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BNT162b2
1.16 Risk Management Plan (Non-REMS) for Biologic License Application # 125742
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PHARMACOVIGILANCE PLAN FOR
BIOLOGIC LICENSE APPLICATION #125742
OF
COVID-19 mRNA vaccine (nucleoside modified) (BNT162b2, PF-07302048)
Date of Report: 17 MAY28 JULY 2021
Version 1. 01
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TABLE OF CONTENTS
LIST OF TABLES .....................................................................................................................3
LIST OF FIGURES ...................................................................................................................5
LIST OF ABBREVIATIONS ....................................................................................................6
1. INTRODUCTION .................................................................................................................8
1.1. Product Details ..........................................................................................................8
2. SAFETY SPECIFICATION ..................................................................................................9
2.1. Elements of the Safety Specification.........................................................................9
2.1.1. Non-Clinical .................................................................................................9
2.1.2. Clinical ........................................................................................................12
2.1.2.a. Limitations of the Human Safety Database ...............................12
2.1.2.b. Populations Not Studied in the Pre-Approval Phase .................45
2.1.2.c. Adverse Events / Adverse Reactions .........................................46
2.1.2.d. Identified and Potential Interactions, Including Food-
Biologic Product and Drug-Biologic Product Interactions ...............58
2.1.2.e. Epidemiology of Indication and Target Population ..................59
2.1.2.f. Pharmacological Class Effects ...................................................70
3. PHARMACOVIGILANCE PLAN ......................................................................................71
3.1. Structure of the Pharmacovigilance Plan ................................................................71
3.1.1. Summary of Ongoing Safety Concerns ......................................................71
3.1.2. Routine Pharmacovigilance Practices.........................................................71
3.1.3. Action Plan for Safety Issues ......................................................................73
3.1.4. Summary of Actions to be Completed, Including Milestones ....................85
3.2. Pharmacovigilance Methods ...................................................................................92
3.2.1. List of Studies Included in the Pharmacovigilance Plan ............................92
REFERENCES ........................................................................................................................93
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LIST OF TABLES
Table 1. Product Details ............................................................................................8
Table 2. Key Safety Findings and Relevance to Human Usage .............................11
Table 3. Exposure to BNT162b2 by Age Group and Dose (C4591001) –
Blinded Placebo-Controlled Follow-up Period ........................................16
Table 4. Exposure to BNT162b2 by Age Group and Dose (C4591001) –
Open-Label Follow-up Period – Subjects Who Originally Received
BNT162b2 ................................................................................................17
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 ......................18
Table 6. Exposure to BNT162b2 by Age Group and Dose (BNT162-01) .............19
Table 7. Exposure to BNT162b2 by Dose (Totals) (C4591001) – Blinded
Placebo-Controlled Follow-up Period ......................................................22
Table 8. Exposure to BNT162b2 by Dose (Totals) (C4591001) – Open-
Label Follow-up Period – Subjects Who Originally Received
BNT162b2 ................................................................................................22
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 ......................22
Table 10. Exposure to BNT162b2 by Dose (Totals) (BNT162-01) .........................24
Table 11. Exposure to BNT162b2 by Dose, Age Group, and Gender
(C4591001) – Blinded Placebo-Controlled Follow-up Period .................25
Table 12. Exposure to BNT162b2 by Dose, Age Group, and Gender
(C4591001) – Open-Label Follow-up Period – Subjects Who
Originally Received BNT162b2 ...............................................................25
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 ................................................................................................26
Table 14. Exposure to BNT162b2 by Dose, Age Group, and Gender
(BNT162-01) ............................................................................................27
Table 15. Exposure to BNT162b2 by Age Group, Dose, and Race/Ethnic
Origin (C4591001) – Blinded Placebo-Controlled Follow-up Period ......28
Table 16. Exposure to BNT162b2 by Age Group, Dose, and Race/Ethnic
Origin (C4591001) – Open-Label Follow-up Period – Subjects
Who Originally Received BNT162b2 ......................................................32
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Table 17. Exposure to BNT162b2 by Age Group, Dose, and Race/Ethnic
Origin (C4591001) – Open-Label Follow-up Period – Subjects
Who Originally Received Placebo and Then Received BNT162b2
After Unblinding .......................................................................................33
Table 18. Exposure to BNT162b2 by Dose and Race/Ethnic Origin
(C4591001) – Blinded Placebo-Controlled Follow-up Period .................36
Table 19. Exposure to BNT162b2 by Dose and Race/Ethnic Origin
(C4591001) – Open-Label Follow-up Period – Subjects Who
Originally Received BNT162b2 ...............................................................37
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 ................................................................................................38
Table 21. Exposure to BNT162b2 by Dose and Race/Ethnic Origin (BNT162-
01) .............................................................................................................39
Table 22. Exposure to BNT162b2 (30 μg) by Special Population (C4591001)
– Blinded Placebo-Controlled Follow-up Period .....................................40
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 ......41
Table 24. Cumulative Estimated Shipped Doses of BNT162b2 by Region
Worldwide ................................................................................................44
Table 25. Exposure of Special Populations Included or not in Clinical Trial
Development Programs ............................................................................45
Table 26. Myocarditis and Pericarditis .....................................................................47
Table 27. Anaphylaxis ..............................................................................................51
Table 28. Vaccine-Associated Enhanced Disease (VAED), including
Vaccine-Associated Enhanced Respiratory Disease (VAERD) ...............53
Table 29. Use in Pregnancy and Lactation ...............................................................56
Table 30. Vaccine Effectiveness ...............................................................................57
Table 31. Use in Paediatric Individuals <12 Years of Age ......................................58
Table 32. Incidence, Prevalence, and Mortality of COVID-19 as of
03 March 2021 .........................................................................................60
Table 33. Distributions of Cases (n=21,895,936) and Deaths (n=382,009) by
Age, Sex, Race, and Cross-Tabulated Age and Sex – United States
as of 08 March 2021, ................................................................................62
Table 34. Risk for COVID-19 Infection, Hospitalization, and Death by Age
Group and by Race/Ethnicity ..................................................................64
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Table 35. Hazard Ratios and 95% Confidence Intervals for COVID-19-related
Death .........................................................................................................65
Table 36. Signs and symptoms among 291 pediatric (age <18 years) and
10,944 adult (age 18–64 years) patients with laboratory confirmed
COVID-19 — United States, 12 February– 2April 2020 .........................67
Table 37. Preconditions among COVID-19 Patients in EU/EEA and UK, by
Severity of Disease. Case-based Data from TESSy Produced 04
March 2021 ...............................................................................................69
Table 38. Comorbidities in individuals tested for COVID-19 in the
Providence St. Joseph Health System – States of California,
Oregon, and Washington, 01 March–31 December 2020 ........................70
Table 39. Ongoing Safety Concerns .........................................................................71
Table 40. Action Plan for Important Identified Risk “Myocarditis and
Pericarditis” ..............................................................................................73
Table 41. Action Plan for Important Identified Risk “Anaphylaxis” .......................75
Table 42. Action Plan for Important Potential Risk “Vaccine-associated
enhanced disease (VAED) including Vaccine-associated enhanced
respiratory disease (VAERD)” .................................................................77
Table 43. Action Plan for Missing Information “Use in Pregnancy and
Lactation” .................................................................................................79
Table 44. Action Plan for Missing Information “Vaccine Effectiveness” ...............81
Table 45. Action Plan for Missing Information “Use in Paediatric Individuals
<12 Years of Age” ....................................................................................82
Table 46. Summary of Safety Concerns and Action Plans .......................................85
LIST OF FIGURES
Figure 1. Age-Sex distribution of COVID-19 Cases as Different Levels of
Severity, EU/EEA and UK. Case-based Data from TESSy produced
on 04 March 2021a ....................................................................................62
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LIST OF ABBREVIATIONS
Abbreviation Definition of Term
AE adverse event
AESI adverse event of special interest
A:G albumin:globulin
ARDS acute respiratory distress syndrome
BALB/c bagg albino
BC Brighton Collaboration
BEST biologics effectiveness and safety
BLA biologics license application
BMI body mass index
BP blood pressure
CD4, CD8 cluster of differentiation -4, 8
CDC Centers for Disease Control and Prevention
CI confidence interval
COPD chronic obstructive pulmonary disease
COVID-19 coronavirus disease 2019
CSR clinical study report
CT clinical trial
DART developmental and reproductive toxicology
DCA data capture aid
DLP data-lock point
DoD Department of Defense
ECDC European Center for Disease Control
EEA European Economic Area
eGFR estimated glomerular filtration rate
EU European Union
EUA emergency use authorization
FDA (US) Food and Drug Administration
GLP good laboratory practice
HbA1c glycated hemoglobin
HBV hepatitis b virus
HCV hepatitis c virus
HIV human immunodeficiency virus
IA interim analysis
ICU intensive care unit
IFN interferon
IL-4 interleukin -4
IM intramuscular(ly)
IMD index of multiple deprivation
IND investigational new drug
LNP lipid nanoparticle
MAA marketing authorization applicant
MedDRA Medical Dictionary for Regulatory Activities
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Abbreviation Definition of Term
MERS-CoV Middle East respiratory syndrome –coronavirus
MHS Military Health System
MIS-C multisystem inflammatory syndrome in children
MOA mechanism of action
modRNA nucleoside -modified messenger ribonucleic acid
mRNA messenger ribonucleic acid
NDA new drug application
NHP nonhuman primate
NICE National Institute for Health and Care Excellence
OCS oral corticosteroids
PK pharmacokinetic
PT Preferred Term
PVP pharmacovigilance plan
RBC red blood cell
RNA ribonucleic acid
RR relative risk
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
SMQ standardised MedDRA query
Tdap tetanus, diphtheria, and acellular pertussis
TESSy The European Surveillance System
Th1 T helper cell type 1
Th2 T helper cell type 2
UK United Kingdom
US United States
USP United States pharmacopeia
V8 variant 8
V9 variant 9
VAED vaccine-associated enhanced disease
VAERD vaccine-associated enhanced respiratory disease
WBC white blood cells
WHO World Health Organization
WOCBP women of childbearing potential
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1. INTRODUCTION
1.1. Product Details
Table 1. Product Detailsa
Product COVID-19 mRNA Vaccine (nucleoside modified), herein after referred to as
BNT162b2 is a nucleoside-modified messenger RNA –(modRNA) encoding
the viral spike (S) glycoprotein of severe acute respiratory syndrome
coronavirus (SARS-CoV-2). Brief description of the
product Chemical class:
Nucleoside-modRNA formulated in lipid particles.
Mechanism of Action:
The modRNA in the BNT162b2 is formulated in lipid particles, which enable
delivery of the RNA 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 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 dose of the BNT162b2 also includes the following ingredients:
lipids (0.43 mg (4-hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)bis(2-
hexyldecanoate), 0.05 mg 2[(polyethylene glycol)-2000]-N,N-
ditetradecylacetamide, 0.09 mg 1,2-distearoyl-sn-glycero-3-
phosphocholine, and 0.2 mg cholesterol), 0.01 mg potassium chloride,
0.01 mg monobasic potassium phosphate, 0.36 mg sodium chloride, 0.07
mg dibasic sodium phosphate dihydrate, and 6 mg 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 with natural rubber latex. Indication Proposed:
Active immunization to prevent COVID-19 caused by SARS-CoV-2 in
individuals 16 years of age and older.
Dosage and route of
administration Proposed:
Series of two doses (0.3 mL each) 3 weeks apart, intramuscularly.
a. COVID-19 mRNA vaccine (nucleoside -modified) US Prescribing Information
Data Lock
Point / Data
cut-off: 16 years and older 13 March 2021 (Pfizer Clinical Database)
23 October 2020 (BioNTech Clinical Database)
28 February 2021 (Pfizer Safety Database)
12 to 15 years older 13 March 2021 (Pfizer Clinical Database)
28 February 2021 (Pfizer Safety Database)
Important Identified Risk
“Myocarditis and pericarditis ” 18 June 2021 (Pfizer Safety Database)
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2. SAFETY SPECIFICATION
2.1. Elements of the Safety Specification
2.1.1. Non-Clinical
Nonclinical evaluation of BNT162b2 included pharmacology (mouse immunogenicity and
NHP immunogenicity and challenge studies), pharmacokinetic (series of biodistribution,
metabolism and pharmacokinetic studies), and toxicity (2 GLP rat repeat-dose toxicity and a
GLP DART) studies in vitro and in vivo. No additional toxicity studies are planned for
BNT162b2.
Nonclinical studies in mice and NHP for BNT162b2 demonstrated both a strong neutralizing
antibody response and a Th1-type CD4+ and an IFN + CD8+ T-cell response. The Th1
profile is characterized by a strong IFNγ, but not IL-4, response indicating the absence of a
potentially deleterious Th2 immune response and is a pattern favored for vaccine safety and
efficacy.1 Rhesus macaques (Study VR-VRT-10671) that had received two IM
immunizations with 100 µg BNT162b2 or saline 21 days apart were challenged with 1.05 ×
106 plaque forming units of SARS-CoV-2 (strain USA-WA1/2020), split equally between the
intranasal and intratracheal routes.2 BNT162b2 provided complete protection from the
presence of detectable viral RNA in the lungs compared to the saline control with no clinical,
radiological or histopathological evidence of vaccine-elicited disease enhancement.
An intravenous rat PK study, using an LNP with the identical lipid composition
asBNT162b2, demonstrated that the novel lipid excipients in the LNP formulation, ALC-
0315 and ALC-0159, distribute from the plasma to the liver. While there was no detectable
excretion of either lipid in the urine, the percent of dose excreted unchanged in feces was
~1% for ALC-0315 and ~50% for ALC-0159. Further studies indicated metabolism played a
role in the elimination of ALC-0315. Biodistribution was assessed using luciferase
expression as a surrogate reporter formulated likeBNT162b2, with the identical lipid
composition. After IM injection of the LNP-formulated RNA encoding luciferase in
BALB/c mice, luciferase protein expression was demonstrated at the site of injection 6 hours
post dose and expression decreased over time to almost reach background levels after 9 days.
Luciferase was detected to a lesser extent in the liver; expression was present at 6 hours after
injection and was not detected by 48 hours after injection. After IM administration of a
radiolabeled LNP-mRNA formulation containing ALC-0315 and ALC-0159 to rats, the
percent of 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 the adrenal glands and ovaries. The metabolism of ALC-0315
and ALC-0159 was evaluated in blood, liver microsomes, S9 fractions, and hepatocytes from
mice, rats, monkeys, and humans. The in vivo metabolism was examined in rat plasma,
urine, feces, and liver samples from the PK study. ALC-0315 and ALC-0159 are
metabolized by hydrolytic metabolism of the ester and amide functionalities, respectively,
and this hydrolytic metabolism is observed across the species evaluated.
In GLP toxicity studies, two variants of the BNT162b2 candidate were tested, designated
“variant 8” and “variant 9” (V8 and V9, respectively). The variants differ only in their codon
optimization sequences which are designed to improve antigen expression, otherwise the
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amino acid sequences of the encoded antigens are identical. BNT162b2 (V9) was evaluated
clinically and submitted for application. Two GLP-compliant repeat-dose toxicity studies
were performed in Wistar Han rats; one with each variant. Both studies were 17 days in
duration with a 3-week recovery period. A GLP-compliant DART study in Wistar Han rats
has also been completed. Safety pharmacology, genotoxicity and carcinogenicity studies
have not been conducted, in accordance with the 2005 WHO vaccine guideline.3
The IM route of exposure was selected for nonclinical investigations 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 routinely 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. Injection site reactions were common
in all vaccine-administered animals and were greater after boost immunizations. Changes
secondary to inflammation included slight and transient reduction in body weights and
transient reduction in reticulocytes, platelets and RBC mass parameters. Decreased
reticulocytes were reported in rats treated with the licensed LNP-siRNA pharmaceutical
Onpattro™ (NDA # 210922) but have not been observed in humans treated with this
biotherapeutic4 suggesting this is a species-specific effect. Decreased platelet counts were
noted after repeat administration, but were small in magnitude of change, likely related to
inflammation-related platelet activation and consumption, and unassociated with other
alterations in hemostasis. Elevated levels of gamma-glutamyl transferase were observed in
the first repeat-dose 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 final clinical candidate. All changes in clinical pathology parameters
and acute phase proteins were reversed at the end of the recovery phase for BNT162b2, with
the exception of low magnitude higher red cell distribution width (consistent with a
regenerative erythroid response) and lower A:G ratios (resulting from acute phase 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 lymph nodes and spleen. Vaccine-related microscopic
findings at the end of the dosing phase consisted of edema and inflammation in injection sites
and surrounding tissues, increased cellularity in the draining iliac lymph nodes, bone marrow
and spleen and hepatocyte vacuolation in the liver. Vacuolation of periportal hepatocytes,
the only test article-related liver microscopic finding, was not associated with any
microscopic evidence of hepatic injury or hepatic functional effects (i.e., liver functional
enzymes were not elevated) and may be associated with hepatocyte uptake of the LNP
lipids.5 Microscopic findings at the end of the dosing phase were partially or completely
recovered in all animals at the end of the 3-week recovery period for BNT162b2. A robust
immune response was elicited to the BNT162b2 antigen.
Administration of BNT162b2 to female rats twice before the start of mating and twice during
gestation at the human clinical dose (30 µg) was associated with non-adverse effects (body
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weight, food consumption and effects localized to the injection site) after each dose
administration. However, there were no effects of BNT162b2 administration on mating
performance, fertility, or any ovarian or uterine parameters in the F0 female rats nor on
embryo-fetal or postnatal survival, growth, or development in the F1 offspring. An immune
response was confirmed in F0 female rats following administration of each vaccine candidate
and these responses were also detectable in the F1 offspring (fetuses and pups).
In summary, the nonclinical safety findings related to BNT162b2 administration primarily
represent an expected immune reaction to vaccine administration and are clinically
manageable or acceptable risks in the intended population. The key safety findings regarding
BNT162b2 from 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 Studiesa Relevance to Human Usage
Pharmacology
NHP Challenge Model
No evidence of vaccine-elicited disease
enhancement.
Suggests low risk of vaccine-enhanced disease
in humans; being investigated in CTs.
Toxicity
Injection site reactions:
Injection site reactions were common and
reversible or showed signs of reversibility at the
end of the 3-week recovery period in nonclinical
studies.
In common with other vaccines, B NT162b2
administration has the potential to generate
injection site reactions such as edema and
erythema at the injection sites. Inflammation and immune activation:
Evidence of inflammation or immune activation
was common, reversible, and included transiently
higher body temperature, higher circulating
WBCs, and higher acute phase reactants.
Secondarily, transiently lower body weights,
reticulocytes, platelets, and RBC mass parameters
were observed.
In common with all vaccines, B NT162b2
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 with 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 magnitude. Developmental and Reproductive Toxicity
No vaccine-related effects on female fertility or the
development of fetuses or offspring were observed
in a DART study of BNT162b2 in rats.
No effects are anticipated in WOCBP,
pregnant women or their offspring.
a. Safety pharmacology, genotoxicity, and carcinogenicity studies were not conducted, in accordance with
2005 WHO vaccine guideline, as they are generally not considered necessary to support development and
licensure of vaccines for infectious diseases.3 In addition, the components of the vaccine construct are lipids and RNA and are not exp ected to have carcinogenic or genotoxic potential.
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2.1.2. Clinical
2.1.2.a. Limitations of the Human Safety Database
The pivotal study was initially planned to enroll approximately 30,000 participants, which
would have a probability of 78% of detecting an AE with a frequency of 0.01% (1/1000) and
a probability of 95% of detecting an AE with a frequency of 0.02% (1/500). The protocol
was amended to enroll approximately 46,000 participants, which would slightly enhance the
ability to detect AEs. However, rarer events might not be detected.
Participants in the pivotal study were initially planned to be followed for up to 24 months in
order to assess the potential for late-occurring adverse reactions, such as the theoretical risk
of VAED. After completing the final efficacy analysis with vaccine efficacy shown to be
95%, and obtaining regulatory authorization to vaccinate in many countries,
Pfizer-BioNTech started to unblind all participants to determine those randomized to placebo
so that they could be offered vaccine in accordance with local authorization. To date, most
placebo subjects have been unblinded to receive active vaccine at or prior to 6 months after
the second dose, therefore, a placebo group for comparison of safety data is only available
for up to 6 months post Dose 2.
2.1.2.a.1. Clinical Trial Exposure
Brief Overview of Development
BioNTech is conducting a first-in-human dose level–finding Phase 1/2 study (BNT162-01) in
Germany to gather safety and immunogenicity data to enable evaluation of 4 vaccines
candidates individually to inform the overall clinical development of a BNT162b2.
BNT162-01 is not conducted under the US IND application but is being conducted under a
German Clinical Trial Application.
Four vaccine candidates were evaluated in Study BNT162-01. Based on safety and
immunogenicity results from this study, 2 vaccine candidates, BNT162b1 and BNT162b2,
were selected for evaluation in Study C4591001, which is a Phase 1/2/3 randomized,
placebo-controlled, observer-blind, dose-finding, vaccine candidate-selection, and efficacy
study in healthy adults (conducted under IND 019736).
Phase 1 of Study C4591001 comprised dose-level–finding evaluations of the 2 selected
vaccine candidates; multiple dose levels (some corresponding to those evaluated in
Study BNT162-01) were evaluated. Study vaccine was administered using the same 2-dose
schedule as in Study BNT162-01 (21 days apart). Dose levels were administered first to an
18- to 55-year age cohort, then to a 65- to 85-year age cohort.
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Both vaccine candidate constructs were safe and well tolerated. BNT162b2 at the 30-µg
dose level was selected and advanced to the Phase 2/3 expanded cohort and efficacy
evaluation primarily because:
the reactogenicity profile for BNT162b2 was more favorable than BNT162b1 in both
younger and older adults with similar immunogenicity results;
in the NHP challenge study (VR-VTR-10671, see Section 2.1.1 ), a trend toward
earlier clearance of BNT162b2 was observed in the nose.
Phase 2 of the study (for which enrollment has completed) comprised the evaluation of safety
and immunogenicity data for the first 360 participants (180 from the active vaccine group
and 180 from the placebo group, with each group divided between the younger and older age
cohorts) entering the study after completion of Phase 1.
The Phase 3 part of the study (which is ongoing) evaluates the efficacy and safety in all
participants (including the first 360 participants from Phase 2). Phase 3 introduced:
enrollment of participants 16 to 17 years of age to be evaluated with the 18- to 55-
year-old cohort,
enrollment of a 12- to 15-year-old cohort,
immunogenicity data from the 12- to 15-year-old cohort (Table 3, Table 5, Table 11,
Table 13, Table 15, and Table 17),anticipated to bridge to the 16- to 25-year-old
cohort.
Participants in the pivotal study were initially planned to be followed for up to 24 months in
order to assess the potential for late-occurring adverse reactions, such as the theoretical risk
of VAED including VAERD. After completing the final efficacy analysis with vaccine
efficacy shown to be 95%, and obtaining regulatory authorisation to vaccinate in many
countries, Pfizer-BioNTech started to unblind all participants to determine those participants
randomised to placebo so that they could be offered vaccine in accordance with local
authorisation. To date, most placebo subjects have been unblinded to receive active vaccine
at or prior to 6 months after the second dose, therefore, a placebo group for comparison of
safety data is only available for up to 6 months post Dose 2.
The initial efficacy analysis on the 16 years and older population was event-driven, with
prespecified interim analyses after accrual of at least 62, 92, and 120 cases and a final
analysis at 164 cases.
A further efficacy analysis has been conducted on 12- to ≤15-year-old cohort participants and
on 16 years and older participants cohort participants reported by 13 March 2021.
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Ongoing BNT162b2 studies at the cut-off of the clinical database (13 March 2021) also
include:
C4591005: A phase 1/2 study to evaluate the safety, tolerability, and immunogenicity
of an RNA vaccine candidate against COVID-19 in healthy Japanese adults.
One hundred sixty participants were randomly assigned in a 3:1 ratio to study
intervention (candidate vaccine: 120, placebo: 40).
C4591015: A phase 2/3 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.
Approximately 4000 pregnant women at 24 to 34 weeks gestation are being
randomized in a 1:1 ratio to vaccine or placebo.
C4591017: A phase 3 study to evaluate the safety, tolerability, and immunogenicity of
multiple production lots and dose levels of BNT162b2 against COVID-19 in healthy
participants.
Approximately 340 participants were randomly assigned to each of 3 US lots and to a
20-μg arm and approximately 170 participants were randomly assigned an EU lot, for
a total of approximately 1530 randomized participants in 5 study arms.
Clinical Trial Exposure
Population for analysis of CTs data in this US Pharmacovigilance Plan includes the
following 2 studies:
C4591001: Phase 1/2/3, placebo-controlled, randomized, observer-blind, dose finding,
study to evaluate the safety, tolerability, immunogenicity, and efficacy of SARS-CoV-2
RNA vaccine candidates against COVID-19 in healthy individuals .
BNT162-01: A multi-site, phase I/II, 2-part, dose-escalation trial investigating the safety
and immunogenicity of four prophylactic SARS-CoV-2 RNA vaccines against COVID-19
using different dosing regimens in healthy adults.
Participants 16 years of age and older At the cut-off date of 13 March 2021, a total of 46,505 participants were vaccinated in the
BNT162b2 clinical development program:
21,745 participants received 2 doses and 360 received 1 dose of BNT162b2 during the
blinded follow-up period; 96 participants from study BNT162-01 received 2 doses of the
vaccine.
19,647 participants, who originally received placebo, then received 1 dose of BNT162b2
in the Open-Label Follow-up period after unblinding. (none from study BNT162-01).
Exposure to BNT162b2 for participants aged 16 years and older in the 2 ongoing studies by
number of doses, and demographic characteristics is shown in Table 3 through Table 21.
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In addition, exposure in clinical studies in special populations is provided in Table 22 and
Table 23.
Participants 12 to 15 years of age
At the cut-off date of 13 March 2021, a total of 2260 participants were vaccinated in the
BNT162b2 clinical development program:
Clinical study exposure data for the 12- to 15 years of age are provided for the ongoing study
C4591001 at the cut-off date of 13 March 2021.
In this study
1124 participants received 2 doses and 7 received 1 dose of BNT162b2 in the Blinded-
Placebo Controlled Follow-up period.
49 participants who originally received placebo, then received 1 dose of BNT162b2 in
the Open-Label Follow-up period after unblinding.
Exposure to BNT162b2 for participants aged 12- to 15 years of age by number of doses and
demographic characteristics is shown in Table 3,Table 5, Table 11, Table 13, Table 15,
Table 17. In addition, exposure in clinical studies in special populations is provided in
Table 22 and Table 23.
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Table 6. Exposure to BNT162b2 by Age Group and Dose (BNT162-01)
Age Group
Dose
Exposure (Number of Doses
Received) No. of Subjects
Exposed to BNT162b2 Total No. of Vaccine Doses
Vaccine 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
2 Doses 5 10
Total 5 10
Vaccine 20 µg
1 Dose 0 0
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Table 6. Exposure to BNT162b2 by Age Group and Dose (BNT162-01)
Age Group
Dose
Exposure (Number of Doses
Received) No. of Subjects
Exposed to BNT162b2 Total No. of Vaccine Doses
2 Doses 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
PFIZER CONFIDENTIAL SDTM Creation: 24NOV2020 (15:06) Source Data: adsl Table Generation: 10MAR2021
(11:32) (Cutoff date:23OCT2020, Snapshot Date: 23OCT2020)
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Table 10. Exposure to BNT162b2 by Dose (Totals) (BNT162-01)
Dose
Exposure (Number of Doses Received) No. of Subjects
Exposed to
BNT162b2 Total No. of Vaccine Doses
Vaccine 1 µg
1 Dose 1 1
2 Doses 11 22
Total 12 23
Vaccine 3 µg
1 Dose 0 0
2 Doses 12 24
Total 12 24
Vaccine 10 µg
1 Dose 1 1
2 Doses 23 46
Total 24 47
Vaccine 20 µg
1 Dose 0 0
2 Doses 24 48
Total 24 48
Vaccine 30 µg
1 Dose 0 0
2 Doses 24 48
Total 24 48
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Table 14. Exposure to BNT162b2 by Dose, Age Group, and Gender (BNT162-01)
No. of Subjects Exposed to
BNT162b2 Total No. of Vaccine Doses
Dose
Age Group Male Female Male Female
Vaccine 1 µg
≥18 years to ≤64 years 7 5 14 9
≥65 years to ≤74 years 0 0 0 0
≥75 years to ≤84 years 0 0 0 0
Total 7 5 14 9
Vaccine 3 µg
≥18 years to ≤64 years 5 7 10 14
≥65 years to ≤74 years 0 0 0 0
≥75 years to ≤84 years 0 0 0 0
Total 5 7 10 14
Vaccine 10 µg
≥18 years to ≤64 years 8 10 16 19
≥65 years to ≤74 years 3 2 6 4
≥75 years to ≤84 years 1 0 2 0
Total 12 12 24 23
Vaccine 20 µg
≥18 years to ≤64 years 7 10 14 20
≥65 years to ≤74 years 1 5 2 10
≥75 years to ≤84 years 0 1 0 2
Total 8 16 16 32
Vaccine 30 µg
≥18 years to ≤64 years 10 8 20 16
≥65 years to ≤74 years 2 4 4 8
≥75 years to ≤84 years 0 0 0 0
Total 12 12 24 24
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Table 21. Exposure to BNT162b2 by Dose and Race/Ethnic Origin (BNT162-01)
Dose
Race/Ethnic Origin No. of Subjects Exposed to
BNT162b2 Total No. of Vaccine Doses
Vaccine 1 µg
Racial Origin
White 12 23
Total 12 23
Ethnic Origin
Non-Hispanic/non -Latino 12 23
Total 12 23
Vaccine 3 µg
Racial Origin
White 12 24
Total 12 24
Ethnic Origin
Non-Hispanic/non -Latino 12 24
Total 12 24
Vaccine 10 µg
Racial Origin
White 24 47
Total 24 47
Ethnic Origin
Non-Hispanic/non -Latino 24 47
Total 24 47
Vaccine 20 µg
Racial Origin
White 24 48
Total 24 48
Ethnic Origin
Non-Hispanic/non -Latino 24 48
Total 24 48
Vaccine 30 µg
Racial Origin
White 24 48
Total 24 48
Ethnic Origin
Non-Hispanic/non -Latino 24 48
Total 24 48
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2.1.2.a.2. Inclusion and Exclusion Criteria
Detailed descriptions of all inclusion and exclusion criteria for clinical studies are provided
in the individual CSRs which were filed to IND 019736.
Inclusion criteria
Healthy participants who are determined by medical history, physical examination
(if required), and clinical judgment of the investigator to be eligible for inclusion in the
study.
Healthy participants with pre-existing stable disease, defined as disease not requiring
significant change in therapy or hospitalization for worsening disease during the 6 weeks
before enrollment, can be included. In order for the overall Phase 3 study population to
be as representative and diverse as possible, the inclusion of participants with known
chronic stable infection with HIV, HCV, or HBV was permitted as the study progressed.
Specific criteria for these Phase 3 participants can be found in the C4591001 protocol,
Section 10.8.
Phase 2/3 only: Participants who, in the judgment of the investigator, are at higher risk
for acquiring COVID-19 (including, but not limited to, use of mass transportation,
relevant demographics, front-line essential workers, and others).
The participants enrolled were 12 years of age and older; the 12- to 15-year-old cohort
was included in the protocol in October 2020.
Exclusion criteria Phase 1 exclusion criteria were stricter than criteria in Phases 2 and 3 of the study.
Participants were excluded from the studies according to the general criteria listed below:
Previous vaccination with any coronavirus vaccine
Reason for exclusion: To avoid confounding the assessment of serological or clinical
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 diagnosis of COVID-19 because these participants may have some
degree of protection from subsequent infection by SARS-CoV-2 and therefore would
confound the pivotal efficacy endpoint. During Phase 2/3, participants with prior
undiagnosed infection were allowed to be enrolled. Screening for SARS-CoV-2 with
nucleic acid amplification test by nasal swab or antibodies to non-vaccine SARS-CoV-2
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antigen by serology was not conducted before vaccine administration in Phase 2/3, but
samples were taken to run these assays after vaccination, thus identifying participants
with unidentified prior infection. This group will be assessed to identify whether prior
infection affects safety.
Is it considered to be included as missing information? No.
Rationale: Safety in study participants with prior infection will be assessed in the pivotal
study.
Immunocompromised individuals with known or suspected immunodeficiency, as
determined by history and/or laboratory/physical examination.
Reason for exclusion: Immunocompromised participants may have impaired immune
responses to vaccines and would therefore limit the ability to demonstrate efficacy,
which is the primary pivotal endpoint.
Is it considered to be included as missing information? No.
Rationale: Participants with potential immunodeficient status were not specifically
included in the study population. However, since the study population is intended to be
as representative as possible of the vulnerable population to COVID-19 illness,
sub-analyses of immunogenicity data in future studies may provide further understanding
of immune responses in this population.
Receipt of blood/plasma products or immunoglobulin, from 60 days before study
intervention administration or planned receipt throughout the study
Reason for exclusion: To avoid confounding the assessment of serological or clinical immune response in the study population.
Is it considered to be included as missing information? No.
Rationale: No impact on the safety of the target population.
Women who are pregnant or breastfeeding
Reason for exclusion: To avoid use in a vulnerable population.
Is it considered to be included as missing information? Yes.
Rationale: It is not known if maternal vaccination with BNT162b2 would have
unexpected negative consequences to the embryo or fetus.
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Other medical or psychiatric condition including recent (within the past year) or
active suicidal ideation/behavior or laboratory abnormality that may increase the
risk of study participation or, in the investigator’s judgment, make the participant
inappropriate for the study
Reason for exclusion: To avoid misleading results deriving from non-compliance to study procedures.
Is it considered to be included as missing information? No.
Rationale: Safety profile of BNT162b2 is not expected to differ in these subjects when
properly administered.
2.1.2.a.2.1. Non-Study Post-Authorization Exposure
It is not possible to determine with certainty the number of individuals who received
BNT162b2 since it was first authorized for emergency use on 01 December 2020. Estimated
worldwide shipped doses may serve as a reasonable indicator of subject exposure by region
and countries; the estimated exposure by gender and age group is not available.
Cumulatively, through the DLP (28 February 2021) approximately 126,212,580 doses of
BNT162b2 were shipped worldwide. The estimated cumulative number of shipped doses of
BNT162b2 by region, are summarized in Table 24.
Table 24. Cumulative Estimated Shipped Dosesa of BNT162b2 by Region Worldwide
Region/Country Total Number of Shipped
Doses % of Doses Europe 51,545,325 40.8%
European Union (27) 36340590 28.8%
European Free Trade Association (3) 513825 0.4%
Switzerland 767520 0.6%
UK 13643175 10.8%
Other Countries 280215 0.2%
Commonwealth of Independent Statesb 0 0.0%
North America 56577885 44.8%
US 54326415 43.0%
Canada 2251470 1.8%
Central and South America 2965170 2.3%
Asia 14467830 11.5%
Oceania 656370 0.5%
Africa 0 0.0%
Total 126,212,580 100.0%
a. Data for US are based on Order Management Dashboard, while for the remaining Regions and Countries are based
on the Order Book which is the most accurate tracker of shipment data.
b. Includes: Armenia, Azerbaijan, Belarus, Georgia, Kazakhstan, Kyrgyzstan, Moldova, Russia, Tajikistan, Turkmenistan, Ukraine, Uzbekistan;
Method Used to Calculate Exposure
Not applicable.
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Exposure
Not applicable.
2.1.2.a.3. Regulatory Actions Related to Safety
There were no withdrawals for safety reasons up to 28 February 2021.
2.1.2.b. Populations Not Studied in the Pre-Approval Phase
There has been limited exposure to BNT162b2 in some special populations and no
epidemiologic studies have been conducted in pregnant/lactating women, pediatric
participants (<12 years of age), and specific subpopulations that were initially excluded from
the BNT162b2 program.
Table 25. Exposure of Special Populations Included or not in Clinical Trial
Development Programs
Type of special population Exposure Pregnant women Available data on BNT162b2 administered to pregnant women are
insufficient to inform on vaccine-associated risks in pregnancy. In a
reproductive and developmental toxicity study, no vaccine-related
adverse effects on female fertility, fetal development, or postnatal
development were reported.
Through the cut-off date of 13 March 2021, there were 50 cases (52
events) originating from Study C4591001 in participant 16 years of
age and older, and all were unique pregnancies. Breastfeeding women Breastfeeding women were not initially included in the BNT162b2
clinical development program.
Data are not available to assess the effects of BNT162b2 on the
breastfed infant or on milk production/excretion.
The developmental and health benefits of breastfeeding should be
considered along with the mother’s clinical need for BNT162b2 and
any potential adverse effects on the breastfed child from BNT162b2
or from the underlying maternal condition. For preventive vaccines,
the underlying maternal condition is susceptible to disease prevented
by the vaccine.
Through the cut-off date of 13 March 2021, there were no CT cases
indicative of exposure during breastfeeding from study C4591001 in
participants 16 years of age and older. Participants with relevant
comorbidities:
• Participants with hepatic
impairment
• Participants with renal impairment
• Participants with cardiovascular
disease
• Immunocompromised participants
• Participants with a disease
severity different from inclusion
criteria in CTs Healthy participants with pre-existing stable disease, defined as
disease not requiring significant change in therapy or hospitalization
for worsening disease during the 6 weeks before enrollment, were
included. This allowed enrollment of a proportion of participants
with common comorbidities such as cardiovascular diseases including
hypertension, chronic pulmonary diseases, asthma, chronic liver
disease, BMI >30 kg/m2, participants with stage 3 or worse chronic
kidney disease, and participants with varying disease severity.
Participants with potential immunodeficient status were not
specifically included in the study population.
Please refer to Table 22 and Table 23 for the exposure of special
populations.
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Table 25. Exposure of Special Populations Included or not in Clinical Trial
Development Programs
Type of special population Exposure
Participants of different racial
and/or ethnic origin Please refer to Table 21 for exposure information by ethnic origin
from the studies.
Subpopulations carrying known and
relevant polymorphisms No data available.
Pediatric participants The safety and effectiveness of BNT162b2 in individuals younger
than 16 years of age have not been established.
Participants 16 years of age and older
A total of 671 pediatric participants 16 to 17 years of age received
BNT162b2 through the DLP of 13 March 2021:
378 participants in the blinded-placebo controlled follow-up
period (Table 3).
293 participants in the open-label follow-up period after the
unblinding (Table 5).
Participants 12 to 15 years of age
One thousand and hundred eighty (1180) pediatric participants 12 to
15 years of age received BNT162b2 through the cut-off date of 13
March 2021 (Table 3 and Table 5).
Elderly (≥65 years old) The safety and effectiveness of BNT162b2 in elderly participants was
consistent with that seen in younger adult participants.
Clinical studies of BNT162b2 included a total of 8846 participants 65
years of age and over; of these, 8827 were from study C4591001,
through the cut-off date of 13 March 2021:
4590 participants in the blinded-placebo controlled follow-
up period (Table 3)
4237 participants in the open-label follow-up period after
unblinding (Table 5).
Nineteen (19) participants 65 years of age and over were from study
BNT162-01 study through the cut-off date of 23 October 2020
(Table 6). 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 PVP:
Risks with minimal and temporary clinical impact on patients (in relation to the severity
of the disease prevented).
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Table 28. Vaccine-Associated Enhanced Disease (VAED), including Vaccine-
Associated Enhanced Respiratory Disease (VAERD)
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,9 as noted above. The table
above shows a favorable balance of severe COVID-19 cases in participants receiving
BNT162b2 versus those receiving placebo, providing reassurance against the potential
risk of VAED/VAERD at this time.
Data from the safety database No post-authorized AE reports have been identified as cases of VAED/VAERD,
therefore, there is no observed data at this time. An expected rate of VAED is
difficult to establish so a meaningful observed/expected analysis cannot be conducted
at this point based on available data. The feasibility of conducting such an analysis
will be re-evaluated on an ongoing basis as data on the virus grows and the vaccine
safety data continues to accrue.
The search criteria utilised to identify potential cases of VAED for this report includes
PTs indicating a lack of effect of the vaccine and PTs potentially indicative of severe
or atypical COVID-19a.
Since the first temporary authorization for emergency supply under Regulation 174 in
the UK (01 December 2020) and through 28 February 2021, the following numbers of
potentially relevant cases were retrieved:
138 cases [0.25% of the total post-authorization dataset], reporting 317 potentially
relevant events.
Seriousness criteria for the total 138 cases: Medically significant (71, of which 8 also
serious for disability), Hospitalization required (non-fatal/non-life threatening) (16, of
which 1 also serious for disability), Life threatening (13, of which 7 were also serious
for hospitalization), Death (38).
Gender: Females (73), Males (57), Unknown (8).
Age (n=132) ranged from 21 to 100 years (mean = 57.2 years, median = 59.5).
Overall event seriousness and outcome are summarized below.
Total Events
N = 317 (%) Serious events 279 (88.0)
Events with Criterion of Hospitalization 91 (28.7)
Distribution of events by Outcomea
Outcome: Death 62 (19.6)
Outcome: Resolved/Resolving 61 (19.2)
Outcome: Not resolved 90 (28.4)
Outcome: Resolved with sequelae 1 (0.3)
Outcome: Unknown/No data 106 (33.4)
a. 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 frequently reported relevant PTs (≥5 events) were: Drug ineffective (135),
Dyspnoea (53), Diarrhoea (30), COVID-19 pneumonia (23), Vomiting (20),
Respiratory failure (8), Seizure (7), Hypoxia (6), Abdominal pain, and Pulmonary embolism (5 each).
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Table 28. Vaccine-Associated Enhanced Disease (VAED), including Vaccine-
Associated Enhanced Respiratory Disease (VAERD)
Conclusion: VAED may present as severe or unusual clinical manifestations of
COVID-19. Overall, there were 37 subjects with suspected COVID-19 and 101
subjects with confirmed COVID 19 following one or both doses of the vaccine; 75 of
the 101 cases were severe, resulting in hospitalisation, disability, life threatening
consequences or death. None of the 75 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 for the
vaccine. Surveillance will continue. Risk factors and
risk groups It is postulated that the potential risk may be increased in individuals producing lower
neutralizing antibody titers or in those demonstrating waning immunity.8,9 Preventability An effective vaccine against COVID-19 that produces high neutralizing titers and a
TH1 predominant CD4+ T cell response and strong CD8+ T cell response, is expected
to mitigate the risk of VAED/VAERD;1,8 that immune profile is elicited by BNT162b2 in clinical and preclinical studies.10,11
Impact on the
risk-benefit
balance of the
biologic product If there were an unfavorable balance in COVID-19 cases, including severe cases, in
the pivotal clinical study between the vaccine and placebo groups, that may signal
VAED/VAERD.
Public health
impact The potential risk of VAED/VAERD could have a public health impact if large
populations of individuals are affected. a. 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 hepatic failure; Deep vein thrombosis; Pulmonary embolism;
Peripheral Ischaemia; Vasculitis; Shock; Acute kidney injury; Renal failure; Altered state of consciousness;
Seizure; Encephalopathy; Meningitis; Cerebrovascular accident; 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 ineffective/Vaccination failure).
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Co-administration studies with BNT162b2 have not been done, therefore there is not
sufficient data to understand the effect on vaccine effectiveness of BNT162b2 or co-
administered vaccines. A co-administration study with seasonal influenza vaccine is
planned. If BNT162b2 is given at the same time as other injectable vaccine(s), the vaccine(s)
should be administered at different injection sites.
2.1.2.e. Epidemiology of Indication and Target Population
Indication
Active immunization against COVID-19 disease caused by SARS-CoV-2 virus in individuals
≥ 16 years of age.
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 beyond China throughout the world. On 30 January 2020, the
WHO declared COVID-19 a Public Health Emergency of International Concern and thus a
pandemic.13
Estimates of SARS-CoV-2 incidence change rapidly. We obtained incidence and prevalence
estimates using data from Worldometer, a trusted independent organization that collects
COVID-19 data from official reports and publishes current global and country-specific
statistics online.14
As of 03 March 2021, the overall number of people who had been infected with
SARS-CoV-2 was over 115 million worldwide,15 an increase of nearly 100 million in the 7
months since 28 July 2020.16 Table 32 shows the incidence and prevalence as of 03 March
2021 for the US, UK, and EU-27 countries. In the EU and the UK, by 03 March 2021 the
total number of confirmed cases had accumulated to almost 27 million people, or 5,226 per
100,000 people (from 1.7 million, or 337 per 100,000 by 28 July 2020). Across countries in
the EU, the number of confirmed cases ranged from 1,072 to 11,836 cases per 100,000
people. Finland and Greece reported the lowest incidence rates while Czech Republic,
Slovenia, and Luxembourg reported the highest.15
In the US, the number of confirmed cases had reached over 29 million (8,864 per 100,000
people) by 03 March 2021.15 This is an increase from 4.5 million (1,357 per 100,000) by
28 July 2020.17
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Table 32. Incidence, Prevalence, and Mortality of COVID-19 as of 03 March 2021 15
Total
Cases Incidence:
Total Cases/
100,000 Active
Casesa Prevalence:
Active Cases/
100,000 Total
Deaths Mortality:
Deaths /
100,000 Population
Global 115,760,943 1,485 21,707,680 278 2,571,518 33 7,794,824,793
EU-27 22,642,536 5,083 6,113,464 1,462 553,363 124 445,424,167
UK 4,194,785 6,157 1,065,282 1,564 123,783 182 68,125,249
EU-27 + UK 26,837,321 5,226 7,178,746 1,398 677,146 132 513,549,416
US 29,456,377 8,864 8,921,400 2,685 531,652 160 332,304,437
EU-27 Countries
Austria 465,322 5,147 21,028 233 8,625 95 9,040,866
Belgium 774,344 6,662 699,566 6,019 22,141 191 11,623,476
Bulgaria 253,183 3,662 33,770 488 10,413 151 6,913,156
Croatia 244,205 5,973 3,322 81 5,555 136 4,088,197
Cyprus 35,620 2,936 33,331 2,747 232 19 1,213,250
Czech Republic 1,269,058 11,836 154,580 1,442 20,941 195 10,722,330
Denmark 212,798 3,665 6,995 120 2,370 41 5,805,897
Estonia 69,193 5,214 17,938 1,352 615 46 1,327,135
Finland 59,442 1,072 12,683 229 759 14 5,546,504
France 3,810,316 5,829 3,461,485 5,295 87,542 134 65,370,546
Germany 2,472,896 2,945 126,785 151 71,711 85 83,963,843
Greece 197,279 1,899 21,157 204 6,597 64 10,388,744
Hungary 439,900 4,561 98,361 1,020 15,324 159 9,643,837
Ireland 221,189 4,446 193,468 3,889 4,357 88 4,974,683
Italy 2,976,274 4,927 437,421 724 98,635 163 60,401,999
Latvia 88,022 4,702 9,233 493 1,654 88 1,872,109
Lithuania 200,349 7,430 10,859 403 3,281 122 2,696,596
Luxembourg 55,902 8,834 3,074 486 643 102 632,773
Malta 23,226 5,251 3,000 678 321 73 442,333
Netherlands 1,101,430 6,418 - - 15,697 92 17,160,343
Poland 1,735,406 4,589 249,567 660 44,360 117 37,818,722
Portugal 806,626 7,926 64,797 637 16,430 161 10,176,690
Romania 812,318 4,242 44,953 235 20,586 108 19,151,141
Slovakia 314,359 5,756 51,570 944 7,489 137 5,461,420
Slovenia 192,266 9,247 10,751 517 3,874 186 2,079,130
Spain 3,136,321 6,706 343,770 735 70,247 150 46,766,954
Sweden 675,292 6,659 - - 12,964 128 10,141,493
a. Active case counts were not available for Netherlands and Sweden; therefore, those two countries are excluded from
the overall prevalence calculations for EU-27 and EU-27 + UK.
The reported numbers refer only to cases that have been tested and confirmed to be carrying
the virus. 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
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asymptomatic are less likely to be tested and therefore mild cases are likely underreported.
The numbers should therefore be interpreted with caution.18
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 03 March 2021, the
overall prevalence for the EU and UK (though not available for Sweden and the Netherlands)
was 1,398 active cases per 100,000,15 compared to 51 per 100,000 on 28 July 2020.16 The
range of reported prevalence was 81 to 6,019 per 100,000: Croatia, Denmark, and Germany
reported the lowest prevalence while Belgium, France and Ireland reported the highest
(Table 32).
In the US, the prevalence on 03 March 2021 was nearly twice as high as the combined
EU+UK estimates, with 2,685 active cases per 100,000.15 The prevalence in the US was 653
per 100,000 on 28 July 2020.16
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 EU/EEA and the UK. In the ECDC’s
TESSy database, COVID-19 case-based data, including age and gender, are available for
over 80% of the official number of cases reported by ECDC epidemic intelligence,19 enabling
estimates of age and gender distribution representative of the European population. TESSy
data on age and sex distributions by severity of symptoms as posted on 04 March 2021 are
shown in Figure 1.20
The top half of the figure represents data ending on 31 July 2020 and the bottom half
presents data from 01 August 2020 to 04 March 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 years.
This likely reflects the age distribution of people who met the requirements for being tested
and is unlikely to reflect the actual distribution of infections in the population. Those with
severe outcomes (hospitalized, severely hospitalized, or fatal) have been disproportionately
older and male compared to COVID-19 cases overall. While age-sex patterns have remained
consistent throughout the pandemic, a notable difference between the periods before and
since 01 August 2020 is that the absolute numbers of cases have increased dramatically in the
latter period compared to the earlier one.
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Figure 1. Age-Sex distribution of COVID-19 Cases as Different Levels of Severity,
EU/EEA and UK. Case-based Data from TESSy produced on
04 March 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 8, 2021. 4 March 2021. “2.2 Age-sex pyramids” Accessed 6
March 202120
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 33.21 Those under age 50 account for 65% of
cases but less than 5% of deaths. For ages 18-74, males account for less than half of cases
but over 60% of deaths.
Table 33. Distributions of Cases (n=21,895,936) and Deaths (n=382,009) by Age, Sex,
Race, and Cross-Tabulated Age and Sex – United States as of
08 March 202121,a
Age x Sex % Event Age
Group Age
% Sex Sex
% Raceb Race
% Age
Group Males Females
Cases 0-4 2 Males 47.8 H/L 20.7 0-4 51.7 48.3
5-17 9.5 Females 52.2 AI/AN 1.2 5-17 49.8 50.2
18-29 22.4 Asian 3.6 18-29 47.1 52.9
30-39 16.3 Black 12.2 30-39 48.2 51.8
40-49 14.9 NH/PI 0.4 40-49 47.7 52.3
50-64 20.5 White 56 50-64 48.5 51.5
65-74 7.8 M/O 6 65-74 49 51
75-84 4.1 75-84 45.7 54.3
85+ 2.4 85+ 33.9 66.1
Deaths 0-4 <0.1 Males 54.3 H/L 12.2 0-4 47.6 52.4
5-17 0.1 Females 45.7 AI/AN 1 5-17 57.7 42.3
18-29 0.5 Asian 4.3 18-29 63 37
30-39 1.1 Black 14.7 30-39 66 34
40-49 2.8 NH/PI 0.2 40-49 66.5 33.5
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Table 33. Distributions of Cases (n=21,895,936) and Deaths (n=382,009) by Age, Sex,
Race, and Cross-Tabulated Age and Sex – United States as of
08 March 202121,a
Age x Sex %
Event Age
Group Age
% Sex Sex
% Raceb Race
% Age
Group Males Females
50-64 14.5 White 63.1 50-64 65 35
65-74 21.3 M/O 4.4 65-74 61.4 38.6
75-84 27.7 75-84 55.8 44.2
85+ 32.1 85+ 41.8 58.2
a. Percentage of missing demographic data varied by types of event and demographic.
b. Except for Hispanics/Latinos, all categories refer to non-Hispanics
Abbreviations: AI/AN=American Indian/Alaska Native, H/L=Hispanic/Latino, M/O=Multiple/Other, NH/PI=Native Hawaiian/Other Pacific Islander
In general, disease has been much less severe among ages 0-24 compared to ages ≥25 years,
with 2.5% hospitalized, 0.8% admitted to an intensive care unit, and <0.1% dying among
ages 0-24, versus 16.6% hospitalized, 8.6% intensive care, and 5% dying among ages
≥25 years.22 Among hospitalized cases with COVID-19 in the US, approximately 90% are
over 40 years old, and between 58% to 66% are at least 60 years old.23 The majority
(approximately 60%) of COVID-19 patients admitted to hospitals in the US have been
male.23,24,25,26,27
African American COVID-19 patients have been reported to have an increased risk of
hospitalization24,28 and mortality,29 compared to white patients in the United States. A CDC
report examined demographic trends among US COVID-19 deaths from May to August of
2020.30 During the observation period, the percentage of US COVID-19 deaths that were
Hispanic increased from 16.3% in May to 26.4% in August, the only racial or ethnic group
among whom the percentage of deaths increased during that time. In terms of setting, 64.3%
of deaths occurred in inpatient hospitals and 21.5% in nursing homes or long-term care
facilities.
As of 08 March 2021, the CDC estimated that the total number of excess deaths (as opposed
to overall deaths in the preceding paragraph) across the US from 01 February 2020 to the
present from all causes (COVID-19 and otherwise) ranged from 509,890-624,307.31 A CDC
report examining US excess deaths associated with race and age, restricted to the period
26 January 2020 to 03 October 2020, estimated that 66% of US excess deaths during that
period were attributable to COVID-19.32 By age, the largest increase in deaths compared to
average expected deaths occurred among adults aged 25-44 (26.5% increase). By race,
increases in deaths compared to expectation were largest among Hispanics (53.6% increase),
Asian Americans (36.6% increase), African Americans (32.9% increase), and Native
Americans and Native Alaskans (28.9% increase), all compared to an excess 11.9% deaths
among non-Hispanic whites.
Risk Factors While anyone can become infected with SARS-CoV-2, symptoms of COVID-19 disease can
range from very mild (or no symptoms) to severe or fatal. A person’s risk of initial infection
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increases through spending time in close physical proximity to others, especially in indoor
spaces with poor ventilation.33 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.33,34,35 According to the CDC, people ages
18-29 have the highest risk of initial infection, while children age 4 and under have the
lowest rate (Table 34).36 Risk of infection is also higher among some ethnic minority
groups.37,38
Table 34. Risk for COVID-19 Infection, Hospitalization, and Death by Age Group 36
and by Race/Ethnicity 37
Rate ratios
Age Group (years) Cases Hospitalization Death
0-4 <1 2 2
5-17 a 1 1 1
18-29 3 7 15
30-39 2 10 45
40-49 2 15 130
50-64 2 25 400
65-74 2 35 1100
75-84 2 55 2800
85+ 2 80 7900
Race/Ethnicity
Non-Hispanic White b 1 1 1
American Indian or Alaska Native, non -Hispanic 1.9 3.7 2.4
Asian, non -Hispanic 0.7 1.1 1.0
Black or African American, non -Hispanic 1.1 2.9 1.9
Hispanic or Latino 1.3 3.2 2.3
a. Rate ratios for each age group are relative to the 5—17-year age category.
b. 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.36,37,38,39,40,41 Risks of hospitalization and death increase
dramatically for every 10-year age group above age 17 (Table 34).36,41 Table 34 also gives
estimated rate ratios for COVID-19 hospitalization and death by race/ethnicity relative to
white, non-Hispanic persons in the US. The highest risks of hospitalization and death were
observed among American Indian or Alaska native persons (RR = 3.7 for hospitalization and
2.4 for death) and Hispanic or Latino persons (RR = 3.2 for hospitalization and 2.3 for
death). These differences in risk among ethnic groups may be attributed to differences in
underlying factors that are correlated with race/ethnicity including socioeconomic status,
access to health care, and occupation-related virus exposure.37
Risk of severe or fatal COVID-19 disease is higher among persons who are current or former
smokers, have lower socioeconomic status, have no or public insurance, or live in
neighborhoods with higher rates of limited English proficiency.38,40,41,42 The CDC has also
recognized other socio-demographic groups who may need to take extra precautions against
COVID-19 due to increased risk for severe illness: pregnant women; breastfeeding mothers;
people with disabilities or developmental/behavioral disorders; people living in rural
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communities, nursing homes, long-term care facilities, or prisons; people experiencing
homelessness; and newly resettled refugee populations.43
Risk for severe or fatal COVID-19 disease also increases with the presence of chronic
medical conditions, including obesity, respiratory 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, autoimmune conditions and
immunosuppression, or higher scores on the WHO Clinical Progression Scale and Charlson
Comorbidity Index.38,39,40,41,42 Table 35 shows the estimated hazard ratios of COVID-19
mortality associated with these chronic conditions and socio-demographics from a cohort
study of 17 million adults in England.41
Table 35. Hazard Ratios and 95% Confidence Intervals for COVID-19-related
Death41
COVID-19 death Hazard Ratio
Characteristic Category Adjusted for
age and sex Fully adjusted
Age 18-39 0.05 (0.04 -0.07) 0.06 (0.04 -0.08)
40-49 0.28 (0.23 -0.33) 0.30 (0.25 - 0.36)
50-59 1.00 (ref) 1.00 (ref)
60-69 2.79 (2.52 -3.10) 2.40 (2.16 -2.66)
70-79 8.62 (7.84 -9.46) 6.07 (5.51 -6.69)
80+ 38.29 (35.02 -41.87) 20.60 (18.70 -22.68)
Sex Female 1.00 (ref) 1.00 (ref)
Male 1.78 (1.71 -1.85) 1.59 (1.53 -1.65)
BMI (kg/m2) Not obese 1.00 (ref) 1.00 (ref)
30-34.9 (obese class I) 1.23 (1.17 –1.30) 1.05 (1.00 –1.11)
35-39.9 (obese class II) 1.81 (1.68 –1.95) 1.40 (1.30 –1.52)
40+ (obese class III) 2.66 (2.39 –2.95) 1.92 (1.72 –2.13)
Smoking Never 1.00 (ref) 1.00 (ref)
Former 1.43 (1.37 –1.49) 1.19 (1.14 –1.24)
Current 1.14 (1.05 –1.23) 0.89 (0.82 –0.97)
Ethnicitya White 1.00 (ref) 1.00 (ref)
Mixed 1.62 (1.26 –2.08) 1.43 (1.11 –1.84)
South Asian 1.69 (1.54 –1.84) 1.45 (1.32 –1.58)
Black 1.88 (1.65 –2.14) 1.48 (1.29 –1.69)
Other 1.37 (1.13–1.65) 1.33 (1.10 –1.61)
IMD quintilee 1 (least deprived) 1.00 (ref) 1.00 (ref)
2 1.16 (1.08 -1.23) 1.12 (1.05 –1.19)
3 1.31 (1.23 –1.40) 1.22 (1.15 –1.30)
4 1.69 (1.59 –1.79) 1.51 (1.42 –1.61)
5 (most deprived) 2.11 (1.98 –2.25) 1.79 (1.68 –1.91)
Blood pressure Normal 1.00 (ref) 1.00 (ref)
High BP or diagnosed
hypertension 1.09 (1.05–1.14) 0.89 (0.85–0.93)
Respiratory disease excluding asthma 1.95 (1.86 –2.04) 1.63 (1.55 –1.71)
Asthmab (vs. none) With no recent OCS use 1.13 (1.07 –1.20) 0.99 (0.93 –1.05)
With recent OCS use 1.55 (1.39 –1.73) 1.13 (1.01–1.26)
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Table 35. Hazard Ratios and 95% Confidence Intervals for COVID-19-related
Death41
COVID-19 death Hazard Ratio
Characteristic Category Adjusted for
age and sex Fully adjusted
Chronic heart disease 1.57 (1.51 –1.64) 1.17 (1.12 –1.22)
Diabetesc (vs. none) With HbA1c < 58 mmol/mol 1.58 (1.51 –1.66) 1.31 (1.24 –1.37)
With HbA1c ≥ 58 mmol/mol 2.61 (2.46 –2.77) 1.95 (1.83 –2.08)
With no recent HbA1c measure 2.27 (2.06–2.50) 1.90 (1.72 –2.09)
Cancer (non-
hematological, vs. none) Diagnosed <1 year ago 1.81 (1.58 –2.07) 1.72 (1.50 –1.96)
Diagnosed 1 -4.9 years ago 1.20 (1.10 –1.32) 1.15 (1.05 –1.27)
Diagnosed ≥ 5 years ago 0.99 (0.93 –1.06) 0.96 (0.91 –1.03)
Hematological
malignancy (vs. none) Diagnosed <1 year ago 3.02 (2.24 –4.08) 2.80 (2.08 –3.78)
Diagnosed 1 -4.9 years ago 2.56 (2.14 –3.06) 2.46 (2.06 –2.95)
Diagnosed ≥ 5 years ago 1.70 (1.46 –1.98) 1.61 (1.39 –1.87)
Reduced kidney
functiond (vs. none) eGFR 30-60 1.56 (1.49 –1.63) 1.33 (1.28 –1.40)
eGFR < 30 3.48 (3.23 –3.75) 2.52 (2.33 –2.72)
Liver disease
2.39 (2.06–2.77) 1.75 (1.51 –2.03)
Stroke or dementia 2.57 (2.46 –2.70) 2.16 (2.06 –2.27)
Other neurological disease 3.08 (2.85 –3.33) 2.58 (2.38 –2.79)
Organ transplant
6.00 (4.73 –7.61) 3.53 (2.77 –4.49)
Asplenia
1.62 (1.19 –2.21) 1.34 (0.98 –1.83)
Rheumatoid arthritis, lupus, or psoriasis 1.30 (1.21 –1.38) 1.19 (1.11 –1.27)
Other immunosuppressive condition 2.75 (2.10 –3.62) 2.21 (1.68 –2.90)
a. Ethnicity hazard ratios were estimated from a model restricted to those with recorded ethnicity.
b. For OCS use, ‘recent’ refers to during the year before baseline.
c. Classification by HbA1c is based on measurements within 15 months of baseline.
d. eGFR is measured in ml min−1 per 1.73 m2 and taken from the most recent serum creatinine
measurement.
e. Index of Multiple Deprivation
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.
The main existing treatment options:
Through 28 February 2021, other COVID-19 vaccines were authorized and recommended for
use in the United States including vaccines from Moderna (NCT04470427), and Johnson &
Johnson/Janssen (NCT04505722). Others may subsequently be approved.
Natural history of the indicated condition in the untreated population, including
mortality and morbidity:
Symptoms of COVID-19
The clinical manifestations of COVID-19 vary widely, from asymptomatic infection in
17-20%,44,45 to critical illness and death. The most common symptoms of COVID-19 are
fever, cough, and shortness of breath (Table 36 ).46
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Table 36. Signs and symptoms among 291 pediatric (age <18 years) and 10,944 adult
(age 18–64 years) patientsa with laboratory confirmed COVID-19 —
United States, 12 February– 2April 202046
No. (%) with sign/symptom
Sign/Symptom Pediatric Adult
Fever, cough, or shortness of breathb 213 (73) 10,167 (93)
Feverd 163 (56) 7,794 (71)
Cough 158 (54) 8,775 (80)
Shortness of breath 39 (13) 4,674 (43)
Myalgia 66 (23) 6,713 (61)
Runny nosec 21 (7.2) 757 (6.9)
Sore throat 71 (24) 3,795 (35)
Headache 81 (28) 6,335 (58)
Nausea/Vomiting 31 (11) 1,746 (16)
Abdominal paind 17 (5.8) 1,329 (12)
Diarrhea 37 (13) 3,353 (31)
a. Cases were included in the denominator if they had a known symptom status for fever, cough, s hortness
of breath, nausea/vomiting, and diarrhea. Total number of patients by age group: <18 years (N = 2,572), 18–
64 years (N = 113,985).
b. Includes all cases with one or more of these symptoms.
c. Runny nose and abdominal pain were less frequently completed than other symptoms; 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 hypoxia. For those
who develop symptoms, the incubation period is usually 4 to 5 days, with 97.5%
experiencing symptoms within 11 days of exposure.47,48 Those with mild COVID-19 recover
at home with supportive care and guidance to self-isolate. Those with moderate disease are
monitored at home and are sometimes recommended to be hospitalized if conditions
worsen.48 Data on rates of re-infection are limited but variants that are not neutralized by
immune antisera, such as the recent South African variant, may lead to increased risk of re-
infection in the future.47
Progression and Timeline of Severe Disease Requiring Hospitalization Those with severe disease will require hospitalization to manage their illness. Based on data
that have been systematically collected for the US by the CDC between 01 August 2020 and
02 March 2021, there were 1,814,606 new hospital admissions for patients with confirmed
COVID-19 in the US.49 For the week ending 28 February 2021, 10 patients per 100,000
population were hospitalized due to COVID-19 in 22 countries of the EU/EEA with available
data.50
The most common symptoms in patients are fever (42-80%), shortness of breath (35-71%),
fatigue (33-62%), cough (77-84%), chills (63%), myalgias (63%), headache (59%), and
diarrhea (33%).51,52,53,54 Approximately 17% to 40% of those hospitalized with COVID-19
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experience severe symptoms necessitating intensive care.23,28,51 More than 75% of patients
hospitalized with COVID-19 require supplemental- oxygen.55
Studies early in the pandemic demonstrated that time from onset of illness to ARDS was 8-
12 -days and time from onset of illness to ICU admission was 9.5–12 days.47 In 17 countries
of the EU/EEA with available data, 1.8 patients per 100,000 population were in the ICU due
to COVID-19 for the week ending 28 February 2021.50 A recent meta-analysis found that, of
patients <19 years of age, 11% went to the ICU, non-invasive ventilation was administered
among 12%, and 4% required mechanical ventilation.45
Mortality
As of 07 March 2021, there were 522,973 deaths reported in the US for all age groups among
28,771,749 cases (1.8% of cases).49 As of 28 February 2021 there were 547,267 deaths
reported for all age groups in the EU/EEA among 22,527,370 cases (2.4% of cases).56 As of
7 March 2021, the UK has seen 124,736 deaths from COVID-19 in all age groups among
4,231,166 cases (2.9% of cases).57 According to a recent meta-analysis of pediatric studies
published through October 2020, the mortality for patients <19 years of age is 2%.45
Mortality data are also presented from Worldometer, an independent organization that
publishes current, reliable COVID-19 statistics online.17 The mortality of SARS-CoV-2
infection is defined as the cumulative number of deaths among detected cases.
As of 03 March 2021, the overall SARS-CoV-2 mortality for the EU + UK was 677,146
deaths, or 132 per 100,000 people. Reported mortality among EU countries and the UK
ranged from 14 to 195 deaths per 100,000 (Table 32). Finland and Cyprus reported the
lowest mortality; Czech Republic, Belgium and Slovenia reported the highest.15
In the US, as of 03 March 2021, the mortality was 531,652 deaths (160 per 100,000 people).
Mortality in the US was similar to that of EU countries Hungary, Portugal, and Italy. 15
Overall reported mortality among hospitalized COVID-19 patients varies from 12.8% to 26%
in the EU and UK. 28,30,58,59 Mortality rates are declining over time, presumably due to an
improved understanding of COVID-19 and its management.58,60
Complications of COVID-19 and Long-COVID Complications of COVID-19 include impaired function of the heart, brain, lung, liver,
kidney, and coagulation system.23,25,54 Based on a meta-analysis of 42 studies, the risk of
thromboembolism was 21% overall and 31% in the ICU, with the pooled odds of mortality
being 74% higher among those who experienced thromboembolism compared to those who
did not.61
COVID-19 symptoms can persist weeks or months beyond the acute infection.62,63 The
NICE guideline scope published on 30 October 2020 defined “Long COVID” signs and
symptoms that continue or develop after acute COVID‑19. It includes both ongoing
symptomatic COVID‑19 (from 4 to 12 weeks) and post‑COVID‑19 syndrome (12 weeks or
more and for which signs and symptoms are not explained by an alternative diagnosis).64
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A meta analysis of 31 studies among patients between 18 to 49 years of age found that
COVID-19 symptoms were experienced for 14 days to 3 months post-infection, including
persistent fatigue (39–73%), breathlessness (39–74%), decrease in quality of life (44–69%),
impaired pulmonary function, abnormal CT findings including pulmonary fibrosis (39–83%),
evidence of peri-/perimyo-/myocarditis (3–26%), changes in microstructural and functional
brain integrity with persistent neurological symptoms (55%), increased incidence of
psychiatric diagnoses (5.8% versus 2.5–3.4% in controls), and incomplete recovery of
olfactory and gustatory dysfunction (33–36%).65 Children who are infected with COVID-19
are at risk of subsequent multisystem inflammatory syndrome (MIS-C) and often develop a
rash following resolution of COVID-19.66,67,45
Important co-morbidities:
Important comorbidities in hospitalized COVID-19 patients include hypertension, diabetes,
obesity, cardiovascular disease, chronic pulmonary disease or asthma, chronic kidney
disease, cancer, and chronic liver disease.24,25,26,51,54 Prevalence of these conditions have
been reported to be lower in mild cases and higher among fatal cases, as shown as shown for
European countries in Table 37 below.
Table 37. Preconditions among COVID-19 Patients in EU/EEA and UK, by Severity
of Disease. Case-based Data from TESSy Produced 04 March 2021
EU/EEA, produced on 04 March 2021 Mild Hosp Severe Fatal
Total N 1,155,969 214,784 35,468 67,011
Asplenia (%) 0 0 0 0
Asthma (%) 0.5 1.6 1.7 1.6
Cancer, malignancy (%) 2.1 7.2 9.7 9.3
Cardiac disorder, excluding hypertension (%) 6.2 18.4 20.7 24.7
Chronic lung disease, excluding asthma (%) 1.8 4.7 5.3 5.3
Current smoking (%) 0.9 0.3 0.4 0.1
Diabetes (%) 3.3 13.9 18.9 15.6
Haematological disorders (%) 0 0.3 0.1 0.2
HIV/other immune deficiency (%) 0.1 0.9 1 0.8
Hypertension (%) 0.7 3.9 4.4 6.3
Kidney-related condition, renal disease (%) 0.3 2.3 2.2 3.7
Liver-related condition, liver disease (%) 0.2 0.7 0.7 0.6
Neuromuscular disorder, chronic neurological (%) 0.6 2.4 1.6 4.2
Obesity (%) 0.2 0.2 0.4 0.2
Other endocrine disorder, excluding diabetes (%) 0.4 0.2 0.1 0.1
Rheumatic diseases including arthritis (%) 0 0 0 0
Tuberculosis (%) 0 0 0 0
None (%) 82.5 42.8 32.7 27.3
Abbreviation: Hosp = Hospitalized
Table 38 below summarizes comorbidities among US COVID-19 patients in a retrospective
cohort study conducted among 629,953 individuals tested for COVID-19 in a large health
system in the US Northwest between 01 March and 31 December 2020.38 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
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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.
Table 38. Comorbidities in individuals tested for COVID-19 in the Providence St.
Joseph Health System – States of California, Oregon, and Washington,
01 March–31 December 202038
Comorbidity Tested
(N= 629,953)
% Positive
(N= 54,645)
% Hospitalized
(N= 8,536)
% Hypertension 23.3 19.8 40.2
Diabetes 9.4 10.9 28.3
Weight
Underweight 2.1 1.7 3.1
Normal 29.0 23.9 24.3
Overweight 31.7 32.6 30.3
Class 1 Obesity 19.8 22.3 21.2
Class 2 Obesity 9.6 11.1 10.9
Class 3 Obesity 7.7 8.6 10.3
Asthma 6.5 5.3 6.7
Chronic Obstructive Pulmonary Disease 4.0 2.6 8.3
Coronary Artery Disease 5.5 3.6 9.7
Myocardial Infarction 2.2 1.6 5.5
Congestive Heart Failure 5.3 3.9 13.2
Kidney Disease 5.6 5.3 17.2
Liver Disease 3.1 2.5 4.0
Cancer 6.1 3.0 6.3
2.1.2.f. Pharmacological Class Effects
There are 2 vaccines (including BNT162b2) with a mRNA platform authorized for
emergency use in multiple US jurisdictions since 11 December 2020. Theoretical 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 efficacy data from study
C4591001 are indicative of the vaccine delivery system’s success in transfecting the RNA
into the appropriate target cells to stimulate an immune response. The RNA itself cannot
integrate into the DNA genome.68,69 The probability of any sequences from the vaccine RNA
being integrated into the human genome by a reverse transcription mediated mechanism is
considered remote, no higher than the probability of host RNA sequences being re-inserted
into the genome, especially given the small quantity of RNA in the vaccine, the barriers to
transfected RNA reaching the nucleus, the non-replicating nature of the vaccine RNA, the
limited stability of RNA in a cellular context, and the expected targeting of transfected cells
for elimination by T cells elicited by the vaccine antigen expressed from the RNA.
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3. PHARMACOVIGILANCE PLAN
3.1. Structure of the Pharmacovigilance Plan
3.1.1. Summary of Ongoing Safety Concerns
Table 39. 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 <12 years of age
3.1.2. Routine Pharmacovigilance Practices
Routine pharmacovigilance activities is a 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 analysis of individual AE reports globally,
following global safety Standard Operating Procedures and regulatory guidance.
Pfizer, on behalf of the marketing authorization applicant (MAA), monitors the safety
profile of its products, evaluates issues potentially impacting product benefit-risk profiles
in a timely manner, and ensures that appropriate communication of relevant information
is conveyed 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 MAA, conducts scientific data gathering activities for the
detection and evaluation of AEs in order to ensure safety monitoring, which is
commensurate with product characteristics.
Signal detection activities include periodic literature review for the life cycle of the
product. This includes reviewing the medical literature for individual case reports that
should be entered into the safety database as well as periodic aggregate literature review
for broader signal detection.
Safety signal evaluation requires the collection, analysis and assessment of information to
evaluate whether there is a potential causal association between an event and the
administration of the product and includes subsequent qualitative or quantitative
characterization of the relevant safety risk to determine appropriate pharmacovigilance
and risk mitigation actions.
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Routine pharmacovigilance activities will include the use of DCAs. They are intended to
facilitate the capture of clinical details about:
the nature and severity 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 anaphylactic 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 Safety Unit performs routine pharmacovigilance activities
including the collection of AEs from various sources and the reporting of AEs to the
regulatory authority as per local regulatory guidelines.
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Table 40. Action Plan for Important Identified Risk “ Myocarditis and Pericarditis ”
detection and, if needed, further risk mitigation during the EUA. In
addition to the collection and monitoring of AEs reported voluntarily by
healthcare professionals providing the vaccine and by individuals
receiving the vaccine, active surveillance studies of the Pfizer-BioNTech
COVID-19 Vaccine under EUA are also planned.
2. Active surveillance of large numbers of individuals vaccinated with the
Pfizer-BioNTech COVID-19 Vaccine is necessary to confirm the safety
profile demonstrated in the clinical study in a broader population under
real-world conditions. Pfizer-BioNTech is conducting active
surveillance studies of individuals vaccinated with the Pfizer--BioNTech
COVID-19 Vaccine under an EUA in populations prioritized in the early
stages of the EUA, e.g., active military and elderly, as described in the
study protocols C4591011 (study planned) and C4591012 (study
ongoing) submitted to FDA on 29 January 2021. The study period is/will
be approximately 30 months following availability of vaccine under
EUA. The studies capture hospitalizations, deaths and serious safety
events of interest, including myocarditis and pericarditis.
Milestones for
evaluation and
reporting C4591009:
• Protocol submission: 31 August 2021
• Monitoring report submission: 31 October 2022
• Interim Analysis submission: 31 October 2023
• Final study report submission: 31 October 2025.
C4591011:
• Interim study reportsa will be submitted on the following dates based on
data collected post-EUA in target populations:
31 December 2021
30 June 2022
31 December 2022
• Final study reports submission: 31 December 2023.
C4591012
• Interim study reports will be submitted on the following dates based on
data collected post-EUA in target populations:
30 June 2021
31 December 2021
30 June 2022
31 December 2022
• Final study reports submission: 31 December 2023.
a. FDA was informed (Response to FDA 12 May 2021 - Information Request Regarding Active
Surveillance Studies) that the first milestone (Interim Report submission due 30 June 2021) is delayed due to
a change in study collaborat ion; therefore it has been removed from this table.
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Table 41. Action Plan for Important Identified Risk “Anaphylaxis”
Actions proposed Communication of this important identified risk via label (Sections 4 -
Contraindications , 5.1 - Management of Acute Allergic Reactions,
Section 6 - Adverse reactions - and 6.2 - Post Authorization Experience ).
C4591001: Phase 1/2/3, placebo-controlled, randomized, observer-blind,
dose-finding study to evaluate the safety, tolerability, immunogenicity, and
efficacy of SARS-CoV-2 RNA vaccine candidates against COVID-19 in
healthy individuals.
C4591009: A non-interventional post-approval safety study of the
Pfizer--BioNTech COVID-19 mRNA vaccine in the United States.
C4591011: Active safety surveillance of the P fizer-BioNTech COVID-19
vaccine in the US Department of Defense population following Emergency
Use Authorization.
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. Objective of proposed
actions Labelling communicates the risk of anaphylaxis.
C4591001: To evaluate the safety, tolerability, immunogenicity, and efficacy
of BNT162b2. Further, an unfavorable imbalance between the vaccine and
control groups in the frequency of COVID-19 disease, in particular for
severe COVID-19 disease, may indicate the occurrence of VAED/VAERD.
Surveillance is planned for 2 years following Dose 2.
C4591009: To assess the occurrence of safety events of interest in the
general US population, pregnant women, the immunocompromised and
persons with a prior history of COVID-19 within 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,
following receipt of the BNT162b2 .
C4591012: To assess whether individuals in the US Veteran’s Affairs Health
System experience increased risk of safety events of interest, following
receipt of the B NT162b2. Rationale for proposed
actions Labeling communicates to health care provider the risk of anaphylaxis.
C4591001: Long-term monitoring throughout the clinical study for up to 2
years to assess the risk for vaccine-associated enhanced disease.
C4591009: Robust surveillance is needed to ensure comprehensive
understanding of real-world safety of the B NT162b2 in the general US
population and 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 expected to receive the B NT162b2 under an
Emergency Use Authorization (EUA). Monitoring by the
sponsor for safety issue
and proposed actions C4591001: Safety evaluations will include AESI, including anaphylaxis;
these will be collected systemically and monitored throughout the Phase 3
study.
C4591009: Post-approval observational studies using real-world data are
needed to assess the association between BNT162b2 and safety events of
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Table 41. Action Plan for Important Identified Risk “Anaphylaxis”
interest, among persons administered the vaccine in both the overall US
population and in populations of interest (e.g., pregnant women, the
immunocompromised and persons with a prior history of COVID-19
infection). This observational study will capture safety events (based on
AESI) including anaphylaxis, in individuals of any age who received the
BNT162b2 since its availability under an EUA using electronic health
records and claims data from data partners participating in the Sentinel
System. This study, will capture hospitalizations, deaths and serious safety
events of interest, including anaphylaxis, as well as selected pregnancy-
related and birth outcomes.
C4591011 and C4591012:
1. The collection of safety data in vaccine recipients is critical to our
understanding of the vaccine safety profile and to enable safety signal
detection and, if needed, further risk mitigation during the EUA. In
addition to the collection and monitoring of AEs reported voluntarily by
healthcare professionals providing the vaccine and by individuals
receiving the vaccine, active surveillance studies of the BNT162b2 under
EUA are also planned.
2. Active surveillance of large numbers of individuals vaccinated with the
BNT162b2 is necessary to confirm the safety profile demonstrated in the
clinical study in a broader population under real-world conditions.
Pfizer-BioNTech plans to conduct active surveillance studies of
individuals vaccinated with the BNT162b2 under an EUA in populations
prioritized in the early stages of the EUA, e.g., active military and
elderly, as described in the study protocols C4591011 and C4591012
submitted to FDA on 29 January 2021. The study period will be
approximately 30 months following availability of vaccine under EUA.
The studies will capture hospitalizations, deaths and serious safety events
of interest, including anaphylaxis. Milestones for
evaluation and
reporting C4591001 (ongoing Study):
• CSR submission upon regulatory request: at any time
• CSR submission 6 months post Dose 2: 31 May 2021
• Final CSR submission with supplemental follow-up: 31 August 2023.
C4591009:
• Protocol submission: 31 August 2021
• Monitoring report submission: 31 October 2022
• Interim Analysis submission: 31 October 2023
• Final study report submission: 31 October 2025.
C4591011 and C4591012: • Interim study reportsa will be submitted on the following dates based on
data collected post-EUA in target populations:
30 June 2021
31 December 2021
30 June 2022
31 December 2022
• Final study reports submission: 31 December 2023.
C4591012
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Table 42. Action Plan for Important Potential Risk “Vaccine-associated enhanced
disease (VAED) including Vaccine-associated enhanced respiratory
disease (VAERD)”
Monitoring by the
sponsor for safety
issue and proposed
actions
Monitoring by the
sponsor for safety
issue and proposed
actions
(Cont’d) C4591001: Protocol prespecified stopping and alert rules were set for detecting
enhanced COVID-19.
Participants in all stages of the study will be monitored for COVID-19 illness
including severe COVID-19 from Visit 1 onward. Cases will undergo blinded
review to identify whether any features of each case appear unusual, in particular
greater severity. Indicators of severity may include accelerated deterioration,
need for hospitalization, need for ventilation, or death. The Data Monitoring
Committee, supported by an unblinded medical monitor, will look for adverse
imbalances between vaccine and control groups in COVID-19 disease outcomes,
in particular for cases of severe COVID-19, that may be a signal for vaccine-
associated enhanced disease on an ongoing basis and at interim analyses. Stopping
rules were set so that enrollment could be paused in the event of an adverse
imbalance.
Additional safety evaluations will include AESI that could represent symptoms of
severe COVID-19 disease; these will be collected systemically and monitored
throughout the Phase 3 study.
C4591008, C4591011, C4591012: The collection of safety data in vaccine
recipients is critical to our understanding of the vaccine safety profile and to
enable efficient safety signal detection and, if needed, further risk mitigation
during the EUA. In addition to the collection and monitoring of AEs reported
voluntarily by healthcare professionals providing the vaccine and by individuals
receiving the vaccine, active surveillance studies of the BNT162b2 under EUA are
also planned. Active surveillance of large numbers of individuals vaccinated with
the BNT162b2 is necessary to confirm the safety profile demonstrated in the
clinical study in a broader population under real-world conditions. Pfizer-
BioNTech plans to conduct active surveillance studies of vaccinated individuals in
populations prioritized in the early stages of the EUA, e.g., healthcare workers,
active military, and elderly, as described in C4591008 protocol submitted to FDA
on 28 January 2021; C4591011 protocol submitted to FDA on 29 January 2021
and C4591012 protocol submitted to FDA on 29 January 2021. The study period
will be approximately 30 months following availability of vaccine under EUA.
The studies will capture hospitalizations, deaths and serious safety events of
interest, including severe COVID-19 (which, if associated with vaccination, may
indicate VAED/VAERD).
C4591009: Surveillance of large numbers of individuals vaccinated with the
BNT162b2 is necessary to confirm the safety profile demonstrated in the clinical
study in a broader population under real-world conditions. This study is intended
to capture a broader sample of vaccinated individuals of any age in the general US
population using large scale data sources. Milestones for
evaluation and
reporting • C4591001 (ongoing Study):
• CSR submission upon regulatory request: at any time
• CSR submission 6 months post Dose 2: 31 May 2021
• Final CSR submission with supplemental follow-up: 31 August 2023.
• Three observational post-authorization safety studies for EUA
(C4591008, C4591011, and C4591012):
• C4591008 and C4591012: Interim study reports will be submitted on the following dates based on data collected post-EUA in target populations:
o 30 June 2021
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Table 43. Action Plan for Missing Information “Use in Pregnancy and Lactation”
C4591011a: To assess whether sub-cohorts of interest, such as pregnant women, in
the MHS experience increased risk of safety events of interest following receipt of
the BNT162b2.
C4591022a: To assess whether pregnant women receiving BNT162b2 experience
increased risk of pregnancy and infant safety outcomes, including major
congenital malformations, spontaneous abortion, stillbirth, preterm delivery, small
for gestational age, and small for age postnatal growth to one year of age. Rationale for
proposed actions Acquisition of data in an unstudied population with potentially different safety
considerations from the time vaccine is available. Monitoring by the
sponsor for safety
issue and proposed
actions C4591015: Monitoring via ongoing clinical study.
C4591009: The collection of safety data in vaccine recipients, including pregnant
women, is critical to our understanding of the vaccine safety profile and to enable
robust safety signal detection and evaluation and, if needed, further risk mitigation
under BLA.
C4591011:
1. The collection of safety data in vaccine recipients is critical to our
understanding of the vaccine safety profile and to enable efficient safety
signal detection and, if needed, further risk mitigation. Active surveillance
studies of the BNT162b2 under EUA are also planned.
2. Active surveillance of large numbers of individuals vaccinated with the
BNT162b2 is necessary to confirm the safety profile demonstrated in the
clinical study in a broader population under real-world conditions. Pfizer-
BioNTech plans to conduct active surveillance studies of individuals
vaccinated with the BNT162b2 under an EUA in populations prioritized in
the early stages of the EUA, e.g., active military and their family members, as
described in C4591011 (protocol submitted to FDA on 29 January 2021).
The study period will be approximately 30 months following availability of
vaccine under EUA. The study will capture hospitalizations, deaths and
serious safety events of interest, including anaphylaxis.
C4591022: This study will monitor rates of pregnancy and infant outcomes in
planned and unplanned pregnancies exposed to BNT162b2 using an established
pregnancy registry. Women receiving BNT162b2 during pregnancy will be
followed from exposure to one-year post-partum. Analyses will be conducted to
evaluate if the pregnant women receiving the vaccine during pregnancy
experience increased risk of pregnancy and infant outcomes compared with 1)
pregnant women who are unvaccinated and 2) pregnant women who have received
an influenza or tetanus, diphtheria, and acellular pertussis (Tdap) vaccine during
pregnancy. Milestones for
evaluation and
reporting C4591015:
Primary endpoints completion: 30 April 2023.
C4591009:
• Protocol submission: 31 August 2021
• Monitoring report submission: 31 October 2022
• Interim Analysis submission: 31 October 2023
• Final study report submission: 31 October 2025.
C4591011:
• Interim study reportsb will be submitted on the following dates based on data
collected post-EUA in target populations:
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Table 44. Action Plan for Missing Information “Vaccine Effectiveness”
Monitoring by the
sponsor for safety
issue and proposed
actions C4591014: Use of primary and secondary data sources to monitor COVID-19
infection in vaccinated individuals.
WI235284: Use of primary and secondary data sources to monitor COVID-19
infection in vaccinated individuals.
WI255886: Use of primary and secondary data sources to monitor COVID-19
infection in vaccinated individuals.
BNT-162-01 cohort 13: Reactogenicity, AE and SAE assessment. Milestones for
evaluation and
reporting C4591014: Final CSR submission: 30 June 2023.
WI235284: Final CSR submission: 30 June 2023.
WI255886: Final CSR submission: 30 June 2023.
BNT-162-01 cohort 13: First IA submission: 30 September 2021.
Table 45. Action Plan for Missing Information “Use in Paediatric Individuals
<12 Years of Age”
Actions proposed C4591001 ≥12 to ≤15 years of age: Phase 1/2/3, placebo-controlled, randomized,
observer-blind, dose-finding study to evaluate the safety, tolerability,
immunogenicity, and efficacy of SARS-CoV-2 RNA vaccine candidates against
COVID-19 in healthy individualsa.
Randomised placebo-controlled study in 2000 participants (1000 active recipients)
of 2 doses of BNT162b2 at a 21-day interval.
C4591007 <12 years of age: Phase 1 open label dose-finding study to evaluate
safety, tolerability, and immunogenicity and phase 2/3 placebo-controlled,
observer- blinded safety, tolerability, and immunogenicity study of a
SARS-CoV-2 RNA vaccine candidate against COVID-19 in healthy children <12
years of age.
Phase 1: open-label dose finding portion up to 3 age groups (participants ≥5 to
<12 years, ≥2 to <5 years, and ≥6 months to <2 years of age) with 16 participants
per dose level. Dose finding is being initiated in this study in participants ≥5 to
<12 years of age based on the acceptable blinded safety assessment of the 30-μg
dose in 12- to 15-year-olds in the C4591001 study. The purpose of Phase 1 is to
identify preferred dose level(s) of BNT162b2 from up to 3 different dose levels in
each age group.
Phase 2/3: Children ≥5 to <12 years of age are randomized 2:1 at selected dose
level of BNT162b2 at a 21-day interval (2250 total subjects; 1500 active vaccine).
Children 2 to < 5 years and 6 to 23 months of age randomized 2:1 placebo
controlled at selected dose level of BNT162b2 at a 21-day interval (1125 total
subjects per age group; 750 active vaccine per age group).
C4591009: A non-interventional post-approval safety study of the
Pfizer-BioNTech COVID-19 mRNA vaccine in the United States.
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Table 45. Action Plan for Missing Information “Use in Paediatric Individuals
<12 Years of Age”
Objective of
proposed actions C4591001 ≥12 to ≤15 years of age: Safety compared to placebo and immune-non-
inferiority of neutralizing antibody immune response compared to subjects 16-25
years of age.
C4591007 <12 years of age: Dose selection. Safety compared to placebo and
immune-non-inferiority by 3 age cohorts of neutralizing antibody immune
response compared to subjects 16-25 years of age. Efficacy if sufficient cases
accrue.
C4591009: To assess the occurrence of safety events of interest in a general US
population (<12 and ≥12 to ≤15 years of age) within selected data sources
participating in the Sentinel System. Rationale for
proposed actions C4591001 ≥12 to ≤15 years of age: Need to collect evidence of safety and
effectiveness to support immunization in this age group.
C4591007 <12 years of age: Need to collect evidence of safety and effectiveness
to support immunization in this age group.
C4591009: Long-term surveillance of large numbers of individuals (<12 and ≥12
to ≤15 years of age) vaccinated with the BNT162b2 is necessary to confirm the
safety profile demonstrated in the clinical study in a broader population under
real-world conditions. Monitoring by the
sponsor for safety
issue and proposed
actions C4591001 ≥12 to ≤15 years of age:
• Electronic diary for reactogenicity 7 days following each dose of vaccine.
• Adverse events for one month after second dose.
• Serious Adverse Events for 6 months after the second dose.
• Related SAEs and related deaths for 24 months after the second dose.
• Collection of COVID-19 and MIS-C cases up to 24 months after the second
dose.
C4591007 <12 years of age:
• Electronic diary for reactogenicity 7 days following each dose of vaccine.
• Adverse events for one month after second dose.
• Serious Adverse Events for 6 months after the second dose.
• Related SAEs and related deaths for 24 months after the second dose.
• Collection of COVID-19 and MIS-C cases up to 24 months after the second
dose.
C4591009: < 12 and ≥12 to ≤15 years of age
• Longitudinal medical care information on outpatient medication dispensing,
vaccine administrations, and inpatient and outpatient diagnoses and procedures
in addition to adjudication of select events via medical records.
• Incidence rates and comparative incidence rate ratios of safety events of
interest (AESIs from FDA’s BEST System70 and CDC’s Vaccine Safety
Datalink71 in addition to vaccine-associated enhanced respirator disease).
• Study period to start on date that BNT162b2 became available under EUA
(December 11, 2020) and will end a minimum of 3 years after this date.
• Risk windows will be defined for safety events of interest that have a
hypothesized increased risk during specific time periods following vaccination.
For other safety events of interest, patients will be followed for a maximum of
1 year.
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Table 46. Summary of Safety Concerns and Action Plans
Safety Concerns Ongoing/Planned Action Summary of Objectives Milestones Due dates
C4591022: Pfizer-BioNTech COVID-19
Vaccine exposure during pregnancy: A
non-interventional post-approval safety
study of pregnancy and infant outcomes
in the Organization of Teratology
Information Specialists
(OTIS)/MotherToBaby Pregnancy
Registry To assess whether pregnant women
receiving BNT162b2 experience
increased risk of pregnancy and
infant safety outcomes, including
major congenital malformations,
spontaneous abortion, stillbirth,
preterm delivery, small for
gestational age, and small for age postnatal growth to one year of age. Protocol submission:
Interim reports
submission:
Final study report
submission: 01 July 2021
31 January 2022
31 January 2023
31 January 2024
31 January 2025
01 December 2025
Vaccine
effectiveness C4591014: Pfizer-BioNTech COVID-
19 BNT162b2 Vaccine Effectiveness
Study - Kaiser Permanente Southern
California.
Planned To estimate the effectiveness of 2
doses of BNT162b2 against
hospitalization and emergency
department admission for acute
respiratory illness due to SARS-
CoV-2 infection. Final CSR
submission: 30 June 2023
Vaccine
effectiveness
(Cont’d) WI235284: Determining RSV Burden
and Outcomes in Pregnant Women and
Older Adults Requiring Hospitalization.
Amendment for COVID VE/ Sub-
study 6.
Planned To estimate the effectiveness of 2
dosed of BNT162b2 against
hospitalization for acute respiratory
illness due to SARS-CoV-2
infection. Final CSR
submission: 30 June 2023
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Table 46. Summary of Safety Concerns and Action Plans
Safety Concerns Ongoing/Planned Action Summary of Objectives Milestones Due dates
WI255886: Avon Community Acquired
Pneumonia Surveillance Study: A Pan-
pandemic Acute Lower Respiratory
Tract Disease Surveillance.
Planned To estimate the effectiveness of 2
doses of BNT162b2 against
hospitalization for acute respiratory
illness due to SARS-CoV-2
infection. Final CSR
submission: 30 June 2023
BNT162-01 cohort 13: Immunogenicity
of Pfizer-BioNTech COVID-19
Vaccine in immunocompromised
subjects, including assessment of
antibody responses and cell-mediated
responses.
Ongoing To assess potentially protective
immune responses in
immunocompromised adults. First IA submission: 30 September 2021
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ANNEX
3.2. Pharmacovigilance Methods
BNT162b2 Vaccine: BNT162b2 Data Capture Aids :
o Pfizer-BioNTech COVID-19 Vaccine VAED Data Capture Aid.
o Pfizer-BioNTech COVID-19 Vaccine Anaphylactic Reaction Data Capture
Aid.
3.2.1. List of Studies Included in the Pharmacovigilance Plan
C4591001
C4591007
C4591008
C4591009
C4591011
C4591012
C4591014
C4591015
C4591022
BNT162-01 cohort 13
WI235284
WI255886
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