Total7 5 14 9
Vaccine 3µg
≥18 years to ≤64 years5 7 10 14
≥65 years to ≤74 years0 0 0 0
≥75 years to ≤84 years0 0 0 0
Total5 7 10 14
Vaccine 10µg
≥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
Total12 12 24 23
Vaccine 20µg
≥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 30µg
≥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
090177e198e191a8\Approved\Approved On: 15-Dec-2021 10:11 (GMT)
FDA-CBER-2022-5812-0220573
BNT162b2
1.16 Risk Management Plan (Non -REMS) for Biologic License Application # 125742
CONFIDENTIAL
Page 31Table 14.Exposure to BNT162b2 by Dose, Age Group, and Gender (BNT162- 01)
No. of Subjects Exposed to
BNT162b2Total No. of Vaccine Doses
Dose
Age GroupMale Fem ale Male Fem ale
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 OriginNumber of Subjects
Exposed to BNT162b2Total 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 Haw aiian 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 Haw aiian or other Pacific Islander 3 6
Multiracial 10 20
Total 378 752
Ethnic origin
Hispanic/Latino 49 98
090177e198e191a8\Approved\Approved On: 15-Dec-2021 10:11 (GMT)
FDA-CBER-2022-5812-0220574
BNT162b2
1.16 Risk Management Plan (Non -REMS) for Biologic License Application # 125742
CONFIDENTIAL
Page 32Table 15.Exposure to BNT162b2 by Age Group, Dose, and Race/Ethnic Origin
(C4591001) – Blinded Placebo -Controlled Follow -up Period
Age Group
Dose
Race/Ethnic OriginNumber of Subjects
Exposed to BNT162b2Total 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 Haw aiian 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
090177e198e191a8\Approved\Approved On: 15-Dec-2021 10:11 (GMT)
FDA-CBER-2022-5812-0220575
BNT162b2
1.16 Risk Management Plan (Non -REMS) for Biologic License Application # 125742
CONFIDENTIAL
Page 33Table 15.Exposure to BNT162b2 by Age Group, Dose, and Race/Ethnic Origin
(C4591001) – Blinded Placebo -Controlled Follow -up Period
Age Group
Dose
Race/Ethnic OriginNumber of Subjects
Exposed to BNT162b2Total Number of
Vaccine Doses
White 3719 7388
Black or African American 430 849
Asian 135 267
American Indian or Alaska Native 30 58
Native Haw aiian 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 Haw aiian or other Pacific Islander 6 12
Multiracial 30 60
Not reported 10 20
Total 3641 7265
Ethnic origin
090177e198e191a8\Approved\Approved On: 15-Dec-2021 10:11 (GMT)
FDA-CBER-2022-5812-0220576
BNT162b2
1.16 Risk Management Plan (Non -REMS) for Biologic License Application # 125742
CONFIDENTIAL
Page 34Table 15.Exposure to BNT162b2 by Age Group, Dose, and Race/Ethnic Origin
(C4591001) – Blinded Placebo -Controlled Follow -up Period
Age Group
Dose
Race/Ethnic OriginNumber of Subjects
Exposed to BNT162b2Total 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 Haw aiian 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
090177e198e191a8\Approved\Approved On: 15-Dec-2021 10:11 (GMT)
FDA-CBER-2022-5812-0220577
BNT162b2
1.16 Risk Management Plan (Non -REMS) for Biologic License Application # 125742
CONFIDENTIAL
Page 35Table 15.Exposure to BNT162b2 by Age Group, Dose, and Race/Ethnic Origin
(C4591001) – Blinded Placebo -Controlled Follow -up Period
Age Group
Dose
Race/Ethnic OriginNumber of Subjects
Exposed to BNT162b2Total 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 OriginNumber of Subjects
Exposed to BNT162b2Total 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 30µg
Racial origin
White 14 14
Asian 1 1
American Indian or Alaska Native 2 2
Total 17 17
090177e198e191a8\Approved\Approved On: 15-Dec-2021 10:11 (GMT)
FDA-CBER-2022-5812-0220578
BNT162b2
1.16 Risk Management Plan (Non -REMS) for Biologic License Application # 125742
CONFIDENTIAL
Page 36Table 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 OriginNumber of Subjects
Exposed to BNT162b2Total 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 2ndDose 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
090177e198e191a8\Approved\Approved On: 15-Dec-2021 10:11 (GMT)
FDA-CBER-2022-5812-0220579
BNT162b2
1.16 Risk Management Plan (Non -REMS) for Biologic License Application # 125742
CONFIDENTIAL
Page 37Table 17.Exposure to BNT162b2 by Age Group, Dose, and Race/Ethnic Origin
(C4591001) – Open -Label Follow -up Period – Subj ects Who Originally
Received Placebo and Then Received BNT162b2 After Unblinding
Age Group
Dose
Race/Ethnic OriginNumber of Subjects
Exposed to BNT162b2Total 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 Haw aiian 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 Haw aiian or other Pacific Islander 17 32
Multiracial 405 781
Not reported 70 127
Total 11132 19551
Ethnic origin
090177e198e191a8\Approved\Approved On: 15-Dec-2021 10:11 (GMT)
FDA-CBER-2022-5812-0220580
BNT162b2
1.16 Risk Management Plan (Non -REMS) for Biologic License Application # 125742
CONFIDENTIAL
Page 38Table 17.Exposure to BNT162b2 by Age Group, Dose, and Race/Ethnic Origin
(C4591001) – Open -Label Follow -up Period – Subj ects Who Originally
Received Placebo and Then Received BNT162b2 After Unblinding
Age Group
Dose
Race/Ethnic OriginNumber of Subjects
Exposed to BNT162b2Total 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 Haw aiian 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 Haw aiian 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
090177e198e191a8\Approved\Approved On: 15-Dec-2021 10:11 (GMT)
FDA-CBER-2022-5812-0220581
BNT162b2
1.16 Risk Management Plan (Non -REMS) for Biologic License Application # 125742
CONFIDENTIAL
Page 39Table 17.Exposure to BNT162b2 by Age Group, Dose, and Race/Ethnic Origin
(C4591001) – Open -Label Follow -up Period – Subj ects Who Originally
Received Placebo and Then Received BNT162b2 After Unblinding
Age Group
Dose
Race/Ethnic OriginNumber of Subjects
Exposed to BNT162b2Total 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 Generatio n:
27MAR2021 (12:46)
(Cutoff Date: 13MAR2021, Snapshot Date: 25MAR2021) Output File:
./nda2_unblinded/C4591001_PVP_BLA/adsl_s942_open
Table 18.Exposure to BNT162b2 by Dose and Race/Ethnic Origin (C4591001) –
Blinded Placebo -Contr olled Follow -up Period
Dose
Race/Ethnic OriginNumber of Subjects
Exposed to BNT162b2Total Number of
Vaccine Doses
Vaccine 10 µg
Racial origin
White 23 46
090177e198e191a8\Approved\Approved On: 15-Dec-2021 10:11 (GMT)
FDA-CBER-2022-5812-0220582
BNT162b2
1.16 Risk Management Plan (Non -REMS) for Biologic License Application # 125742
CONFIDENTIAL
Page 40Table 18.Exposure to BNT162b2 by Dose and Race/Ethnic Origin (C4591001) –
Blinded Placebo -Contr olled Follow -up Period
Dose
Race/Ethnic OriginNumber of Subjects
Exposed to BNT162b2Total 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 Haw aiian 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
090177e198e191a8\Approved\Approved On: 15-Dec-2021 10:11 (GMT)
FDA-CBER-2022-5812-0220583
BNT162b2
1.16 Risk Management Plan (Non -REMS) for Biologic License Application # 125742
CONFIDENTIAL
Page 41Table 19.Exposure to BNT162b2 by Dose and Race/Ethnic Origin (C4591001) –
Open -Label Follow -up Period – Subjects Who Originally Received
BNT162b2
Dose
Race/Ethnic OriginNumber of Subjects
Exposed to BNT162b2Total 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 2ndDose 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 OriginNumber of Subjects
Exposed to BNT162b2Total 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 Haw aiian 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
090177e198e191a8\Approved\Approved On: 15-Dec-2021 10:11 (GMT)
FDA-CBER-2022-5812-0220584
BNT162b2
1.16 Risk Management Plan (Non -REMS) for Biologic License Application # 125742
CONFIDENTIAL
Page 42Table 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 OriginNumber of Subjects
Exposed to BNT162b2Total 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 OriginNo. of Subjects Exposed to
BNT162b2Total No. of Vaccine Doses
Vaccine 1µg
Racial Origin
White 12 23
Total 12 23
Ethnic Origin
Non-Hispanic/non -Latino 12 23
Total 12 23
Vaccine 3µg
Racial Origin
White 12 24
Total 12 24
Ethnic Origin
Non-Hispanic/non -Latino 12 24
Total 12 24
Vaccine 10µg
Racial Origin
White 24 47
Total 24 47
Ethnic Origin
Non-Hispanic/non -Latino 24 47
Total 24 47
Vaccine 20µg
Racial Origin
White 24 48
Total 24 48
Ethnic Origin
090177e198e191a8\Approved\Approved On: 15-Dec-2021 10:11 (GMT)
FDA-CBER-2022-5812-0220585
BNT162b2
1.16 Risk Management Plan (Non -REMS) for Biologic License Application # 125742
CONFIDENTIAL
Page 43Table 21. Exposure to BNT162b2 by Dose and Race/Ethnic Origin (BNT162-01)
Dose
Race/Ethnic OriginNo. of Subjects Exposed to
BNT162b2Total No. of Vaccine Doses
Non-Hispanic/non -Latino 24 48
Total 24 48
Vaccine 30µg
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_race rtf
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)
nbTotal Number
of
Vaccine Doses
Subjects with any baseline comorbidity 10371 26487
AIDS/HIV 100 196
Any Malignancy + Metastatic Solid Tumor + Leukemia +
Lymphoma852 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 Failure651 1298
Dem entia 7 14
Diabetes With/Without Chronic Complication 1706 3385
Hem iplegia or Paraplegia 4 8
Peptic Ulcer Disease 63 126
Obese 7689 15262
Note: Comorbidity is based on Charlson Com orbidity 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 pr eferred terms Hemiplegia and Paraplegia.
a. N = number of subjects in the specified group.
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Page 44Table 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)
nbTotal 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 ≥95thpercentile [12 -15 Years of age]).
PFIZER CONFIDENTIAL SDTM Creation: 25MAR2021 (19:25) Source Data: admh Table Generation:
27MAR2021 (12:47)
(Cutoff Date: 13MAR2021, Snapshot Date: 25MAR2021) Output File:
./nda2_unblinded/C4591001_PVP_BLA/admh_s953
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)
nbTotal Number
of
Vaccine Doses
Subjects with any baseline comorbidity 8981 21590
AIDS/HIV 86 161
Any Malignancy + Metastatic Solid Tumor + Leukemia +
Lymphoma734 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 Failure567 1075
Dem entia 9 17
Diabetes With/Without Chronic Complication 1555 2928
Hem iplegia 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 ≥95thpercentile [12 -15 Years of age]).
PFIZER CONFIDENTIAL SDTM Creation: 25MAR2021 (19:25) Source Data: admh Table Generation:
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Page 45Table 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)
nbTotal Number
of
Vaccine Doses
(Cutoff Date: 13MAR2 021, Snapshot Date: 25MAR2021) Output File:
./nda2 unblinded/C4591001 PVP BLA/admh s953 open
Exposure in p articipants 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 BNT162b2Total Number of
Vaccine Doses
Vaccine 30 µg
1 Dose 7 7
2 Doses 1124 2248
Total 1131 2255
PFIZER CONFIDENTIAL SDTM Creation: 30SEP2021 (11:35) Source Data: adsl Table Generation:
04NOV2021 (12:52)
(Data Cutoff Date: 02SEP2021, Database Snapshot Date: 27SEP2021) Output File:
./nda2_unblinded/C4591001_PVP_adl6mpd2/adsl_s922
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 Un blinding
Dose
Exposure (Number of Doses Received)Number of Subjects
Exposed to BNT162b2Total 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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Page 46Table 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 Un blinding
Dose
Exposure (Number of Doses Received)Number of Subjects
Exposed to BNT162b2Total 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
BNT162b2Total Number of Vaccine Doses
Dose
Age GroupaMale Female Male Female
Vaccine 30 µg
≥12 years to ≤15
years567 564 1128 1127
a. Based on age at vaccination.
PFIZER CONFIDENTIAL SDTM Creation: 30SEP2021 (11:35) Source Data: adsl Table Generation:
04NOV2021 (12:52)
(Data Cutoff Date: 02SEP2021, Database Snapshot Date: 27SEP2021) Output File:
./nda2 unblinded/C4591001 PVP adl6mpd2/adsl 1215 s932 blind
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
BNT162b2Total Number of Vaccine Doses
Dose
Age GroupaMale Female Male Female
Vaccine 30 µg
≥12 years to ≤15
years518 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.
PFIZER CONFIDENTIAL SDTM Creation: 30SEP2021 (11:35) Source Data: adsl Table Generation:
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Page 47Table 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
BNT162b2Total Number of Vaccine Doses
Dose
Age GroupaMale Female Male Female
(Data Cutoff Date: 02SEP2021, Database Snapshot Date: 27SEP2021) Output File:
./nda2_unblinded/C4591001_PVP_a dl6mpd2/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 OriginNumber of Subjects
Exposed to BNT162b2Total 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
Native4 8
Native Haw aiian or other Pacific
Islander3 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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Page 48Table 28.Exposure to BNT162b2 by Race/Ethnic Origin (C4591001) – 12-15 Years
–Blinded Placebo -Controlled Follow -up Period
Age Groupa
Dose
Race/Ethnic OriginNumber of Subjects
Exposed to BNT162b2Total Number of
Vaccine Doses
a. Based on age at vaccination.
PFIZER CONFIDENTIAL SDTM Creation: 30SEP2021 (11:35) Source Data: adsl Table Generation:
04NOV2021 (12:52)
(Data Cutoff Date: 02SEP2021, Database Snapshot Date: 27SEP2021) Output File:
./nda2_unblinded/C4591001_PVP_adl6m pd2/adsl_1215_s942_blind
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 OriginNumber of Subjects
Exposed to BNT162b2Total 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
Native2 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.
PFIZER CONFIDENTIAL SDTM Creation: 30SEP2021 (11:35) Source Data: adsl Table Generation:
04NOV2021 (12:52)
(Data Cutoff Date: 02SEP2021, Database Snapshot Date: 27SEP2021) Output File:
./nda2_unblinded/C4591001_PVP_adl6mpd2/adsl_1215_s942_plac
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Page 49Table 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)
nbTotal Number of
Vaccine Doses
Subjects with any baseline
comorbidity249 494
Chronic Pulmonary Disease 119 235
Mild Liver Disease + Moderate or
Severe Liver Disease2 4
Diabetes With/Without Chronic
Com plication2 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 or Paraplegia only includes preferred terms Hemiplegia and Para plegia. 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]).
PFIZER CONFIDENTIAL SDTM C reation: 05OCT2021 (18:33) Source Data: admh Table Generation:
04NOV2021 (12:52)
(Data Cutoff Date: 02SEP2021, Database Snapshot Date: 27SEP2021) Output File:
./nda2_unblinded/C4591001_PVP_adl6mpd2/admh_1215_s953_blind
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Page 50Table 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)
nbTotal Number of
Vaccine Doses
Subjects with any baseline
comorbidity214 425
Chronic Pulmonary Disease 114 226
Rheumatic Disease 2 4
Diabetes With/Without Chronic
Com plication2 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 be longing
to these categories were identified by medical history data collected during the study.
Note: Hemiplegia or Paraplegia only includes preferred terms Hemiplegia and Paraplegia. No participants
were identified.
a. N = number of subjects in the sp ecified group.
b. n = Number of subjects reporting at least 1 occurrence of any comorbidity or obese ( BMI
≥95th percentile [12 -15 Years of age]).
PFIZER CONFIDENTIAL SDTM Creation: 05OCT2021 (18:33) Source Data: admh Table Generation:
04NOV2021 (12:52 )
(Data Cutoff Date: 02SEP2021, Database Snapshot Date: 27SEP2021) Output File:
./nda2_unblinded/C4591001_PVP_adl6mpd2/admh_1215_s953_plac
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Page 512.1.2.a.2. Inclusion and Exclusion Criteria
Detailed descriptions of allinclusion and exclusion criteria for clinical studies are provided
in the individual CSRs which were filed to IND 019736 .
Inclusion criteria
Health y participants who are determined b y medical history, ph ysical examination
(ifrequired), and clinical judgm ent of the investigator to be eligible for inclusion in the
study .
Health y 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 enr ollment, can be included. In order for the overall Phase 3 stud y population to
be as representative and diverse as possible, the inclusion of participants with known
chronic stable infection with HIV, HCV, or HBV waspermitted 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 -lineessential 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 a ccording 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
microbiological di agnosis 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 infecti on 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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Page 52antigen b y serology wasnot conducted before vaccine administration in Phase 2/3, but
samples were taken to run th ese assay s 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 :Safet y instudy 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 through out 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 safet y 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 COVI D-19 mRNA vaccine is being studies in
C4591015 to explore unexpected negative consequences to the embryo or foetus .
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Page 53Other 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 particip ation or, in the investigator’s judgment, make the participant
inappropriate for the study
Reason for exclusion :To avoid misleading results deriving from non -compliance to
study procedures .
Is it considered to be included as missing information ? No .
Ratio nale:Safet y profile of BNT162b2 is not expected to differ in these subjects when
properl y administered.
2.1.2.a.2.1. Non-Study Post -Authori zation Exposure
Cumulatively , through 30 September 2021, approximately 1,709,812,866 doses of
BNT162 b2 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),3from 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 DosesTotal Number of
Administered Doses
Europe 41.1% 703267110 571473911
European Uniona(27) 30.0% 513505785 415939686
Additional EEA Countriesa
(3)0.4% 7006155 5674986
Switzerlanda0.3% 4500990 3690812
UKb3.6% 61213230 50194849
Other Countriesc6.3% 107217045 87917977
Commonwealth of
Independent Statesd0.6% 9823905 8055602
North Am ericae18.5% 316093695 264597240
US 15.8% 270020505 226817224
Canada 2.7% 46073190 37780016
Central and South Americaf12.5% 213085680 174730258
3The 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 w ere 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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Page 54Table 32.Cumulative Estimated Shipped/Administered Doses of BNT162b2 by
Region Worldwide
Region/Country/Other % of Doses Total Number of
Shipped DosesTotal Number of
Administered Doses
Asia 23.6% 404077581 331343616
Japana10.7% 183498120 150468458
Other Countriesg12.9% 220579461 180875158
Oceania 1.4% 23158980 18990364
Australia/New Zealanda1.4% 23158980 18990364
Other Countries 0.0% 0 0
Africah2.9% 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 A ugust 2021 and in Canada a full approval (NDS) replacing the
pre-existing authorization for emergency supply was granted during the current reporting period on
16September 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, Argentina,
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, Suriname and Trinidad&Tobago that are pa rt 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 w here 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, Rw anda, 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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Page 552.1.2.a.3. Regulatory Actions Related to Safety
There were no withdrawals for safety reasons up to 30 September 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 subpopulation sthat were initially excluded from
the BNT162b2 program.
Table 33.Exposure of Special Populations Included or n ot in Clinical Trial
Development Programs
Type of special population Exposure
Pregnant women Available data on BNT162b2 administered to pregnant w omen 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 , or postnatal
development were reported.
Participants 16 years of age and older
Through the cut -off date of 13 Ma rch 2021, there w ere 50 cases ( 52
events) originating from Study C4591001 inparticipant 16 years of
age and older , and all wereunique pregnancies.
Participants 12 -15 years of age
Through the cut -off date of 02September 2021, there w ere no CT
cases of pregnancies from study C4591001 in participants 12 -15 years
of age .
Breastfeeding w omen Breastfeeding w omenwere 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 w ere 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 02September 2021, there w ere no CT
cases indicative of exposure during breastfeeding from study
C4591001 in participants 12 -15 years of age.
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Page 56Table 33.Exposure of Special Populations Included or n ot in Clinical Trial
Development Programs
Type of special population Exposure
Participants with relevant
comorbidities:
•Participants with hepatic
impairm ent
•Participants with renal impairment
•Participants with cardiovascular
disease
• Immunocompromised participants
•Participants with a disease
severity different from inclusion
criteria in CTsHealthy participants with pre- existing stable disease, defined as
disease not requiring significant change in therapy or hospitalization
for w orsening disease dur ing the 6 w eeks before enrollment, were
included . This allow edenrol lment 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 w orse 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 andTable 31 for the
exposure of special populations.
Participants of different racial
and/or ethnic originPlease refer to Table 15, Table 16, Table17, Table 18, Table 19,
Table 20, Table 21, Table 28and Table 29for exposure information
by ethnic origin from the studies.
Subpopulations carry ing known and
relevant polymorphismsNo data available.
Pediatric participants The safety and effectiveness of BNT162b2 in individuals younger
than 5years of age have not been established.
Participants 16 to 17 years of age
A total of 671 p ediatric 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 02September 2021 (Table 24and
Table 25).
Elderly (≥6 5 years old) The safety and effectiveness of BNT162b2 in elderly participants was
consistent with that seen in younger adult participants.
Clinical studies of BNT162b2 include da total of 8846 participants 65
years of age and over ; of these, 8827were from study C4591001 ,
through the cut -off date of 13 March 2021:
4590participants intheblinded -placebo controlled follow -
up period (Table3)
4237 participants in the open -label follow -up period after
unblinding (Table 5).
Nine teen (19) participants 65 years of age and over were from study
BNT162- 01study through the cut -off date of 23 October 2020
(Table6).
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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 necessitating inclusion in the list of safety concerns in the P VP:
Risks with minimal and temporary clinical impact on patients (in relation to the severit y
of the disease prevented).
The following reactogenicity events are identified risks not included in the list of safet y
concerns in the PVP: Injection site pain, Fever, Chills, Fatigue, Headache, Muscle pain,
and Joint pain.
Very rare potential risks for an y med icinal 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 Risks and Import ant Potential Risks
Important Identified Risk s
Table 34.Myocarditis and Pericarditis
Potential
mechanisms,
evidence source and
strength of evidenceA 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 mole cular mimicry), a general systemic inflammatory response
from vaccination or a hypersensitivity response.
Characterisation of
the riskParticipants 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 strategybin
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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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 Regulation 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
Myocarditi s and Pericarditis search strategy:b490 cases reported events related to
myocarditis and 371 cases reported events related t o pericarditis (in 38 of these
823cases, the subjects developed both myocarditis and pericarditis related events).
Myocarditis (490 cases ):
These 490 cases w ere individually revie wed and assessed according to Brighton
Collaboration (BC) Myocarditis Cas e 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 w ere 464 cases meeting BC Level 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,
Norw ay (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 event 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 Outcom e
Outcome: Death 14 (3.0)
Outcome: Resolved/Resolving 149 (32.1)
Outcome: Not resolved 106 (22.8)
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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),
Norw ay, Spain (24 each), Canada (10), Australia (9), Greece (7), Germany (6),
Belgium, Denmark, Netherlands, Sw itzerland (5 each); the remaining 20 cases
originated from 11 different countries.
Gender: Female s (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 summar ized below .
Total Events
N = 372 (%)
Serious events 370 (99.5)
Events with Criterion of Hospitalization 206 (55.4)
Distribution of events by Outcom e
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 data base (cut-off date 0 2September 2021) :
One (1)case w asretrieved with the Myocarditis and Pericarditis search strategybin
the CTdatabase through the cut -off date of 02September 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 follow ing day. The SAE
wasdeem ed not related to study treatment by the investigator.
Pericardit is:
There w ere no cases reporting pericarditis as SAE.
Data from the safety database (cut- off date 30 September 2021) :
Through 30September 2021, 180 potentially relevant cases (0.03%of the total
post-authori zation dataset) were retrieved from the Myocarditis and Pericarditis
search strategy:b154cases reported myocarditis and 61 cases reported pericarditis
(in 35of these180cases, the subjects developed both myocarditis and pericarditis).
Myocarditis ( 154 cases )
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These 154cases w ere individually revie wed and assessed according to Brighton
Collaboration (BC) Myocarditis Case Definition and Level of Certainty
Classific ation, 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 3cases (excluding 1 Level 5 case) are presented below :
Country of incidence: Hong Kong (39), US (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 c ountries .
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 153cases are summa rized below .
Total Events
N = 153(%)
Serious events 153* (100 .0)
Events with Criterion of Hospitalization 110(71.9)
Distribution of events by Outcom e
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 1case where myocarditis was captured as non -serious and upgraded
to serious after the DLP.
Pericarditis ( 61 cases )
These 61 cases w ere individually revie wed 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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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 w ith
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 4different 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 61cases are summarized below .
Total Events
N = 61 (%)
Serious events 61 (100 .0)
Events with Criterion of Hospitalization 17 (27.9)
Distribution of events by Outcom e
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
groupsPost-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 productThe vaccine continues to have a favorable risk benefit balance
Public health impact Considering the low rates of myocarditis and pericarditis reported follow ing
vacci nation, balanced with the risk of death and illness (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 w ere 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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Potential
mechanisms,
evidence source and
strength of evidenceInteraction 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 airw ay com prom ise), and
rash (including hives).
Characterisation of
the riskParticipants 16 years of age and older
Data from the CT dataseta(cut- off date 18 June 2021)
Through 18 June 2021,bthere 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,bthere 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 Outcom e*
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 02September 2021 , there were no casesbreporting 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 er2021, there w ere 43 casesb(41 Anaphylactic reaction , 4
Anaphylactic shock , and 1 Anaphylactoid reaction ) in individuals 12 to 15 years of
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Page 63Table 35.Anaphylaxis
age(0.01% of total post -authori zation 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 Outcom e
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 w ill continue.
Risk factors and risk
groupsKnown hypersensitivity to any components of the vaccine.
Preventability Prevention of anaphylaxis may not be possible, particularly with the 1stdose 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 productAnaphylactic 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 sho ck,
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
evidenceThis 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 chal lenge in some animal models administered SARS -CoV -1
(murine, ferret and non -human primate models) or MERS -CoV (mice model)
vaccines .1,6This pote ntial risk has been included based on these animal data with
these related betacoronaviruses. Historically, disease enhancement in vaccinated
children following infection with natural virus has been observed w ith an inactivated
respiratory syncytial virus vaccine.7
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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 allow ing for Fc -mediated increase in viral entry to cells).8
Characterization
of the riskParticipant 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
20 (0.0, 0.0) 6(0.0) (0.0, 0.1)
Within 7 days
PD10 (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
PD20 (0.0, 0.0) 2(0.0) (0.0, 0.0)
Totald1(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 leas t 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 severe 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 individuals 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,9as 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 dataseta(cut- off date 18 June 2021) :
There w ere no cases indicative of VAED/VAERD as SAEs in the CT dataset through
the DLP of 1 8June 2021.
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Associated Enhanced Respiratory Disease (VAERD)
Data from the safety database (cut- off date 1 8 June 2021)
No post -authorized AE reports have been identified as cases of VAED/VAERD,
therefore, t here is no observed d ataat this time. An expected rate of VAED is
difficult to establish so a meaningful observed/expected analysis cannot be conducted
atthis 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 authorization for emergency supply under Regulation 174 in
the UK (01 December 202 0) and through the DLP 18 June 2021, there w ere 584 cases
(0.2% of the total post -authorization dataset), reporting 1427 potentially relevant
events.
Seriousness criteria for the total 584 cases: Medically significant (452, of w hich 10
also serious for dis ability), Hospitalization required (non -fatal/non -life threatening)
(115, of which 3 also serious for disability), Life threatening (34, of which 22 w ere
also serious for hospitalization), 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
Hospitalization612 (42.9)
Distribution of events by Outcom e*
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 Low est Level Term s 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 frequently reported relevant PTs ( ≥2% ) were: Drug ineffe ctive ( 390),
Vaccination failure (194), Dyspnoea ( 180), COVID- 19 pneumonia ( 179), Diarrhoea
(111), Respiratory failure (52), Vomiting (5 0), 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 follow ing
one or both doses of the vaccine; 288 of the 425 cases were severe, resulting in
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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 w ere no cases reporting VAED/VAERD as SAEs in the CT database through
the DLP of 02September 2021.
Data from the safety databaseb(cut- off date 30 September 2021) :
Through the DLP 30 September 2021, there w ere 2 cases (reporting 6 potentially
relevant events) indicative of VAED or VAERD in the safety database involving
individuals 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 e vent seriousness and outcome are summarized below:
Total Events
N = 6
Serious events 6
Events with Criterion of
Hospitalization6
Distribution of events by Outcom e
Outcome: Death 0
Outcome: Resolved/Resolving 4
Outcome: Unknown/No data 2
Therelevant PTs reported in these 2 cases were: Diarrhoea, Drug ineffective,
Multisystem inflammatory syndrome in children, Seizure, Vaccination failure, and
Vom iting (1 each).
Conclusion: VAED may present as severe or unusual clinical manifestations of
COVI D-19. In both cases, the subjects had confirmed COVID -19 following 2 doses of
the vaccine. Upon revie w, these 2 cases unlikely represent VAED as the clinical
course was not descriptive of an unusual clinical manifestation of COVID -19
infection .
In this rev iew 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 groupsIt is postulated that the potential risk may be increased i n individuals producing low er
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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Page 67Table 36.Vaccine -Associated Enhanced Disease (VAED), including Vaccine -
Associated Enhanced Respiratory Disease (VAERD)
to mitigate the risk of VAED/VAERD;1,8that immune profile is elicited by BNT162b2
in clinical and preclinical studies.10,11
Impact on the
risk-benefit
balance of the
biologic productIfthere 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
impactThe potential risk of VAED/VAERD could have a public healt h 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; Jaundice; Acute hepa tic failure; Deep vein thrombosis; Pulmonary embolism;
Peripheral Ischaemia; Vasculitis; Shock; Acute kidney injury; Renal failure; Altered state of consciousness;
Seizure; Encephalopathy; Meningitis; Cerebrovascular accident; Thrombocytopenia; 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 PTs (Drug ineffectiv e/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 w omen 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 w ill be important to follow these women for pregnancy and birth outcomes. The timing of
vaccination in a pregnant woman and the subsequen t 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 w oman may be at risk of exposure to SARS -CoV- 2 will
influence the benefit risk considerations for use of the vacci ne.
Population in need of further characterization:
The lack of data iscommunicated 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 studi es
(C4591009 andC4591011 ) are planned and 2 non -interventi onal studies (C4591021, and C4591022 ) are
ongoing to assess use of BNT162b2 in pregnancy (see3.1.3 –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
(01December 2020) and through 18 June 2021, there were 2636 cases ( 0.8% of the total P ost-authorization
dataset) reporting use during pregnancy orlactation .
Overall event seriousness and outcome are summarized below:
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Page 68Table 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 Outcom e*
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%) w ere: 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 w as 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 w ith sequelae. Thro ugh 30 September 2021, there w ere 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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Page 69Table 38.Vaccine Effectiveness
Evidence source:
Although vaccine efficacy in acontrolled clinical stud yis 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 obtain ed 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 d ate: 18 June 2021)
Since the first temporary authorization for emergency supply under Regulation 174 in the UK
(01December 2020) and through 18 June 2021, there w ere 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 Outcom e
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 w as captured as non -serious and upgraded to serious after the DLP.
The PT Drug ineffective was reported in 4765cases, Vaccination failure was reported in 1608cases; t he
most frequently co-reported PTs ( ≥2%) w ere: 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 Septem ber 2021)
Through 30 September 2021, there w ere 2 9 cases retrieved reporting lack of efficacy . Upon review, 1 case
was not considered to be true lack of efficacy because the subject developed 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 w ere 2 8relevant cases reporting lack
of efficacy in individuals 12 to 15 years of age; overall event serious ness and outcome are summarized
below :
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Page 70Table 38.Vaccine Effectiveness
Total Events
N = 28(%)
Serious events 28(100)
Events with Criterion of Hospitalization 2(7.1)
Distribution of events by Outcom e
Outcome: Death 0
Outcome: Resolved/Resolving 4(14.3)
Outcome: Not resolved 1(3.6)
Outcome: Unknown/No data 23(82.1)
The PT sDrug ineffective and Vaccination failure werereported in 19and9cases , respectively ; the
co-reported events reported more than once were coded to the PTs :COVID -19 (24), Pyrexia (5),
Headache (4), Su spected 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 Information identified in
the Pharmacovigilance Plan.
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Page 71Table 39.Use in P aediatric I ndividuals <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 :
Theare no data in individuals less than 5years 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 6years of age )are ongoing;
1 clinical study [C4591023 (<6 months; ≥5 to <1 2 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 Databas ea(cut- off date 30 September 2021)
Since the first temporary authorization for emergency supply under Regulation 174 in the UK
(01December 2020) and through 30 September 2021, there were 56 casesb(0.01% of the total P ost-
authorization dataset) involving indivi duals below 5years 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 Outcom e
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 , My algia, and Nausea (4
each).
§ Missing information has been rew orded 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 w ere 29 additional pediatric cases under 5 years of
age; at the DLP of 30 September 2021, follow -up information w as 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 Interactions , Including Food -Biologic Product and
Drug -Biologic Product Interactions
As noted in the WHO Guidelines on Nonclinical Evaluation of Vaccines,3pharmacokinetics
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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Page 72Co-administration studies with BNT162b2 have not been done , therefore th ere is not
sufficient data to understand the effect o nvaccine 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 cause
was recognized in Wuhan City, Hubei Province, China .12 The number of infected cases
rapidly increased and spread bey ond 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 inc idence 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 onlin e.14
As of 15 August 2021 , the overall number of people who had been infected with
SARS -CoV -2 was over 207million worldwide,15an increase of 92million in the 5months
since 03 March 2021.16 Table 40shows the incidence and prevalence as of 15 August 2021
for the US, UK, and EU -27 countries. In the EU and the UK, b y 15 August 2021 the total
number of confirmed cases had accumulated to 41 million people, or 8,074 per 100,000
people (from 27 million, or 5,226per 100,000 b y03 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 and German yreported the lowest i ncidence rates while Czech Republic, Slovenia,
and L uxembourg reported the highest.15
In the US, the number of confirmed cases had reached over 37million cases (11,236 per
100,000 people) b y 15 August 2021.15 This is an increase from 29 million ( 8,864 per
100,000) by 03 March 2021 .16
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Page 73Table 40.Incidence, Prevalence, and Mortality of COVID -19 as of 15 August 202115
Total
CasesIncidence:
Total
Cases/
100,000Active
CasesPrevalence:
Active
Cases/
100,000Total
DeathsMortality:
Deaths /
100,000Population
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 +
UK41,484,576 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
Republic1,676,222 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
Luxembourg74,595 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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Page 74Table 40.Incidence, Prevalence, and Mortality of COVID -19 as of 15 August 202115
Total
CasesIncidence:
Total
Cases/
100,000Active
CasesPrevalence:
Active
Cases/
100,000Total
DeathsMortality:
Deaths /
100,000Population
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 carry ing 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 as ymptomatic are less likel y to be tested and therefore mild cases are likel y
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, respectivel y15compared to approximately 1,50 0 per 100,000 for both the EU and
UK on 03 March 2021.16The range of reported prevalence was 15to 1,544 per 100,000:
Slovakia, Romania, and Czech R epublic reported the lowest prevalence while Spain, Cy prus,
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 100,000.15This is a decrease of approximately 700 per 100,000 since 03 March 2021,
when the prevalence was 2,685 p er 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 b y ECDC epidemic intelligence,18enabling estimates
of age and gender distribution representative of the European population. TESSy data on age
and sex distributions by severit y of s ymptoms 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 similar 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 y ears.
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Page 75This 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, severel y hospitalized [admitted to intensive care and/or
required respiratory support] , or fatal) have been disproportionately older and male compared
to COVI D-19 cases overall. While age -sex patterns have remained consistent throughout the
pandemic, a notable difference between the periods before and since 01 Aug ust 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. 12August 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 41as of 14 August 2021.20At 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 41and Table 42are
drawn, respectivel y, from 29,346,352 cases and 513,204 deaths. Those under age 50 account
for roughl y 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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Page 76Table 41. Distribution of Cases (n=29,346,352) by Age, Sex, Race, and Cross -
Tabulated Age and Sex --United States as of 14 August 2021a20
Event Age
GroupAge
%Sex Sex % RacebRace
%Age
GroupMales
%Fem ales
%
Cases 0-4 2.2 Males 47.7 H/L 28.3 0-4 51.7 48.3
5-11 4.2 Fem ales 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/O ther 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 2021a20
Event Age
GroupAge % Sex Sex % RacebRace
%Age
GroupMales
%Fem ales
%
Deaths 0-4 <0.1 Males 54.2 H/L 18.5 0-4 51.5 48.5
5-11 <0.1 Fem ales 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, d isease 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% d ying among ages
≥25years.21Among 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 admitted to hospitals in the US have been
male.22,23,24,25,26
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Page 77African American COVID- 19 patients have been reported to have an increased risk of
hospitalization23,27and mortality ,28compared 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 onl y 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 ofthe total number of excess deaths (as opposed to overall
deaths in the preceding paragraph) across the US from 26 Januar y2020 to 27February 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 2 020 broke down excess deaths
by demographics30: by ageduring that period , the largest increase in deaths compared to
average expected deaths occurred among adults a ged 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% increase) , 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 b y age groups and
2020 sub- periods that a re presented in Table 43. The table shows that earl y in 2020, 5- 9 year
olds were experiencing less COVID -19 than 0 -4 year olds, but by the end of the y ear 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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Page 78Table 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- PeriodAge Group
(years)Number
of CasesCases 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 44shows that, among the pediatri c
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 1,945,831individuals 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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Page 79COVID -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 indivi duals 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 pos itive,
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 s ymptoms) to severe or fatal. A person’s risk of initial infection increases
through spending time in close ph ysical proximity to others, especiall y in indoor spa ces 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.35,36Among children, the primary source of
infection is an infected adult living in the same household.37According 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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Page 80Table 45. Risk for COVID -19 infection, Hospitalisation, and Death by Age Group and by
Race/Ethnicity39
Rate ratiosa
Age Group (years) CasescHospitali sationdDeathe
0-4 <1 <1 <1
5-17 1 <1 <1
18-29b1 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 f1 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 tw o significant
digits.
b.Rate ratios for each age group are relative to the 18 -29-year age cate gory. This group w as selected as the
reference group because it has accounted for the largest 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 w ere based on the 2019 Vintage population
(https://www.census.gov/newsroom/press -releases/2019/popest -nation html).
d.Includes all hospitalizations reported through COVID -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
onJuly 12, 2021). The denominators used to calculate rates were based on the 2019 Vintage population
(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 t ypicall y 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).38,46Table 45also
gives estimated rate ratios for COVID -19 hospitali sation and death b y race/ethnicity relative
to white, non -Hispanic persons in the US. The highest risks of hospitalisation and death
were observed among American Indian or Alaska native persons (RR = 3.4 for
hospitali sation and 2.4 for death) and Hispanic or Latino persons (RR = 2.8for
hospitali sation and 2.3 for death). These differences in risk among ethnic groups may be
attributed to differences in underly ing factors that are correlated with race/ethnicity including
socioeconomic status, access to health care, and occupation -related virus exposure .39
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Page 81Risk 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 proficie ncy.40,42,46TheCDC 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 disabilities; people with developmental, behavioura l, or substance abuse
disorders; and newl y resettled refugee populations.47
Among adults, r isk for severe or fatal COVID -19 disease increases with the presence of
chronic medical conditions, including obesit y, 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, HI V, 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 mortalit y asso ciated 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 underl ying medical conditions also increases risk of severe or
fatal disease among children aged 5 -17.49,50,51, 52In particular, childhood obesity has been
consistent ly associated with two to three times the risk of severe disease or hospitalization .49,
52,53, 54,. For man y 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 regionFully 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)
Form er 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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Page 82Table 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 regionFully adjusted
Other 1.38 (1.17 -1.63) 1.38 (1.16 -1.63)
IMD quintilea1 (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
hypertension1.09 (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
measure2.19 (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)
Hem atological
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 Lmin−1per 1.73 m2and 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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Page 83The 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 as ymptomatic infection in
17-45%across age groups ,55, 56 57, 58to critical illness and death. The rate of as ymptomatic
infection decreases with increasing age and long- term care facilities are associated with a
lower rate of as ymptomatic infection when compared to household transmission or other
healthcare facilities.58A recent meta -analy sis has estimated that 46.7% of infections in
children are asymptomatic.58The 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) patientsawith laboratory confirmed COVID -19 —
United States, 12 February– 2April 202059
No. (%) with sign/symptom
Sign/Symptom Pediatric Adult
Fever, cough, or shortness of breathb213 (73) 10,167 (93)
Feverd163 (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 nosec21 (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 painc17 (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; therefore,
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 hy poxia. For those
who develop s ymptoms, the incubation period is us ually 4 to 5 day s, with 97.5%
experiencing s ymptoms within 11 day s of exposure.61,62Those with mild COVID-19 recover
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Page 84at 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.62Data on rates of re -infection are limited but variants that are not neutralized by
immune antisera, suc h 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 sy stematically 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.63For 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 .64Based on data from 23 states and New York Cit y, as of August 19, 2021,
1.6%-3.6% of children with COVI D-19 have been hospitalised and 0.0 -0.03% of children
with COVI D-19 have died.65
The most common sy mptoms in patients are fever (42-80%), shortness of breath (35 -71%),
fatigue (33-62%), cough (77- 84%), chills (63%), my algias (63%), headache (59%), and
diarrhea (33%) .66,67,68,69 COVID -19 patients also commonly experience gustatory disorders
(44%) and olfactory disorders (53%).70Among unhospitalised children < 18 y ears of age,
89% experienced one or more ty pical sy mptoms of COVID, including fever, cough,
shortness of breath, and 22% experienced all three. 67Approximately 17% to 40% of those
hospitalised with COVI D-19 experience severe s ymptoms 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, y ounger age, and male sex .34
More than 75% of patients hospitali sed with COVID -19 require supplemental oxy gen.71
Studies early in the pandemic demonstrated that time from onset of illness to ARDS was
8-12days and time from onset of illness to ICU admission was 9.5–12 day s. 61In 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 2021.72A recent meta -analysis
found that, of patients <19 y ears of age, 11% went to the I CU, 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 746,566deaths
reported for all age groups in the EU/EEA among 35 ,381,520cases ( 2.1% of cases).74As 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 recen t meta -analysis of paediatric studies
published through October 2020, the mortalit y for paediatric patients is 0.1 -2%.56,21In 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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Page 85PCR- 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 15August 2021, the overall SARS -CoV -2 mortality for the EU + UK was
878,344 deaths, or 171 per 100,000 people. Reported mortality among EU countries and the
UK ranged from 18 to 312deaths per 100,000 ( Table 40). Finland and C yprus reported the
lowest mortality ; Hungary , Czech Republic, and Bulgaria report ed the highest.15
In the US, as of 15August 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 hospitali sed 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- COV ID
Complications of COVID-19 include impaired function of the heart, brain, lung, liver,
kidney , and coagulation sy stem.22,25,80 Based on a meta -analysis of 42 studies, the risk of
thromboembolism was 21% overall and 31% in the I CU, with the pooled odds of mortality
being 74% higher among those who exper ienced thromboembolism compared to those who
did not.81
COVID -19 s ymptoms can persist weeks or months bey ond the acute infection.82,83The
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 s yndrome (12 weeks or
more and for which signs and sy mptoms are not explained by an alternative diagnosis).84
A meta analysis of 31 studies among patients between 18 to 49 y ears of age found that
COVID -19 s ymptoms were experienced for 14 day s to 3 months post -infection, including
persistent fatigue (39 –73%), breathlessness (39 –74%), decrease in quality of life (44–69%),
impaired pulmonary function, abnormal CT findings including pulmonary fibrosis (39–83%),
evidence of peri -/perim yo-/myocarditis (3–26%), changes in microstructural and functional
brain integrity with persistent neurological s ymptoms (55%), increased incidence of
psychiatric diagnoses (5.8% ve rsus 2.5–3.4% in controls), and incomplete recovery of
olfactory and gustatory dysfunction (33 –36%).85 Post-acute COVID s ymptoms in children
with asy mptomatic or mild disease appear to be less severe than in adults, with the most
common sy mptoms being a post -viral cough (4%), fatigue (2%), or both s ymptoms (1%)
with the duration of sy mptoms lasting 3 to 8 weeks.86
Children who are infected with COVI D-19 are at risk of subsequent multisy stem
inflammatory syndrome (MI S-C) and often develop a rash followin g resolution of COVID -
19.56,87,88As of August 19, 2021 there were 4,403 cases of MIS-C reported to health
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Page 86departments in the U S.89Additional sy mptoms of MI S-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 COVI D-19 patients i nclude hy pertension, 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 48below using TESSy data posted on 12 Aug ust 2021.91
Table 48. Preconditions among COVID- 19 Patients in EU/EEA, by Severity of
Disease. Case -based Data from TESSy Reported 12August 202191
EU/EEA, report ed on 12August 2021
Mild Hosp italised 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
Haem atological 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 49below 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 the 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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Page 87Table 49. Comorbidities in individuals tested for COVID- 19 in the Providence St.
Joseph Health S ystem – States of California, Oregon, and Washington,
01March –31 December 202040
Com orbidityTested
(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
Underw eight 2.1 1.7 3.1
Normal 29.0 23.9 24.3
Overw eight 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 as ymptomatic 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 asy mptomatic 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 recorded
204 adolescents aged 12 -17 who were hospitalized for likely primaril y COVID -related
reasons.31 Among the 204 adolescents, 70.6% had at least one major underly ing 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. Theor etical concerns
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 effica cy data from study
C4591001 are indicative of the vaccine delivery system’s success in transfecting the RNA
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Page 88into the appropriate target cells to stimulate an immune response. The RNA itself cannot
integrate into the DNA genome.92,93 The probabilit y of an y sequences from the vaccine RNA
being integrated into the human genome b y 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 qua ntity 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 elicited 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 enhanced respiratory disease (VAERD)
Missing Information Use in pregnancy and lactation
Vaccine effectiveness
Use in pediatric individuals <5 years of age§
§ Missing information has been rew orded to reflect the current state.
3.1.2. Routine Pharmacovigilance Practice s
Routine pharmacovigilance activities area critical component of activities relating to the
detection, assessment, understanding and prevention of risks . The objective of routine
pharmacovigilance is to have processes in place to assure the ongoing and timely
collection, processing, follow-up, and anal ysis of individual AE reports globally ,
following global safet y Standard Operating Procedures and regulatory guidance.
Pfizer, on behalf of the marketing authorization holder (MAH),monitors the safet y profile
of its products, evaluates issues pote ntially impacting product benefit -risk profiles in a
timely manner, and ensures that appropriate communication of relevant information is
convey ed in a timely manner to regulatory authorities and other interested parties as
appropriate and in accordance with international principles and prevailing regulations.
Pfizer, on behalf of the MAH, conducts scientific data gathering activities for the
detection and evaluation of AEs to ensure safet y monitoring, which is commensurate
with product characteristics.
Signal detection activities include periodic literature review for the life cy cle of the
product. This includes reviewing the medical literature for individual case reports that
should be entered into the safet y database as well as periodic aggregate lit erature review
for broader signal detection.
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Page 89Safety signal evaluation requires the collection, analy sis,and assessment of information
to evaluate whether there is a potential causal association between an event and the
administration of the product and i ncludes subsequent qualitative or quantitative
characterization of the relevant safet y risk to determine appropriate pharmacovigilance
and risk mitigation actions.
Routine pharmacovigilance activities will include the use of DCAs. They are intended to
facilitate the capture of clinical details about:
the nature and severit y of COVID- 19 illness in individuals who have received the
COVID -19 vaccine and is anticipated to provide insight into potential cases of
vaccine lack of effect or VAED.
potential anaph ylactic reactions in individuals who have received the COVID-19
vaccine.
A web -based AE reporting portal will be available for vaccine providers and recipients,
to assist with anticipated high volume of reports (based on expected large target
population). The portal will capture key adverse event data in the initial interaction and
will provide automated intake into the Pfizer safety database via E2B for safety review.
At the country level, the Drug Safet y Unit performs routine pharmacovigilance activit ies
including the collection of AEs from various sources and the reporting of AEs to the
regulatory authorit y as per local regulatory guidelines.
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Page 903.1.3. Action Plan for Safety Issues
Action Plan for Important I dentified Risks
Table 51.Action Plan for Important Identified Risk “ Myocarditis and Pericarditis”
Actions proposed Communication of this important identified risk via label ( Section 5.2 -
Myocarditis and Pericarditis , Section 6.2 -Post Marketing Experience ).
C4591009: A non -interventional post -approval safety study of the
Pfizer -BioNTech COVID -19 vaccine in the United States.
C4591011: Active safety surveillance of the Pfizer -BioNTech COVID -19
vaccine in the US Department of Defense population following Emergency
Use Authorizatio n.
C4591012: Post -emergency use authorization active safety surveillance
study among individuals in the Veteran’s Affairs Health System receiving
Pfizer -BioNTech Coronavirus Disease 2019 (COVID- 19) vaccine.
C4591021 : Post Conditional approval active survei llance study among
individuals in Europe receiving the Pfizer BioNTech Coronavirus Disease
2019 (COVID- 19) vaccine.
C4591038 (former, C4591021 substudy : Post Conditional approval active
surveillance study among individuals in Europe receiving the Pfizer
BioNTech Coronavirus Disease 2019 (COVID- 19) vaccine. Substudy to
investigate natural history of post-vaccination myocarditis and pericarditis .
C4591036 -Pediatric Heart Netw ork Study : Low interventional cohort study
of myocarditis /pericarditis associated with Comirnaty in persons less than
21years of age.
C4591031 substudy B: A randomized, placebo -controlled, observer -blind,
cross -over substudy to evaluate the safety and tolerability of a booster (third)
dose of BNT162b2. Participants ≥12 years of age to ≤30 years of age who
have completed a 2 -dose primary series of BNT162b2 (30 μg doses) at least
6 months ( ≥12 months for those 12 -17 years of age) prior to randomization
will be enrolled .
C4591007 substudy –Troponin group : A Phase 3 substudy of 750
participants 5 to <12 years of age (randomized 2:1 to receive BNT162b2 10
µg or placebo) and 500 participants 12 -16years of age (open label receipt
of BNT162b2 30 µg).
Objective of proposed
actions Labelling communicates the risk of myocarditis and pericarditis.
C4591009: To assess the occurrence of safety events of interest, including
myocarditis and pericarditis, in the general US population of all ages ,
pregnant w omen, the immunocompromised and persons with a prior history
of COVID -19 w ithin selected data sources participating in the US Sentinel
System .
C4591011: To assess whether individuals in the US DoD Military Health
System (MHS) experience increased risk of safety events of interest,
including myocarditis and pericarditis, fol lowing receipt of the
Pfizer -BioNTech COVID -19 Vaccine.
C4591012: To assess whether individuals in the US Veteran’s Affairs Health
System experience increased risk of safety events of interest, including
myocarditis and pericarditis, follow ing receipt of thePfizer -BioNTech
COVID -19 Vaccine.
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Page 91Table 51.Action Plan for Important Identified Risk “ Myocarditis and Pericarditis”
C4591021 : To assess the potential increased risk of adverse events of special
interest (AESI), including myocarditis/pericarditis after being vaccinated
with COVID -19 vaccine .
C4591038 (former, C4591021 substudy ): To describe the natural history of
post-vaccination myocarditis/pericarditis, including recovery status, risk
factors, and/or identification of serious cardiovascular outcomes within 1
year of myocarditis/pericarditis diagnosis among individuals vaccinated with
BNT162b2 as well as individuals not vaccinated with a COVID- 19 vaccine.
C4591036: Pediatric Heart Netw ork Study : To characterize the clinical
course, risk factors, resolution, long -term sequelae, and quality of life in
children and young adults <21 years with acute post -vaccine
myocarditis /pericarditis .
C4591031 substudy B:To obtain serum samples within the first ~4 days
after vaccination for potential Troponin I testing, in order to evaluate the
frequency of subclinical myocarditis amongst individu als 12 to 30 years of
age.
C4591007 substudy –Troponin group : To obtain serum samples w ithin the
first ~4 days after vaccination for potential Troponin I testing, in order to
evaluate the frequency of subclinical myocarditis amongst individuals 5 to
<16years of age.
Rationale for proposed
actionsLabeling communicates to health care provider the risk of myocarditis and
pericarditis .
C4591009 and C4591021 : Robust surveillance is needed to ensure
comprehensive understanding of real -world safety of the Pfizer -BioNTech
COVID -19 Vaccine in large samples of general US (C4591009) and EU
(C4591021) population sand in subcohorts of interest, including pregnant
women, immunocompromised individuals and persons with a prior history of
COVID -19 infection.
C4591011 and C4591012: Robust surveillance is needed to ensure
comprehensive understanding of real -world safety. This surveillance strategy
consists of complementary approaches to ensure timely signal identification
and evaluation in populations who have received the Pfizer -BioNTech
COVID -19 Vaccine under an Emergency Use Authorization (EUA).
C4591038 (former, C4591021 substudy ): Study is needed to describe natural
history of myocarditis and pericarditis in persons after vaccination with
Pfizer -BioNTech
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