Comirnaty Epar Risk Management Plan - en

COVID-19 mRNA VACCINE
RISK MANAGEMENT PLAN (RMP)
For a summary of the RMP, please refer to PART VI.

COVID-19 mRNA VACCINE
RISK MANAGEMENT PLAN
RMP Version number: 1.0
Data lock point for this RMP: 17 December 2020
Date of final sign off: 21 December 2020
Rationale for submitting an updated RMP: Responses to the PRAC Rolling Review
Management Plan Updated Assessment Report received on 18 December 2020.
Summary of significant changes in this RMP:
RMP Part/Module Major Change (s)

PART I. PRODUCT(S) No changes made.
OVERVIEW
PART II. SAFETY SPECIFICATION
Module SI. Epidemiology of the Minor change.
Indication(s) and Target
Populations
Module SII. Non-Clinical Part of Minor change.
the Safety Specification
Module SIII. Clinical Trial No changes made.
Exposure
Module SIV. Populations Not Text in Table 16 updated for use in pregnant and breastfeeding women.
Studied in Clinical Trials
Module SV. Post-Authorisation Minor change.
Experience
Module SVI. Additional EU No changes made.
Requirements for the Safety
Specification
Module SVII. Identified and - The list of safety concerns has been updated:
Potential Risks • Added Important Identified Risk (Anaphylaxis)
• Added Missing information [Use in immunocompromised patients;
Use in frail patients with co-morbidities (e.g. chronic obstructive
pulmonary disease (COPD), diabetes, chronic neurological disease,
cardiovascular disorders); Use in patients with autoimmune or
inflammatory disorders]
• Renamed Missing information (from “Use in pregnancy” to “Use in
pregnancy and while breast feeding”).
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Risk Management Plan 20 December 2020

Module SVIII. Summary of the - The list of safety concerns has been updated:
Safety Concerns • Added Important Identified Risk (Anaphylaxis)
pregnancy and while breast feeding”)
PART III. PART III.1 Routine Pharmacovigilance Activities
PHARMACOVIGILANCE - Monthly summary safety reports text has been updated to meet the
PLAN (INCLUDING POST request about Bell’s palsy.
AUTHORISATION SAFETY
- Text related to frequency of analyses of adverse event and product
STUDIES)
complaint has been updated to meet the request.
PART III.2 Additional Pharmacovigilance Activities
- List of studies has been updated to address the safety concerns.
PART III.3. Summary Table of Additional Pharmacovigilance Activities
- List of studies has been updated to address the safety concerns.
PART IV. PLANS FOR POST No changes made.
AUTHORISATION EFFICACY
STUDIES
PART V. RISK MINIMISATION PART V.1. Routine Risk Minimisation Measures
MEASURES (INCLUDING - Routine Risk Minimisation Measures updated for the safety concerns.
EVALUATION OF THE
EFFECTIVENESS OF RISK PART V.3. Summary of Risk Minimisation Measures
MINIMISATION ACTIVITIES) - Summary of Risk Minimisation Measures updated for the new safety
concerns added.
- New studies added for addressing the safety concern Anaphylaxis.
PART VI. SUMMARY OF THE PART VI. IIA List of Important Risks and Missing Information
RISK MANAGEMENT PLAN - The list of safety concerns has been updated:
• Added Important Identified Risk (Anaphylaxis)
PART VI. II.B Summary of Important Risks
- The list of safety concerns has been updated:
• Added Important Identified Risk (Anaphylaxis)
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PART VI. II.C.1 Studies which are Conditions of the Marketing
Authorisation
PART VI. SUMMARY OF THE
RISK MANAGEMENT PLAN - Study C4591001 moved from PART VI. II.C.2 to this section.
(cont’d) PART VI. II.C.2 Other Studies in Post-Authorisation Development
Plan:
- Study C4591001 moved from this section to PART VI. II.C.1.
PART VII. ANNEXES TO THE Annex 2:
RISK MANAGEMENT PLAN - List of studies has been updated to address the new safety concerns.
- New studies added for addressing the safety concern Anaphylaxis.
Annex 7 updated to include Traceability and Vaccination Reminder
Card
Annex 8:
- Changes respect version 0.3 added.
Other RMP versions under evaluation:
None
QPPV name1: Barbara De Bernardi
QPPV oversight declaration: The content of this RMP has been reviewed and approved by
the marketing authorisation applicant´s QPPV. The electronic signature is available on file.
1
QPPV name will not be redacted in case of an access to documents request; see HMA/EMA Guidance
document on the identification of commercially confidential information and personal data within the structure
of the marketing-authorisation application; available on EMA website http://www.ema.europa.eu
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LIST OF ABBREVIATIONS
Abbreviation Definition of Term
AE adverse event
AESI Adverse event of special interest
A:G albumin:globulin
BMI body mass index
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
ECDC European Center for Disease Control
ED emergency department
EEA European Economic Area
EHR electronic health records
EMA European Medicines Agency
EUA emergency use authorization
EU European Union
FDA (US) Food and Drug Administration
GLP good laboratory practice
HBV hepatitis b virus
HCV hepatitis c virus
HIV human immunodeficiency virus
IA interim analysis
ICU intensive care unit
IFN interferon
IM intramuscular(ly)
IND investigational new drug
LNP lipid nanoparticle
LoQ List of questions
MAA marketing authorization applicant
MedDRA Medical Dictionary for Regulatory Activities
mRNA messenger ribonucleic acid
NDA new drug application
NHP nonhuman primate
PC product complaint
PK pharmacokinetic
RA rheumatoid arthritis
RBC red blood cell
RMP risk management plan
RNA ribonucleic acid
SAE serious adverse event
SARS severe acute respiratory syndrome
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Abbreviation Definition of Term

SARS-CoV-2 severe acute respiratory syndrome coronavirus 2
siRNA small-interfering RNA
SmPC summary of product characteristics
SPEAC Safety Platform for Emergency vACcines
TESSy The European Surveillance System
TH2 T helper cell type 2
TME targeted medical event
UK United Kingdom
US United States
V8 variant 8
V9 variant 9
VAC4EU Vaccine monitoring Collaboration for Europe
VAED vaccine-associated enhanced disease
VAERD vaccine-associated enhanced respiratory disease
WBC white blood cells
WHO World Health Organization
WOCBP women of child-bearing potential
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TABLE OF CONTENTS
LIST OF ABBREVIATIONS....................................................................................................4
LIST OF TABLES.....................................................................................................................8
LIST OF FIGURES ...................................................................................................................9
PART I. PRODUCT(S) OVERVIEW .....................................................................................10
PART II. SAFETY SPECIFICATION ....................................................................................12
Module SI. Epidemiology of the Indication(s) and Target Population (s).....................12
Module SII. Non-Clinical Part of the Safety Specification............................................17
Module SIII. Clinical Trial Exposure.............................................................................20
Module SIV. Populations Not Studied in Clinical Trials...............................................57
SIV.1. Exclusion Criteria in Pivotal Clinical Studies Within the
Development Programme ................................................................................57
SIV.2. Limitations to Detect Adverse Reactions in Clinical Trial
Development Programmes...............................................................................59
SIV.3. Limitations in Respect to Populations Typically Under-Represented
in Clinical Trial Development Programmes ....................................................59
Module SV. Post-Authorisation Experience ..................................................................60
SV.1. Post-Authorisation Exposure......................................................................60
SV.1.1. Method Used to Calculate Exposure.........................................61
SV.1.2. Exposure....................................................................................61
Module SVI. Additional EU Requirements for the Safety Specification ......................62
Module SVII. Identified and Potential Risks .................................................................62
SVII.1. Identification of Safety Concerns in the Initial RMP Submission...........62
SVII.1.1. Risks not Considered Important for Inclusion in the List
of Safety Concerns in the RMP .........................................................63
SVII.1.2. Risks Considered Important for Inclusion in the List of
Safety Concerns in the RMP .............................................................66
SVII.2. New Safety Concerns and Reclassification with a Submission of an
Updated RMP...................................................................................................68
SVII.3. Details of Important Identified Risks, Important Potential Risks,
and Missing Information..................................................................................68
SVII.3.1. Presentation of Important Identified Risks and Important
Potential Risks ...................................................................................68
SVII.3.2. Presentation of the Missing Information ................................70
Module SVIII. Summary of the Safety Concerns ..........................................................73
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PART III. PHARMACOVIGILANCE PLAN (INCLUDING POST-

AUTHORISATION SAFETY STUDIES) .........................................................................74
III.1. Routine Pharmacovigilance Activities ..................................................................74
III.2. Additional Pharmacovigilance Activities..............................................................79
III.3. Summary Table of Additional Pharmacovigilance Activities...............................87
III.3.1. On-Going and Planned Additional Pharmacovigilance Activities ...........87
PART IV. PLANS FOR POST AUTHORISATION EFFICACY STUDIES ........................91
PART V. RISK MINIMISATION MEASURES (INCLUDING EVALUATION OF
THE EFFECTIVENESS OF RISK MINIMISATION ACTIVITIES)...............................92
V.1. Routine Risk Minimisation Measures ....................................................................92
V.2. Additional Risk Minimisation Measures Risk Minimisation Measures ................94
V.3. Summary of Risk Minimisation Measures .............................................................94
PART VI. SUMMARY OF THE RISK MANAGEMENT PLAN .........................................97
I. The Medicine and What It Is Used For.......................................................................97
II. Risks Associated With the Medicine and Activities to Minimise or Further
Characterise the Risks ...............................................................................................97
II.A List of Important Risks and Missing Information.........................................98
II.B Summary of Important Risks ........................................................................98
II.C Post-Authorisation Development Plan ........................................................102
II.C.1 Studies which are Conditions of the Marketing
Authorisation ...................................................................................102
II.C.2 Other Studies in Post-Authorisation Development Plan............102
PART VII. ANNEXES TO THE RISK MANAGEMENT PLAN........................................103
REFERENCES ......................................................................................................................104
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LIST OF TABLES
Table 1. Distribution and Estimated Cumulative Incidence of Reported
Laboratory-Confirmed COVID-19 Cases, by Gender and Age Group —
United States, 22 January – 30 May 2020 ..........................................................14
Table 2. Preconditions among COVID-19 Patients in EU/EEA and UK, by
Severity of Disease. Case-based Data from TESSy Produced on
24 September 2020 .............................................................................................16
Table 3. Key Safety Findings and Relevance to Human Usage .......................................19
Table 4. Exposure to BNT162b2 by Age Group and Dose (C4591001) ..........................22
Table 5. Exposure to BNT162b2 by Age Group and Dose (BNT162-01) .......................24
Table 6. Exposure to BNT162b2 by Age Group and Dose – Children and Elderly
Subjects (C4591001)...........................................................................................27
Table 7. Exposure to BNT162b2 by Dose (Totals) (C4591001) ......................................28
Table 8. Exposure to BNT162b2 by Dose (Totals) (BNT162-01) ...................................29
Table 9. Exposure to BNT162b2 by Dose, Age Group, and Gender (C4591001) ...........31
Table 10. Exposure to BNT162b2 by Dose, Age Group, and Gender (BNT162-01).........32
Table 11. Exposure to BNT162b2 by Age Group, Dose, and Race/Ethnic Origin
(C4591001) .........................................................................................................34
Table 12. Exposure to BNT162b2 by Age Group, Dose, and Race/Ethnic Origin
(BNT162-01).......................................................................................................38
Table 13. Exposure to BNT162b2 by Dose and Race/Ethnic Origin (C4591001) .............48
Table 14. Exposure to BNT162b2 by Dose and Race/Ethnic Origin (BNT162-01) ..........50
Table 15. Exposure to BNT162b2 (30 μg) by Special Population (C4591001) .................55
Table 16. Exposure of Special Populations included or not in Clinical Trial
Development Programmes..................................................................................59
Table 17. Summary of Safety Concerns .............................................................................62
Table 18. Anaphylaxis ........................................................................................................68
Table 19. Vaccine-Associated Enhanced Disease (VAED), including Vaccine-
Associated Enhanced Respiratory Disease (VAERD)........................................69
Table 20. Use in pregnancy and while breast feeding ........................................................70
Table 21. Use in immunocompromised patients.................................................................71
Table 22. Use in frail patients with co-morbidities (e.g. chronic obstructive
cardiovascular disorders) ....................................................................................71
Table 23. Use in patients with autoimmune or inflammatory disorders.............................71
Table 24. Interaction with other vaccines ...........................................................................71
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Table 25. Long term safety data..........................................................................................72

Table 26. Summary of Safety Concerns .............................................................................73
Table 27. Additional Pharmacovigilance Activities ...........................................................82
Table 28. On-going and Planned Additional Pharmacovigilance Activities ......................87
Table 29. Description of Routine Risk Minimisation Measures by Safety Concern..........92
Table 30. Summary Table of Pharmacovigilance Activities and Risk Minimisation
Activities by Safety Concern ..............................................................................94
Table 31. List of Important Risks and Missing Information...............................................98
Table 32. Important Identified Risk: Anaphylaxis..............................................................98
Table 33. Important Potential Risk: Vaccine-associated enhanced disease (VAED)
including Vaccine-associated enhanced respiratory disease (VAERD) .............99
Table 34. Missing Information: Use in pregnancy and while breast feeding ...................100
Table 35. Missing Information: Use in immunocompromised patients............................100
Table 36. Missing Information: Use in frail patients with co-morbidities (e.g.
chronic obstructive pulmonary disease (COPD), diabetes, chronic
neurological disease, cardiovascular disorders)................................................100
Table 37. Missing Information: Use in patients with autoimmune or inflammatory
disorders............................................................................................................101
Table 38. Missing Information: Interaction with other vaccines ......................................101
Table 39. Missing Information: Long term safety data ....................................................101
LIST OF FIGURES
Figure 1. Age-Gender distribution of COVID-19 Cases as Different Levels of
Severity, EU/EEA and UK. Case-based Data from TESSy produced on
07 August 2020 a .................................................................................................13
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PART I. PRODUCT(S) OVERVIEW

Active substance(s) COVID-19 mRNA Vaccine is single-stranded, 5’-capped
(INN or common name) messenger RNA (mRNA) produced using a cell-free in vitro
transcription from the corresponding DNA templates, encoding the
viral spike (S) protein of SARS-CoV-2.
Pharmacotherapeutic group(s) Not yet assigned

(ATC Code)
Marketing Authorisation Applicant BioNTech Manufacturing GmbH
Medicinal products to which this 1

RMP refers
Invented name(s) in the European Comirnaty

Economic Area (EEA)
Marketing authorisation procedure Centralised
Brief description of the product: Chemical class
Nucleoside-modified messenger RNA is formulated in LNP
Summary of mode of action
The nucleoside-modified messenger RNA in Comirnaty is
formulated in LNPs, which enable delivery of the RNA into host
cells to allow expression of the SARS-CoV-2 S antigen. The
vaccine elicits both neutralizing antibody and cellular immune
responses to the spike (S) antigen, which may contribute to
protection against COVID-19.
Important information about its composition
The COVID-19 mRNA Vaccine:
 is nucleoside-modified messenger RNA formulated in LNPs;
 is a white to off-white frozen dispersion
(pH:6.9 – 7.9).
 Excipients:
• ((4-hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)bis(2-
hexyldecanoate) (ALC-0315)
• 2-[(polyethylene glycol)-2000]-N,N-ditetradecylacetamide
(ALC-0159)
• 1,2-Distearoyl-sn-glycero-3-phosphocholine (DSPC)
• cholesterol,
• potassium chloride,
• potassium dihydrogen phosphate,
• sodium chloride,
• disodium phosphate dihydrate,
• sucrose,
• water for injections.
Hyperlink to the Product Please refer to Module 1.3.1 of this submission
Information:
Indication in the EEA Proposed:
Active immunisation to prevent COVID-19 caused by
SARS-CoV-2 virus, in individuals 16 years of age and older.
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Dosage in the EEA Proposed:

Administered intramuscularly after dilution as a course of 2 doses
(0.3 mL each) at least 21 days apart.
Pharmaceutical form and strengths Proposed:
Concentrate dispersion for injection.
After dilution each vial contains 5 doses of 0.3 mL
Is/will the product be subject to Yes
additional monitoring in the EU?
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PART II. SAFETY SPECIFICATION

Module SI. Epidemiology of the Indication(s) and Target Population (s)
Indication
Active immunisation to prevent COVID-19 caused by SARS-CoV-2 virus, in individuals

16 years of age and older.
Incidence:
The COVID-19 is caused by a novel coronavirus labelled 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.1 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.2
Estimates of SARS-CoV-2 incidence change rapidly. As of 9 November 2020, the overall

number of people who had been infected with SARS-CoV-2 was over 50 million worldwide.
In the EU and the UK, the number of confirmed cases had accumulated to over 9 million
people, corresponding to 337 per 100,000 people. Across countries in the EU, the number of
confirmed cases ranged from 40 to 1,017 cases per 100,000 people. Slovakia, Greece and
Hungary reported an incidence below 50 per 100,000 whereas Spain, Sweden and
Luxembourg reported over 700 confirmed cases per 100,000 people.
In the US, the number of confirmed cases had reached over 10 million cases (3,126 per
100,000 people) by the beginning of November 2020. 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 varied quality of
reporting across countries. People who carry the virus but remain asymptomatic are less
likely to be tested and therefore mild cases are likely underreported. The numbers should
therefore be interpreted with caution.3
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 9 November 2020,
the overall prevalence for EU countries was 37.0 active cases per 100,000. The range of
reported prevalence was 2.8 to 337.7 per 100,000 with Finland, Estonia and Hungary at the
low end and Portugal, Luxembourg and Belgium at the high end.
In the US, the prevalence on the same date was similar to the EU estimates, with 31.5 active
cases per 100,000.3
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Demographics of the population in the proposed indication and risk factors for the
disease:
While anyone can become infected with SARS-CoV-2, symptoms of COVID-19 can range
from very mild (or no symptoms) to severe. Risk factors for developing severe disease,
include age over 60 years, male gender, diabetes, severe obesity, chronic kidney disease and
congestive heart failure.4,5,6,7
The ECDC has since the beginning of the pandemic continuously collected COVID-19
information from all countries who are members of EU/EEA and the UK. In their database
TESSy COVID-19 case-based data, including age and gender, are available for
approximately 40% of the official number of cases reported by ECDC epidemic intelligence.8
All countries included in EU/EEA and UK, except Spain, Slovenia and Liechtenstein, have at
some point during the pandemic provided case-based data to TESSy, enabling estimates of
age and gender distribution representative of the European population.
According to TESSy case-based data, accessed 7 August 2020, (Figure 1), the gender
distribution of persons testing positive for SARS-Cov-2 in the European population is similar
for most age groups. However, males and older age groups are over-represented among the
more severe cases (defined as hospitalized, severe, or fatal). Few cases were reported in
people aged younger than 20 years. This data 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.8 The distribution of age was different in the period of January-May
compared to June-July. Between January and May 2020, 40% of cases were ≥60 years old
and the largest proportion (18.7%) of cases were reported in the 50-59 years age group. In
contrast, between June and July, persons aged ≥60 years accounted for 17.3% of cases and
the largest proportion (19.5%) of cases were reported in the 20-29-year age group.9
Figure 1. Age-Gender distribution of COVID-19 Cases as Different Levels of Severity,

EU/EEA and UK. Case-based Data from TESSy produced on
07 August 2020 a
Note: ”mild”= a case that has not been reported as hospitalized or a case that resulted in death.
a. Data from ECDC. COVID-19 Surveillance report. Week 31, 2020. 7 August 2020. “2.2 Age-sex pyramids”.10
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In the US, surveillance data collected between 22 January 2020 and 30 May 2020 showed a
similar age distribution of infected cases in both genders (Table 1). Among 1,320,488
laboratory-confirmed COVID-19 cases, overall incidence per 100,000 persons was higher
among individuals aged 40 - 49 years (541.6) and 50 - 59 years (550.5) than among those
aged 60 - 69 years (478.4) and 70 - 79 years (464.2). Estimates were highest among persons
aged ≥80 years (902.0) and lowest among children aged ≤9 years (51.1).11 During
June-August, the COVID-19 pandemic in the US affected a larger proportion of younger
persons than during January–May 2020. In this period, incidence was highest in persons
aged 20-29 years, accounting for >20% of all confirmed cases. The shift toward younger
ages occurred in all four US Census regions, regardless of changes in incidence during this
period, and was reflected in COVID-19–like illness-related ED visits, positive SARS-CoV-2
reverse transcription-polymerase chain reaction test results, and confirmed COVID-19
cases.12
Of the 599,636 (45%) cases with information on both race and ethnicity in US surveillance
data collected between 22 January 2020 and 30 May 2020, 36% were non-Hispanic white,
33% were Hispanic, 22% were black, 4% were non-Hispanic Asian, 4% were non-Hispanic,
other or multiple race, 1.3% were American Indian/Alaskan Native, and <1% were
non-Hispanic Native Hawaiian or other Pacific Islander.11 An increased rate ratio of
COVID-19 cases and hospitalization compared to White, non-Hispanic has been reported for
all other race and ethnicity groups, underlying factors including socioeconomic status, access
to health care and occupations are likely to be the actual risk factors.13
Table 1. Distribution and Estimated Cumulative Incidence of Reported

Laboratory-Confirmed COVID-19 Cases, by Gender and Age Group —
United States, 22 January – 30 May 2020a
Males Females
Age group (years) Proportion Cumulative Proportion Cumulative
(%) Incidence* (%) Incidence*
0-9 1.7 52.5 1.4 49.7
10-19 3.8 113.4 3.7 121.4
20-29 13.3 370.0 14.3 434.6
30-39 16.8 492.8 15.8 490.5
40-49 17.0 547.0 16.2 536.2
50-59 18.4 568.8 17.3 533.0
60-69 14.5 526.9 12.7 434.6
70-79 8.2 513.7 7.7 422.7
≥ 80 6.4 842.0 10.8 940.0
a. Data from Stokes.11
* Per 100,000 people
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.4,14 The majority (approximately
60%) of COVID-19 patients admitted to hospitals in the US have been male.4,6,14,15,16,17,18
African American COVID-19 patients have been reported to have an increased risk of
hospitalization4,15 and mortality,19 compared to white patients in the US.
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The main existing treatment options:
At the time that this vaccine was in advanced development there were other vaccines in
similar late-phase development including vaccines from Moderna (NCT04470427), Sinovac
(NCT04456595), AstraZeneca (NCT04516746), Johnson & Johnson (NCT04505722), which
may subsequently be approved, as may others currently in earlier development. The FDA on
18 December 2020 issued an emergency use authorization for the Moderna COVID-19
vaccine.
Natural history of the indicated condition in the untreated population, including

mortality and morbidity:
The natural history of COVID-19 is not yet fully understood. In the US, 14% of individuals
testing positive for SARS-CoV-2 22 January – 30 May 2020 were reported to require
hospitalization. The rate was lowest (<9%) among age groups <50 years, and highest among
those older than 70 years (33%) and among patients with underlying health conditions
(45.4%).11
Based on rates of severe disease reported in mainland China and assuming severe cases
would be hospitalized, a demography-adjusted and under-ascertainment-adjusted model
estimated the proportion of infected individuals requiring hospitalization. The proportions
ranged from 8.2% in the age group 50-59 years to 18.4% in those older than 80 years. In the
age groups below 50 years, less than 5% of infections were estimated to lead to
hospitalization.20
Approximately 17% to 40% of those hospitalized with COVID-19 experience severe

symptoms necessitating intensive care.5,7,15 More than 75% of patients hospitalized with
COVID-19 require supplemental oxygen.5,21 The most common symptoms in hospitalized
patients are fever (up to 90% of patients), dry cough (60%-86%), shortness of breath
(53%-80%), fatigue (38%), nausea/vomiting or diarrhoea (15%-39%), and myalgia (15%-
44%).7,14,17,21,22,23 Complications of COVID-19 include impaired function of the heart, brain,
lung, liver, kidney, and coagulation system.15,17,21 Venous and arterial thromboembolic
events occur in 10% to 25% in hospitalized patients with COVID-19 and in the ICU, venous
and arterial thromboembolic events may occur in up to 31% to 59% of patients.21
As of 28 July 2020, the total number of COVID-19 related deaths in the EU and UK was
over 100,000 and, in the US more than 150,000 people had died from COVID-19.3 Overall
reported mortality among hospitalized COVID-19 patients varies from 12.8% to 26% in
Europe5,23,24 and 20%-23% in the US.7,15,17 In the US, studies have also reported up to 40%
mortality in patients admitted to the ICU.14,15,17 Age older than 60 years, male gender,
hypertension, cardiovascular disease and chronic pulmonary disease, have been shown to be
independently associated with in-hospital death of COVID-19 patients.7,14,24
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.7,11,14,16,17,18,21 Prevalence of these conditions have
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been reported to be lower in mild cases and higher among fatal cases, as shown in Table 2
below.
Table 2. Preconditions among COVID-19 Patients in EU/EEA and UK, by Severity

of Disease. Case-based Data from TESSy Produced on 24 September 2020
Precondition Mild % Hospitalized % Fatal %
(N=66,257) (N=48,494) (N=12,796)
Asplenia 0 0 0
Asthma 1.5 3.1 4.3
Cancer, malignancy 1.3 4.1 5.4
Cardiac disorder, excluding hypertension 3.9 12.1 16.1
Chronic lung disease, excluding asthma 3.0 6.3 9.2
Current smoking 2.4 0.3 0.3
Diabetes 2.8 11.6 14.2
Haematological disorders 0.1 0.7 0.6
HIV/other immune deficiency 0.5 1.6 1.8
Hypertension 2.2 9.0 18.4
Kidney-related condition, renal disease 0.6 4.1 8.1
Liver-related condition, liver disease 0.3 1.6 1.7
Neuromuscular disorder, chronic neurological 1.3 3.8 7.2
Obesity 0.6 0.3 0.1
Other endocrine disorder, excluding diabetes 0.2 0.3 0.2
Rheumatic diseases including arthritis 0 0.1 0
Tuberculosis 0 0 0
None 79.3 41.2 12.4
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Module SII. Non-Clinical Part of the Safety Specification

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)
studies in vitro and in vivo. A DART study has been completed. No additional toxicity
studies are planned for BNT162b2.
Nonclinical studies in mice and NHP for BNT162b2 (COVID-19 mRNA vaccine)
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.25 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.26 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 as
COVID-19 mRNA vaccine, 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 like COVID-19
mRNA vaccine, 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 COVID-19 mRNA vaccine 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 amino acid sequences of the encoded antigens are identical.
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COVID-19 mRNA vaccine (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
DART study in Wistar Han rats has been completed. Safety pharmacology, genotoxicity and
carcinogenicity studies have not been conducted, in accordance with the 2005 WHO vaccine
guideline.27
The IM route of exposure was selected for nonclinical investigation 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 COVID-19 mRNA vaccine 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 oedema and erythema at the injection sites, transient elevation in body temperature,
elevations in WBC 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 biotherapeutic28 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 haemostasis. Elevated levels of gamma-glutamyl transferase were
observed in the first repeat-dose toxicity study with COVID-19 mRNA vaccine (V8) without
evidence of cholestasis or hepatobiliary injury but was not recapitulated in the second repeat
dose-toxicity study with COVID-19 mRNA vaccine (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 COVID-19 mRNA vaccine, 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 COVID-19
mRNA vaccine. 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 oedema 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 portal 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.29 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 COVID-19 mRNA vaccine. A robust immune response
was elicited to the COVID-19 mRNA vaccine antigen.
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In summary, the nonclinical safety findings related to COVID-19 mRNA vaccine

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 COVID-19 mRNA vaccine from nonclinical studies and their relevance to
human usage are presented in Table 3. There was no evidence of vaccine-elicited disease
enhancement.
Table 3. Key Safety Findings and Relevance to Human Usage

Key Safety findings from Nonclinical Studies a,b Relevance to Human Usage
Pharmacology
NHP Challenge Model
 No evidence of vaccine-elicited disease  Suggests low risk of vaccine-enhanced
enhancement. disease in humans; being investigated in CTs.
Toxicity
Injection site reactions:
 Injection site reactions were common and  In common with other vaccines, COVID-19
reversible or showed signs of reversibility at the mRNA vaccine administration has the
end of the 3-week recovery period in nonclinical potential to generate injection site reactions
studies. such as oedema and erythema at the injection
sites.
Inflammation and immune activation:
 Evidence of inflammation or immune activation  In common with all vaccines, COVID-19
was common, reversible, and included transiently mRNA vaccine administration has the
higher body temperature, higher circulating WBCs, potential to generate inflammation which can
and higher acute phase reactants. Secondarily, lead to increased body temperature, higher
transiently lower body weights, reticulocytes, circulating WBCs and higher acute phase
platelets, and RBC mass parameters were observed. proteins.
 Decreased reticulocytes have not been
observed in humans treated with the
LNP-siRNA pharmaceutical Onpattro28,
suggesting this finding in rats is a species-
specific effect.
 COVID-19 mRNA vaccine 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 Toxicityb
 No vaccine-related effects on female fertility or the  No effects are anticipated in WOCBP,
development of fetuses or offspring were observed pregnant women or their offspring.
in a DART study of BNT162b2 in rats.
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.27 In addition, the components of the vaccine construct are lipids and RNA and are not expected to
have carcinogenic or genotoxic potential.
b. Based on audited study data. A DART study evaluating COVID-19 mRNA vaccine will be completed by
31-Mar-2021.
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Module SIII. Clinical Trial Exposure

BioNTech conducted a German first-in-human dose level–finding Phase 1/2 study
(BNT162-01) to gather safety and immunogenicity data to enable evaluation of 4 vaccines
candidates individually to inform the overall clinical development of a COVID-19 mRNA
vaccine.
BNT162-01 is not conducted under the US IND application but is being conducted under a
German Clinical Trial Application. The protocol for this study is provided in
Module 5.3.5.1.
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 (provided in Module 5.3.5.1), which is a
Phase 1/2/3 randomized, placebo-controlled, observer-blind, dose-finding, vaccine
candidate-selection, and efficacy study in healthy adults.
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.
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 favourable than BNT162b1 in both
younger and older adults with similar immunogenicity results;
 in the NHP challenge study (VR-VTR-10671 – cross ref. with Module SII), a trend toward
earlier clearance of BNT162b2 was observed in the nose.
Phase 2 of the study (for which enrolment 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
enrolment of adolescents 16 to 17 years of age to be evaluated with the 18- to 55-year-old
cohort, as well as enrolment of a 12- to ≤16-year-old cohort, and immunogenicity data from
adolescents 12- to ≤16 years of age are anticipated to bridge to the 16- to 25-year-old cohort.
The pivotal study was initially planned to enrol 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
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was amended to enrol 44,000 participants, which slightly enhanced the ability to detect AEs.
However, rarer events might not be detected.
Participants are planned to be followed for up to 24 months. This is particularly relevant for
assessing the potential for late-occurring adverse reactions, such as the theoretical risk of
VAED including VAERD.
The efficacy evaluation is event-driven, with prespecified interim analyses after accrual of at
least 62, 92, and 120 cases and a final analysis at 164 cases.
Clinical study exposure data are being provided for ongoing studies as of 14 November 2020
for study C4591001 and as of 02 October 2020 for study BNT162-01.
At the DLP, a total of 43,734 participants were vaccinated in the COVID-19 mRNA vaccine
clinical development program:
 21,937 participants were exposed to BNT162b2 (COVID-19 mRNA vaccine), including

96 participants from study BNT162-01.
 21,797 participants were exposed to PLACEBO (none from study BNT162-01).
Population for analysis of CTs data in this RMP includes the following 2 studies:
 C4591001: Phase 1/2/3, placebo-controlled, 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.
Exposure to COVID-19 mRNA vaccine for participants in 2 ongoing studies by number of

doses, and demographic characteristics is shown in Table 4 through Table 15.
In addition, exposure in clinical studies in special populations is provided in Table 16.
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Table 4. Exposure to BNT162b2 by Age Group and Dose (C4591001)

Age Group Number of Subjects Total Number of
Dose Exposed to BNT162b2 Vaccine Doses
Exposure (Number of Doses Received)
≥16 years to ≤17 years

Vaccine 30 µg
1 Dose 61 61
2 Doses 77 154
Total 138 215

Vaccine 10 µg
2 Doses 12 24
Total 12 24
Vaccine 20 µg
2 Doses 12 24
Total 12 24
Vaccine 30 µg
1 Dose 825 825
2 Doses 11830 23660
Total 12655 24485
>55 years
Vaccine 10 µg
2 Doses 12 24
Total 12 24
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Table 4. Exposure to BNT162b2 by Age Group and Dose (C4591001)

Vaccine 20 µg
2 Doses 12 24
Total 12 24
Vaccine 30 µg
1 Dose 323 323
2 Doses 8629 17258
Total 8952 17581
Note: 30 μg includes data from phase 1 and phase 2/3.
PFIZER CONFIDENTIAL SDTM Creation: 17NOV2020 (10:49) Source Data: adsl Table Generation: 19NOV2020 (00:22) (Cutoff date: 14NOV2020,
Snapshot Date: 16NOV2020) Output File: (CDISC)/C4591001_RMP_Phase1_2_3/adsl_s912
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Table 5. Exposure to BNT162b2 by Age Group and Dose (BNT162-01)

Age Group No. of Subjects Exposed to BNT162b2 Total No. of Vaccine Doses
Dose
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 11 22
Total 12 23
Vaccine 20 µg
1 Dose 0 0
2 Doses 12 24
Total 12 24
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Dose
Vaccine 30 µg
1 Dose 0 0
2 Doses 12 24
Total 12 24
>55 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 12 24
Total 12 24
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Dose
Vaccine 20 µg
1 Dose 0 0
2 Doses 12 24
Total 12 24
Vaccine 30 µg
1 Dose 0 0
2 Doses 12 24
Total 12 24
PFIZER CONFIDENTIAL SDTM Creation: 03NOV2020 (21:23) Source Data: adsl Table Generation: 18NOV2020 (14:42) (Cutoff date:02OCT2020, Snapshot Date:
02OCT2020)
Output File: ex_b2_age_dose2.rtf
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Table 6. Exposure to BNT162b2 by Age Group and Dose – Children and Elderly Subjects (C4591001)


Vaccine 30 µg
1 Dose 1 1
2 Doses 48 96
Total 49 97
≥65 years
Vaccine 10 µg
2 Doses 12 24
Total 12 24
Vaccine 20 µg
2 Doses 12 24
Total 12 24
Vaccine 30 µg
1 Dose 121 121
2 Doses 4435 8870
Total 4556 8991

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Table 7. Exposure to BNT162b2 by Dose (Totals) (C4591001)
Dose Number of Subjects Total Number of

Exposure (Number of Doses Received) Exposed to BNT162b2 Vaccine Doses
Vaccine 10 µg
2 Doses 24 48
Total 24 48
Vaccine 20 µg
2 Doses 24 48
Total 24 48
Vaccine 30 µg
1 Dose 1209 1209
2 Doses 20536 41072
Total 21745 42281

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Table 8. Exposure to BNT162b2 by Dose (Totals) (BNT162-01)

Dose No. of Subjects Exposed to Total No. of Vaccine
Exposure (Number of Doses Received) BNT162b2 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
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Table 8. Exposure to BNT162b2 by Dose (Totals) (BNT162-01)

Dose No. of Subjects Exposed to Total No. of Vaccine
Exposure (Number of Doses Received) BNT162b2 Doses
Vaccine 30 µg
1 Dose 0 0
2 Doses 24 48
Total 24 48
02OCT2020)
Output File: ex_b2_dose.rtf
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Table 9. Exposure to BNT162b2 by Dose, Age Group, and Gender (C4591001)
Number of Subjects Exposed to BNT162b2 Total Number of Vaccine Doses

Dose Male Female Male Female
Age Group
Vaccine 10 µg
≥18 years to ≤55 years 5 7 10 14
>55 years 2 10 4 20
Total 7 17 14 34
Vaccine 20 µg
≥18 years to ≤55 years 6 6 12 12
>55 years 5 7 10 14
Total 11 13 22 26
Vaccine 30 µg
≥16 years to ≤17 years 75 63 117 98
≥18 years to ≤55 years 6437 6218 12397 12088
>55 years 4680 4272 9177 8404
Total 11192 10553 21691 20590

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Table 10. Exposure to BNT162b2 by Dose, Age Group, and Gender (BNT162-01)
No. of Subjects Exposed to Total No. of Vaccine Doses
BNT162b2
Age Group
Vaccine 1 µg
≥18 years to ≤55 years 7 5 14 9
>55 years 0 0 0 0
Total 7 5 14 9
Vaccine 3 µg
≥18 years to ≤55 years 5 7 10 14
>55 years 0 0 0 0
Total 5 7 10 14
Vaccine 10 µg
≥18 years to ≤55 years 4 8 8 15
>55 years 8 4 16 8
Total 12 12 24 23
Vaccine 20 µg
≥18 years to ≤55 years 2 10 4 20
>55 years 6 6 12 12
Total 8 16 16 32
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Table 10. Exposure to BNT162b2 by Dose, Age Group, and Gender (BNT162-01)
No. of Subjects Exposed to Total No. of Vaccine Doses
BNT162b2
Age Group
Vaccine 30 µg
≥18 years to ≤55 years 8 4 16 8
>55 years 4 8 8 16
Total 12 12 24 24
02OCT2020)
Output File: ex_b2_age_dose_sex2.rtf
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Table 11. Exposure to BNT162b2 by Age Group, Dose, and Race/Ethnic Origin (C4591001)

Race/Ethnic Origin
Subjects ≥16 years to ≤17 years

Vaccine 30 µg
Racial Origin
White 102 158
Black or African American 21 35
Asian 7 8
Native Hawaiian or other Pacific Islander 2 4
Multiracial 6 10
Total 138 215
Ethnic Origin
Hispanic/Latino 17 24
Non-Hispanic/non-Latino 121 191
Total 138 215
Subjects ≥18 years to ≤55 years

Vaccine 10 µg
Racial Origin
White 11 22
Asian 1 2
Total 12 24
Ethnic Origin
Hispanic/Latino 1 2
Total 12 24
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Race/Ethnic Origin
Vaccine 20 µg
Racial Origin
White 10 20
Total 12 24
Ethnic Origin
Hispanic/Latino 1 2
Total 12 24
Vaccine 30 µg
Racial Origin
White 9917 19153
Asian 681 1332
American Indian or Alaska Native 118 211
Multiracial 418 825
Not reported 81 160
Total 12655 24485
Ethnic Origin
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Race/Ethnic Origin
Not reported 64 121

Total 12655 24485
Subjects >55 years

Vaccine 10 µg
Racial Origin
White 12 24
Total 12 24
Ethnic Origin
Total 12 24
Vaccine 20 µg
Racial Origin
White 12 24
Total 12 24
Ethnic Origin
Total 12 24
Vaccine 30 µg
Racial Origin
White 7842 15403
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Race/Ethnic Origin
Asian 248 490

Multiracial 112 223
Not reported 22 44
Total 8952 17581
Ethnic Origin
Not reported 56 112
Total 8952 17581

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Table 12. Exposure to BNT162b2 by Age Group, Dose, and Race/Ethnic Origin (BNT162-01)
Dose
Race/Ethnic Origin
Subjects ≥18 to ≤55 years
Vaccine 1 µg
Racial Origin
White 12 23
Asian 0 0
Native Hawaiian or Other Pacific Islander 0 0
Other 0 0
Not Reported 0 0
Unknown 0 0
Total 12 23
Ethnic Origin
Hispanic/Latino 0 0
Not reported 0 0
Unknown 0 0
Total 12 23
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Dose
Race/Ethnic Origin
Vaccine 3 µg
Racial Origin
White 12 24
Asian 0 0
Other 0 0
Not Reported 0 0
Unknown 0 0
Total 12 24
Ethnic Origin
Hispanic/Latino 0 0
Not reported 0 0
Unknown 0 0
Total 12 24
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Dose
Race/Ethnic Origin
Vaccine 10 µg
Racial Origin
White 12 23
Asian 0 0
Other 0 0
Not Reported 0 0
Unknown 0 0
Total 12 23
Ethnic Origin
Hispanic/Latino 0 0
Not reported 0 0
Unknown 0 0
Total 12 23
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Dose
Race/Ethnic Origin
Vaccine 20 µg
Racial Origin
White 12 24
Asian 0 0
Other 0 0
Not Reported 0 0
Unknown 0 0
Total 12 24
Ethnic Origin
Hispanic/Latino 0 0
Not reported 0 0
Unknown 0 0
Total 12 24
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Dose
Race/Ethnic Origin
Vaccine 30 µg
Racial Origin
White 12 24
Asian 0 0
Other 0 0
Not Reported 0 0
Unknown 0 0
Total 12 24
Ethnic Origin
Hispanic/Latino 0 0
Not reported 0 0
Unknown 0 0
Total 12 24
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Dose
Race/Ethnic Origin
Subjects >55 to ≤85 years
Vaccine 1 µg
Racial Origin
White 0 0
Asian 0 0
Other 0 0
Not Reported 0 0
Unknown 0 0
Total 0 0
Ethnic Origin
Hispanic/Latino 0 0
Not reported 0 0
Unknown 0 0
Total 0 0
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Dose
Race/Ethnic Origin
Vaccine 3 µg
Racial Origin
White 0 0
Asian 0 0
Other 0 0
Not Reported 0 0
Unknown 0 0
Total 0 0
Ethnic Origin
Hispanic/Latino 0 0
Not reported 0 0
Unknown 0 0
Total 0 0
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Dose
Race/Ethnic Origin
Vaccine 10 µg
Racial Origin
White 12 24
Asian 0 0
Other 0 0
Not Reported 0 0
Unknown 0 0
Total 12 24
Ethnic Origin
Hispanic/Latino 0 0
Not reported 0 0
Unknown 0 0
Total 12 24
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Dose
Race/Ethnic Origin
Vaccine 20 µg
Racial Origin
White 12 24
Asian 0 0
Other 0 0
Not Reported 0 0
Unknown 0 0
Total 12 24
Ethnic Origin
Hispanic/Latino 0 0
Not reported 0 0
Unknown 0 0
Total 12 24
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Dose
Race/Ethnic Origin
Vaccine 30 µg
Racial Origin
White 12 24
Asian 0 0
Other 0 0
Not Reported 0 0
Unknown 0 0
Total 12 24
Ethnic Origin
Hispanic/Latino 0 0
Not reported 0 0
Unknown 0 0
Total 12 24
02OCT2020)
Output File: ex_b2_age_dose_race.rtf
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Table 13. Exposure to BNT162b2 by Dose and Race/Ethnic Origin (C4591001)

Race/Ethnic Origin Exposed to BNT162b2 Vaccine Doses
Vaccine 10 µg
Racial Origin
White 23 46
Asian 1 2
Total 24 48
Ethnic Origin
Hispanic/Latino 1 2
Total 24 48
Vaccine 20 µg
Racial Origin
White 22 44
Total 24 48
Ethnic Origin
Hispanic/Latino 1 2
Total 24 48
Vaccine 30 µg
Racial Origin
White 17861 34714
Asian 936 1830
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Table 13. Exposure to BNT162b2 by Dose and Race/Ethnic Origin (C4591001)

Race/Ethnic Origin Exposed to BNT162b2 Vaccine Doses

Multiracial 536 1058
Not reported 103 204
Total 21745 42281
Ethnic Origin
Not reported 120 233
Total 21745 42281

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Table 14. Exposure to BNT162b2 by Dose and Race/Ethnic Origin (BNT162-01)

Dose No. of Subjects Exposed to BNT162b2 Total No. of Vaccine Doses
Race/Ethnic Origin
Vaccine 1 µg
Racial Origin
White 12 23
Asian 0 0
Other 0 0
Not Reported 0 0
Unknown 0 0
Total 12 23
Ethnic Origin
Hispanic/Latino 0 0
Not reported 0 0
Unknown 0 0
Total 12 23
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Race/Ethnic Origin
Vaccine 3 µg
Racial Origin
White 12 24
Asian 0 0
Other 0 0
Not Reported 0 0
Unknown 0 0
Total 12 24
Ethnic Origin
Hispanic/Latino 0 0
Not reported 0 0
Unknown 0 0
Total 12 24
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Race/Ethnic Origin
Vaccine 10 µg
Racial Origin
White 24 47
Asian 0 0
Other 0 0
Not Reported 0 0
Unknown 0 0
Total 24 47
Ethnic Origin
Hispanic/Latino 0 0
Not reported 0 0
Unknown 0 0
Total 24 47
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Race/Ethnic Origin
Vaccine 20 µg
Racial Origin
White 24 48
Asian 0 0
Other 0 0
Not Reported 0 0
Unknown 0 0
Total 24 48
Ethnic Origin
Hispanic/Latino 0 0
Not reported 0 0
Unknown 0 0
Total 24 48
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Race/Ethnic Origin
Vaccine 30 µg
Racial Origin
White 24 48
Asian 0 0
Other 0 0
Not Reported 0 0
Unknown 0 0
Total 24 48
Ethnic Origin
Hispanic/Latino 0 0
Not reported 0 0
Unknown 0 0
Total 24 48
02OCT2020)
Output File: ex_b2_dose_race.rtf
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Table 15. Exposure to BNT162b2 (30 μg) by Special Population (C4591001)
Population Number of Subjects Exposed Total Number of

to BNT162b2 (30 μg) Vaccine Doses
(Na= 21720)
nb
Subjects with any baseline comorbidity 10017 25215
AIDS/HIV 99 177
Any Malignancy + Metastatic Solid Tumor + Leukemia + Lymphoma 845 1660
Chronic Pulmonary Disease 1730 3379
Renal Disease 139 274
Rheumatic Disease 75 142
Mild Liver Disease + Moderate or Severe Liver Disease 145 282
Cerebrovascular Disease + Peripheral Vascular Disease + Myocardial Infarction + Congestive Heart 645 1265
Failure
Dementia 7 14
Diabetes With/Without Chronic Complication 1693 3301
Hemiplegia or Paraplegia 4 8
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Table 15. Exposure to BNT162b2 (30 μg) by Special Population (C4591001)
Population Number of Subjects Exposed Total Number of

to BNT162b2 (30 μg) Vaccine Doses
(Na= 21720)
nb
Peptic Ulcer Disease 62 120

Obese (≥30.0 kg/m2) 7488 14593
Note: Comorbidity is based Charlson Comorbidity Index categories. Participants identified as belonging to these categories were identified by medical history
data collected during the study.
Note: Hemiplegia or Paraplegia only includes preferred terms Hemiplegia and Paraplegia.
a. n = Number of subjects reporting at least 1 occurrence of any comorbidity or BMI (≥30.0 kg/m 2).
b. N = number of subjects in the specified group.
PFIZER CONFIDENTIAL SDTM Creation: 17NOV2020 (10:04) Source Data: admh Table Generation: 18NOV2020 (23:16) (Cutoff date: 14NOV2020,
Snapshot Date: 16NOV2020) Output File: (CDISC)/C4591001_RMP_Phase1_2_3/admh_s953
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Module SIV. Populations Not Studied in Clinical Trials

SIV.1. Exclusion Criteria in Pivotal Clinical Studies Within the Development
Programme
Detailed descriptions of all inclusion and exclusion criteria for clinical studies are provided
in the individual CSRs which were filed in Module 5.3.5.1.
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 enrolment, 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 (please refer to Module 5.3.5.1).
 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).
Exclusion criteria
The participants enrolled were 12 years of age and older; with the 12- to ≤16-year-old cohort
most recently being included in the protocol. 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 SAR-CoV-2 with
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nucleic acid amplification test by nasal swab or antibodies to non-vaccine SARS-CoV-2

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.
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? Yes.
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.
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 COVID-19 mRNA vaccine would
have unexpected negative consequences to the embryo or foetus.
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 Other medical or psychiatric condition including recent (within the past year) or
active suicidal ideation/behaviour 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.
Rationale: Safety profile of COVID-19 mRNA vaccine is not expected to differ in these
subjects when properly administered.
SIV.2. Limitations to Detect Adverse Reactions in Clinical Trial Development

Programmes
The clinical studies are limited in size and, therefore, unlikely to detect very rare adverse
reactions, or adverse reactions with a long latency.
SIV.3. Limitations in Respect to Populations Typically Under-Represented in Clinical

Trial Development Programmes
There has been limited exposure to COVID-19 mRNA vaccine in some special populations
and no epidemiologic studies have been conducted in pregnant/breastfeeding women,
paediatric participants (<16 years of age), and specific subpopulations that were excluded
from the data.

Development Programmes
Type of special population Exposure
Pregnant women Available data on COVID-19 mRNA vaccine administered to pregnant
women are insufficient to inform on vaccine-associated risks in pregnancy.
Therefore, administration of Comirnaty in pregnancy should only be
considered when the potential benefits outweigh any potential risks for the
mother and foetus.
Through the DLP, there were 11 cases (11 events) originating from Study
C4591001, and all were unique pregnancies.
Breastfeeding women Breastfeeding women were not included in the COVID-19 mRNA vaccine
clinical development program.
Data are not available to assess the effects of COVID-19 mRNA vaccine 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 COVID-19 mRNA
vaccine and any potential adverse effects on the breastfed
newborn/infant/toddler from COVID-19 mRNA vaccine or from the
underlying maternal condition. For preventive vaccines, the underlying
maternal condition is susceptible to disease prevented by the vaccine.
There were no CT cases indicative of exposure during breastfeeding.
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Development Programmes
Type of special population Exposure
Women who were breastfeeding were excluded from study participation.
Participants with relevant Healthy participants with pre-existing stable disease, defined as disease not
comorbidities: requiring significant change in therapy or hospitalization for worsening
disease during the 6 weeks before enrolment, were included. This allowed
• Participants with hepatic enrolment of a proportion of participants with common comorbidities such
impairment as cardiovascular diseases including hypertension, chronic pulmonary
• Participants with renal diseases, asthma, chronic liver disease, BMI >30 kg/m2, participants with
impairment stage 3 or worse chronic kidney disease, and participants with varying
• Participants with disease severity.
cardiovascular disease Please refer to Table 15 for the exposure of special populations.
• Immunocompromised
Participants with potential immunodeficient status were not specifically
participants
included in the study population.
• Participants with a disease
severity different from
inclusion criteria in CTs
Population with relevant Please refer to Table 11 to Table 14 for exposure information by ethnic
different ethnic origin origin from the studies.
Subpopulations carrying No data available.
relevant genetic
polymorphisms
Paediatric participants The safety and effectiveness in individuals younger than 16 years of age
have not yet been established. The use in adolescents aged between 12 and
15 years is not in scope for the proposed indication. Forty-nine (49)
children 12 to 15 years of age received COVID-19 mRNA vaccine
(Table 6).
Elderly (≥65 years old) Clinical studies of COVID-19 mRNA vaccine included 4580 participants
65 years of age and over (Table 6).
Abbreviations: BMI = body mass index; CT = clinical trial; DLP = data lock point.
Module SV. Post-Authorisation Experience

SV.1. Post-Authorisation Exposure
As of 17 December 2020, COVID-19 mRNA vaccine (BNT162b2) has not been marketed in
any country/region. The number of individuals who have been vaccinated under temporary
authorization or emergency use authorisation is not available.
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The available information related to COVID-19 mRNA vaccine shipment through

17 December 2020, is provided below.
Countries Total Number of Doses

United States 2,823,600
United Kingdom 2,464,800
Israel 340,275
Puerto Rico 33,150
N Mariana Islands 5850
American Samoa 5850
Saudi Arabia 4875
Guam 3900
US Virgin Islands 975
Total 5,683,275
SV.1.1. Method Used to Calculate Exposure

Not applicable.
SV.1.2. Exposure
Not applicable.
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Module SVI. Additional EU Requirements for the Safety Specification

Potential for misuse for illegal purposes
COVID-19 mRNA vaccine does not have characteristics that would make it attractive for use
for illegal purposes; therefore, there is only a low potential for COVID-19 mRNA vaccine
misuse for illegal purposes.
Module SVII. Identified and Potential Risks

In accordance with EMA RMP guidance for COVID-19 vaccines, the below factors were
taken into consideration for the generation of the safety specification and are not determined
to be identified or potential risks.
 The vaccine construct and the formulation. The COVID-19 mRNA vaccine consists
of non-infectious, non-replicating RNA in a lipid-based formulation, which delivers the
RNA to cells in the immunized person. Protein expression from the RNA is transient,
and as is RNA itself. There is no toxicity associated with the LNP or its metabolism
(Study reports 38166 and 20GR142). Vacuolation of hepatocytes was observed in rat
toxicity studies and believed to be associated with the uptake of the LNP and was without
evidence of any effect on liver function. The liver vacuolation was reversed
approximately 3-weeks after the last administration.
 The degradation of the active substance / antigen and potential impact on safety
related to this; (e.g. for mRNA-based vaccines). Like endogenous mRNA in the
cytosol, vaccine RNA in cytosol is degraded. The COVID-19 mRNA contains no known
toxic products of the degradation of the RNA or the lipids in the formulation.
 The vaccine does not contain an adjuvant.
SVII.1. Identification of Safety Concerns in the Initial RMP Submission

The safety concerns of COVID-19 mRNA vaccine in the initial RMP are listed in Table 17.
Table 17. Summary of Safety Concerns

Important Identified Risks Anaphylaxis
Important Potential Risks Vaccine-associated enhanced disease (VAED) including Vaccine-associated
enhanced respiratory disease (VAERD)
Missing Information Use in pregnancy and while breast feeding
Use in immunocompromised patients
Use in frail patients with co-morbidities (e.g. chronic obstructive pulmonary
disease (COPD), diabetes, chronic neurological disease, cardiovascular
disorders)
Use in patients with autoimmune or inflammatory disorders
Interaction with other vaccines
Long term safety data
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SVII.1.1. Risks not Considered Important for Inclusion in the List of Safety Concerns
in the RMP
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 RMP.
Reasons for not including an identified or potential risk in the list of safety concerns in
this RMP include:
Risks with minimal and temporary clinical impact on patients (in relation to the severity of
the disease prevented).
The following reactogenicity events are identified risks not considered as Important:
Injection site pain, Injection site swelling and Injection site redness, Fever, Chills, Fatigue,
Headache, Muscle pain, and Joint pain.
Very rare potential risks for any medicinal treatment, including vaccines, which are well
known to healthcare professionals are not included in the list of safety concerns.
In acknowledgment of the EMA core RMP19 guidance, the reactogenicity profile of

COVID-19 mRNA vaccine is discussed below with respect to observed differences in
solicited reactogenicity systemic events between Dose 1 and Dose 2. The observed
differences do not impact the safety profile of the vaccine and are not proposed to be
included in the list of safety concerns, rather they are discussed for completeness in the
presentation of the safety profile.
Reactogenicity
At the time of the safety cut-off date (14 November 2020), the Phase 2/3 reactogenicity
subset was comprised of 8183 participants (≥12 years of age), which included the 360
participants in Phase 2. The reactogenicity data were collected by participants’ e-diary for
reporting prompted local reactions and systemic events for 7 days after each dose.
Adolescents 12 to 15 years of age were analysed in a separate group; these are preliminary
data provided in support of the EUA indication which is for ≥16 years of age.
 Local Reactions
In the BNT162b2 group, pain at the injection site was reported more frequently in the
younger group (16-55 years) than in the older group (> 55 years), and frequency was similar
after Dose 1 compared with Dose 2 of BNT162b2 in the younger group (83.1% vs 77.8%)
and in the older group (71.1% vs 66.1%).
In the BNT162b2 group, frequencies of redness and swelling were similar in the younger and
older age group after Doses 1 and 2. Frequencies of redness were similar after Dose 1
compared with Dose 2 of BNT162b2 in the younger age group (4.5% vs 5.9%) and in the
older age group (4.7% vs 7.2%). Frequencies of swelling were similar after Dose 1 compared
with Dose 2 of BNT162b2 in the younger age group (5.8% vs 6.3%, respectively) and in the
older age group (6.5% vs 7.5%). In the placebo group, redness and swelling were reported
infrequently in the younger (≤1.1%) and older (≤1.1%) groups after Doses 1 and 2.
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Overall, across age groups, pain at the injection site did not increase after Dose 2, and
redness and swelling were generally similar in frequency after Dose 1 and Dose 2. Most
local reactions were mild or moderate in severity. Few severe local reactions were reported
after either dose. The frequency of any severe local reactions after Dose 1 and after Dose 2
was ≤0.6%. No grade 4 (potentially life-threatening) reactions were reported.
Across age groups, local reactions for the BNT162b2 group after either dose had a median
onset day between Day 1 and Day 3 (Day 1 was the day of vaccination) and ranges were
similar in the younger and older age groups. Across age groups, local reactions for this
group after either dose resolved with median durations between 1 to 2 days, which were
similar in the younger and older age groups.
No clinically meaningful differences in local reactions were observed by age and/or or

baseline SARS-CoV-2 status subgroups.
 Systemic Events
Systemic events were generally increased in frequency and severity in the younger age group
(16-55 years) compared with the older age group (> 55 years), with frequencies and severity
increasing with number of doses (Dose 1 vs Dose 2). Vomiting and diarrhoea were
exceptions, with vomiting reported similarly infrequently in both age groups and diarrhoea
reported at similar incidences after each dose.
Systemic events in the younger group compared with the older group, with frequencies
increasing with number of doses (Dose 1 vs Dose 2), were:
fatigue: younger group (47.4% vs 59.4%) compared to older group (34.1% vs 50.5%)
 headache: younger group (41.9% vs 51.7%) compared to older group (25.2% vs 39.0%)
 muscle pain: younger group (21.3% vs 37.3%) compared to older group (13.9% vs
28.7%)
 chills: younger group (14.0% vs 35.1%) compared to older group (6.3% vs 22.7%)
 joint pain: younger group (11.0% vs 21.9%) compared to older group (8.6% vs 18.9%)
 fever: younger group (3.7% vs 15.8%) compared to older group (1.4% vs 10.9%)
 vomiting: reported less frequently in the older group and was similar after either dose
 diarrhoea: reported less frequently in the older group and was similar after each dose.
 Systemic events were generally reported less frequently in the placebo group than in the
BNT162b2 group, for both age groups and doses, with some exceptions. In the younger
age group, vomiting and diarrhoea (after Dose 1 and Dose 2) were reported at similar
frequencies in the placebo group and the BNT162b2 group. In the older age group, fever
and joint pain (after Dose 1) and vomiting and diarrhoea (after Dose 1 and Dose 2) were
reported at similar frequencies in the placebo group and the BNT162b2 group.
Following both Dose 1 and Dose 2, use of antipyretic/pain medication was slightly less
frequent in the older age group (19.9% vs 37.7%) than in the younger age group (27.8% vs
45.0%) after both doses, and medication use increased in both age groups after Dose 2 as
compared with after Dose 1. Use of antipyretic/pain medication was less frequent in the
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placebo group than in the BNT162b2 group and was similar after Dose 1 and Dose 2 in the
younger and older placebo groups (9.8% to 22.0%).
After the first and second dose and in both age groups, the majority of systemic events were
mild or moderate in severity. Systemic events across age groups after Dose 1 of BNT162b2
were generally lower in frequency than after Dose 2: fever (2.7% vs 13.6%), fatigue (41.5%
vs 55.5%), headache (34.5% vs 46.1%), chills (10.6% vs 29.6%), muscle pain (18.0% vs
33.5%), and joint pain (9.9% vs 20.5). Diarrhoea and vomiting frequencies were generally
similar. The frequency of any severe systemic event after Dose 1 was ≤0.9%. After Dose 2,
systemic events had frequencies of < 2% with the exception of fatigue (3.8%) and headache
(2.0%).
In the placebo group, severe fever was reported at a similar frequency (≤0.4%) after Dose 1
and Dose 2. One participant in the younger BNT162b2 group reported fever of 41.2°C only
on Day 2 after Dose 2 and was nonfebrile for all other days of the reporting period. One
other participant in the younger group reported fever that reached a high temperature of
42.3°C on Day 4 after Dose 1 that lasted in total for 3 days; the participant was nonfebrile at
the end of the reporting period.
Across age groups, median onset day for most systemic events after either dose of
BNT162b2 was Day 2 to Day 3 (Day 1 was the day of vaccination), and ranges were similar
in the younger and older age groups. Across age groups, all systemic events resolved with
median duration of 1 day, which was similar in the younger and older age groups.
Other than fatigue and headache, most systemic events were infrequent in placebo recipients.
Antipyretic/pain medication use in the younger adolescent group was modestly increased
after Dose 2 compared to Dose 1 (30.6% vs 41.3%) and was greater than use in the placebo
group (9.8% vs 13%).
No clinically meaningful differences in systemic events were observed by age and/or

baseline SARS-CoV-2 status subgroups. In summary, increases in some systemic
reactogenicity events (fever, chills, headache, fatigue, muscle pain and joint pain) were
observed in the week following Dose 2 when compared with the week following Dose 1.
The differences are small enough that they are unlikely to discourage vaccinees from
completing the full 2-dose regimen for vaccination neither do they impact the benefit risk
profile of the vaccine overall. Overall, the reactogenicity events have only temporary clinical
impact on patients in relation to the potential severity of the disease prevented.
Adverse Events of Special Interest (AESI)
COVID-19 mRNA vaccine study C4591001 did not pre-specify AESI however, Pfizer
utilizes a dynamic list of TME terms to be highlighted in clinical study safety data review.
TMEs include events of interest due to their association with COVID-19 and terms of interest
for vaccines in general and may include Preferred Terms, High Level Terms, High Level
Group Terms or Standardised MedDRA Queries.
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For the purpose of the RMP and summary safety reports, an AESI list was composed taking
into consideration the available lists of AESIs from the following expert groups and
regulatory authorities:
Brighton Collaboration (SPEAC)30

 ACCESS protocol31
 US CDC (preliminary list of AESI for VAERS surveillance)32
 MHRA (unpublished guideline).
The AESI list is comprised of medical conditions to allow for changes and customization of
MedDRA terms as directed by AE reports and the evolving safety profile of the vaccine:
 Immune/Autoimmune-mediated neurological, haematological and vasculitis events;

 Events associated with severe COVID-19;
 Serious thrombotic and embolic events.
The AESIs are taken in consideration for all routine and additional pharmacovigilance
activities.
SVII.1.2. Risks Considered Important for Inclusion in the List of Safety Concerns in
the RMP
Important Identified Risk: Anaphylaxis
Risk-benefit impact
Anaphylaxis is a serious adverse reaction that, although very rare, can be life-threatening.
Important Potential Risk: Vaccine-Associated Enhanced Disease (VAED), including

Vaccine-Associated Enhanced Respiratory Disease (VAERD)
Risk-benefit impact
Although not observed or identified in clinical studies with COVID-19 vaccines, there is a
theoretical risk, mostly based on non-clinical betacoronavirus data, of VAED occurring
either before the full vaccine regimen is administered or in vaccinees who have waning
immunity over time. If VAED were to be identified as a true risk, depending on its incidence
and severity, it may negatively impact the overall vaccine benefit risk assessment for certain
individuals.
Missing Information: Use in Pregnancy and while breast feeding
Risk-benefit impact
The safety profile of the vaccine is not known in pregnant or breastfeeding women due to
their exclusion from the pivotal clinical study. Accordingly, maternal COVID-19 impact to
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either embryo or foetus is also not known. It is important to obtain long term follow-up on
women who were pregnant at or around the time of vaccination so that any potential negative
consequences to the pregnancy can be assessed and weighed against the effects of maternal
COVID-19 on the pregnancy.
Missing Information: Use in immunocompromised patients
Risk-benefit impact
The safety profile of the vaccine is not known in immunocompromised individuals due to
their exclusion from the pivotal clinical study. The efficacy of the vaccine may be lower in
immunocompromised individuals, thus decreasing their protection from COVID-19.
Missing Information: Use in frail patients with co-morbidities (e.g. chronic obstructive
pulmonary disease (COPD), diabetes, chronic neurological disease, cardiovascular
disorders)
Risk-benefit impact
There is limited information on the safety of the vaccine in frail patients with co-morbidities
who are potentially at higher risk of severe COVID-19.
Missing Information: Use in patients with autoimmune or inflammatory disorders
Risk-benefit impact
There is limited information on the safety of the vaccine in individuals with autoimmune or
inflammatory disorders and a theoretical concern that the vaccine may exacerbate their
underlying disease.
Missing Information: Interaction with other vaccines
Risk-benefit impact
BNT162b2 mRNA vaccine will be used in individuals who also may receive other vaccines.
Studies to determine if co-administration of BNT162b2 mRNA vaccine with other vaccines
may affect the efficacy or safety of either vaccine have not been performed.
Missing Information: Long term safety data
Risk-benefit impact
The long-term safety of BNT162b2 mRNA vaccine is unknown at present, however further
safety data are being collected in ongoing Study C4591001 for up to 2 years following
administration of dose 2 of BNT162b2 mRNA vaccine.
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SVII.2. New Safety Concerns and Reclassification with a Submission of an Updated

RMP
Not applicable.
SVII.3. Details of Important Identified Risks, Important Potential Risks, and Missing
Information
SVII.3.1. Presentation of Important Identified Risks and Important Potential Risks
SVII.3.1.1. Important Identified Risk: Anaphylaxis
Table 18. Anaphylaxis

Potential Interaction of an allergen with IgE on basophils and mast cells triggers release of
mechanisms, histamine, leukotrienes and other mediators that cause diffuse smooth muscle
evidence source and contraction and vasodilation with plasma leakage. This can manifest clinically with
strength of evidence dyspnea, hypotension, swelling (sometimes leading to airway compromise), and
rash (including hives).
Characterisation of Data from the ongoing Phase 3 clinical Study C4591001 have been reviewed and
the risk information pertinent to anaphylactic reactions observed in the study is summarized
below.
Data from the CT database: 2 serious events (Anaphylactic reaction and
Anaphylactic shock) were reported. Anaphylactic reaction due to a bee sting in a
BNT162b2 recipient, and Anaphylactic shock due to an ant bite in a placebo
recipient; both events were deemed not related to study treatment by the
Investigator.
Data from the safety database: 2 serious events (Anaphylactic reaction and
Anaphylactoid reaction) were reported during the emergency use authorization.
Risk factors and risk Known hypersensitivity to any components of the vaccine.
groups
Preventability Prevention of anaphylaxis may not be possible, particularly with the 1st dose of a
vaccine; therefore, healthcare professionals administering the vaccine must be
vigilant for early signs and symptoms.
Impact on the risk- Anaphylactic reaction in an individual can be impactful (medically important)
benefit balance of the because it is a potentially life-threatening event requiring medical intervention.
biologic product
Public health impact Minimal due to rarity of the event. Although the potential clinical consequences of
an anaphylactic reaction are severe, this is a known risk of vaccines to healthcare
professionals with negligible public health impact. Almost 22,000 subjects were
exposed to BNT162b2 in the clinical studies and no events of vaccine-related
anaphylaxis were observed. It is unknown how many events will be observed in the
post-marketing setting but expected to be very rare.
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SVII.3.1.2. Important Potential Risk: Vaccine-Associated Enhanced Disease (VAED),

including Vaccine-Associated Enhanced Respiratory Disease (VAERD)

Associated Enhanced Respiratory Disease (VAERD)
Potential This potential risk is theoretical because it has not been described in association
mechanisms, with the COVID-19 mRNA vaccine or it has not been reported from any other late
evidence source and phase clinical trial of other human vaccine. Animal models of SARS-CoV-2
strength of evidence infection have not shown evidence of VAED after immunization, whereas cellular
immunopathology has been demonstrated after viral challenge in some animal
models administered SARS-CoV-1 (murine, ferret and non-human primate models)
or MERS-CoV (mice model) vaccines.25,33 This potential risk has been included
based on these animal data with these related betacoronaviruses. Historically,
disease enhancement in vaccinated children following infection with natural virus
has been observed with an inactivated respiratory syncytial virus vaccine.34
Potential mechanisms of enhanced disease may include both T cell-mediated [an
immunopathological response favouring T helper cell type 2 (TH2) over T helper
cell type 1 (TH1)] and antibody-mediated immune responses (antibody responses
with insufficient neutralizing activity leading to formation of immune complexes
and activation of complement or allowing for Fc-mediated increase in viral entry to
cells).35
Characterisation of
the risk Confirmed Case of Postvaccination Severe COVID-19 – Safety Population
(C4591001)
BNT162b2 (30 μg) Placebo
(Na=21721) (Na=21729)
Timing nb (%) (95% CIc) nb (%) (95% CIc)
PD1 Before Dose 2 0 (0.0, 0.0) 4 (0.0) (0.0, 0.0)

Within 7 days PD1 0 (0.0, 0.0) 0 (0.0, 0.0)
Within 14 days PD1 0 (0.0, 0.0) 3 (0.0) (0.0, 0.0)
PD2 1 (0.0) (0.0, 0.0) 5 (0.0) (0.0, 0.1)
Within 7 days PD2 0 (0.0, 0.0) 1 (0.0) (0.0, 0.0)
Within 14 days PD2 0 (0.0, 0.0) 2 (0.0) (0.0, 0.0)
Totald 1 (0.0) (0.0, 0.0) 9 (0.0) (0.0, 0.1)
Note: This table includes subjects from Phase 2/3 only.
Abbreviations: PD1 = post-dose 1; PD2 = post-dose 2.
a. N = number of subjects in the specified group. This value is the denominator for the
percentage calculations.
b. n = Number of subjects reporting at least 1 occurrence of the specified event.
c. Exact 2-sided CI based on the Clopper and Pearson method.
d. Total is the sum of PD1 and PD2.
PFIZER CONFIDENTIAL SDTM Creation: 17NOV2020 (10:49) Source Data: adc19ef
Table Generation: 19NOV2020 (00:22) (Cutoff date: 14NOV2020, Snapshot Date:
16NOV2020) Output File: (CDISC)/C4591001_RMP_Phase1_2_3/adeff_s901
If VAED/VAERD were to occur in vaccinated individuals, it may manifest as a

modified and/or more severe clinical presentation of SARS-CoV-2 viral infection
upon subsequent natural infection. This may result in individuals assumed to be at
lower risk for severe COVID-19 having more severe disease, for individuals at
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Associated Enhanced Respiratory Disease (VAERD)
known risk for severe COVID-19 (e.g. older or immunocompromised) having
higher rates of fatal outcomes, or for observation of an unfavourable imbalance in
severe COVID-19 cases in vaccinated individuals when compared to those not
vaccinated. It is challenging if not impossible 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 needs to be at a population
level,36 as noted above. The table above shows a favourable balance of severe
COVID-19 cases in participants receiving COVID-19 mRNA vaccine versus those
receiving placebo, providing reassurance against the potential risk of
VAED/VAERD at this time.
Risk factors and risk It is postulated that the potential risk may be increased in individuals producing
groups lower neutralizing antibody titers or in those demonstrating waning immunity.35,36
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;25,35 that immune profile is elicited
by BNT162b2 in clinical and preclinical studies.37,38
Impact on the risk- If there were an unfavourable balance in COVID-19 cases, including severe cases,
benefit balance of the in the pivotal clinical study between the vaccine and placebo groups, that may
biologic product 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.
SVII.3.2. Presentation of the Missing Information
Table 20. Use in pregnancy and while breast feeding

Evidence source:
The safety profile of the vaccine is not known in pregnant or breastfeeding women due to their exclusion
from the pivotal clinical study. There may be pregnant women who choose to be vaccinated despite the lack
of safety data. It will be important to follow these women for pregnancy and birth outcomes. The timing of
vaccination in a pregnant woman and the subsequent immune response may have varying favourable or
unfavourable impacts on the embryo/foetus. The clinical consequences of SARS-CoV-2 infection to the
woman and foetus during pregnancy is not yet fully understood and the pregnant woman’s baseline health
status may affect both the clinical course of her pregnancy and the severity of COVID-19. These factors and
the extent to which the pregnant woman may be at risk of exposure to SARS-CoV-2 will influence the
benefit risk considerations for use of the vaccine.
Population in need of further characterization:
The lack of data will be communicated in product labelling; clinical study of the safety and immunogenicity
of COVID-19 mRNA vaccine in pregnant women, is planned.
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Table 21. Use in immunocompromised patients

Evidence source:
The vaccine has not been studied in individuals with overt immunocompromised conditions. Therefore,
further safety data will be sought in this population.
Population in need of further characterisation:
Safety data will be collected in individuals with compromised immune function due to acquired or genetic
conditions or conditions requiring the use of immunosuppressants as this population of individuals in the
active surveillance studies and the clinical studies proposed by the MAA (see Section PART III).
Table 22. Use in frail patients with co-morbidities (e.g. chronic obstructive
cardiovascular disorders)
Evidence source:
The vaccine has been studied in individuals with stable chronic diseases (e.g. hypertension, obesity),
however it has not been studied in frail individuals with severe co-morbidities that may compromise immune
function due to the condition or treatment of the condition. Therefore, further safety data will be sought in
this population.
Safety data will be collected in individuals who are frail due to age or debilitating disease in the active
surveillance studies and through routine pharmacovigilance.
Table 23. Use in patients with autoimmune or inflammatory disorders

Evidence source:
There is limited information on the safety of the vaccine in patients with autoimmune or inflammatory
disorders.
Safety data will be collected in individuals with autoimmune or chronic inflammatory diseases, including
those who may be on immunosuppressants in the active surveillance studies.
Table 24. Interaction with other vaccines

Evidence source:
There are no data on interaction of BNT162b2 mRNA vaccine with other vaccines at this time.
All reports describing interactions of COVID-19 vaccine with other vaccines per national recommendations
in individuals will be collected and analysed as per routine PV activities. Interactions with commonly used
non-COVID-19 vaccines, such as influenza vaccine, are proposed to be studied in a future clinical study.
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Table 25. Long term safety data

Evidence source:
At this time, 2-month post dose 2 safety data are available for approximately half of the patients who have
received BNT162b2 mRNA vaccine in Study C4591001. The study is ongoing.
Anticipated risk/consequence of missing information:
At the time of vaccine availability, the long-term safety of BNT162b2 mRNA vaccine is not fully known,
however there are no known risks with a potentially late onset. Data will continue to be collected from
participants in ongoing study C4591001 for up to 2 years following the 2nd dose of vaccine. Additionally,
active surveillance studies are planned to follow long-term safety in vaccine recipients for 2 years following
Dose 2.
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Module SVIII. Summary of the Safety Concerns
Table 26. Summary of Safety Concerns

Important Identified Risks Anaphylaxis
Important Potential Risks Vaccine-associated enhanced disease (VAED) including Vaccine-associated
enhanced respiratory disease (VAERD)
Missing Information Use in pregnancy and while breast feeding
Use in frail patients with co-morbidities (e.g. chronic obstructive pulmonary
disease (COPD), diabetes, chronic neurological disease, cardiovascular
disorders)
\
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PART III. PHARMACOVIGILANCE PLAN (INCLUDING POST-

AUTHORISATION SAFETY STUDIES)
III.1. Routine Pharmacovigilance Activities
Routine pharmacovigilance for the lifecycle of a product is a critical component to the
detection, assessment, understanding and mitigation of AEs. Objectives of routine
pharmacovigilance includes having processes in place to assure the ongoing and timely
collection, processing, follow-up, and analysis of individual AE reports and aggregate data
globally, following global safety Standard Operating Procedures and regulatory guidance.
Pfizer, on behalf of the 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 safety 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, gathers
data for signal detection and evaluation commensurate with product characteristics.
Routine pharmacovigilance activities beyond the receipt and review of individual AE reports
(e.g. ADRs) include:
 Data Capture Aids have been created for this vaccine. 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 mRNA vaccine and is anticipated to provide insight into potential cases of
vaccine lack of effect or VAED. The DCA is provided in Annex 4;
 potential anaphylactic reactions in individuals who have received the COVID-19
mRNA vaccine. This DCA is in preparation and will be submitted.
 Signal detection activities for the lifecycle of vaccines consist of individual AE
assessment at case receipt, regular aggregate review of cases for trends and statistically
disproportionately reported product-adverse event pairs. Aggregated and statistical
reviews of data are conducted utilizing Pfizer’s software interactive tools. Safety signal
evaluation requires the collection, analysis and assessment of information to evaluate
potential causal associations between an event and the product and includes subsequent
qualitative or quantitative characterization of the relevant safety risk to determine
appropriate continued pharmacovigilance and risk mitigation actions. Signal detection
activities for the COVID-19 mRNA vaccine, will occur on a weekly basis. In addition,
observed versus expected analyses will be conducted as appropriate as part of routine
signal management activity.
 Routine signal detection activities for the COVID-19 mRNA vaccine will include routine
and specific review of AEs consistent with the AESI list provided in
PART II.SVII.1.1 – Risks not considered important for inclusion in the list of safety
concerns in the RMP.
 In addition, published literature is reviewed weekly for individual case reports and
broader signal detection purposes.
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 Regulatory authority safety alerts monitoring.

 A web-based AE reporting portal will be available for vaccine providers (e.g.
pharmacists, nurses, physicians and others who administer vaccines) and recipients, to
assist with anticipated high volume of reports (based on expectations of a large target
population for vaccination). 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 Pfizer Drug Safety Units perform 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.
 The serious adverse event (SAE)/product complaint (PC) Joint Report for Sterile
Injectables is run monthly. In addition, the AE/PC Joint report and the AE/PC Lot/Lot
profile Report is run quarterly and is a statistical report that identifies any data that could
constitute a safety signal over time. The AE/PC Lot/Lot Profile report complements the
monthly AE trending performed by Safety and the monthly PC trending performed by
Product Quality.
Monthly summary safety reports
In addition to routine 6-monthly PSUR production, monthly summary safety reports will be
compiled to support timely and continuous benefit risk evaluations. Topics covered by
monthly summary safety reports will include:
 Interval and cumulative number of reports, stratified by report type (medically

confirmed/not) and by seriousness (including fatal separately);
 Interval and cumulative number of reports, overall and by age groups and in special
populations (e.g. pregnant women);
 Interval and cumulative number of reports per HLT and SOC;
 Summary of the designated medical events;
 Reports per EU country;
 Exposure data (including age-stratified);
 Changes to reference safety information in the interval, and current CCDS;
 Ongoing and closed signals in the interval;
 AESI reports – numbers and relevant cases;
 Fatal reports – numbers and relevant cases;
 Risk/benefit considerations.
The submission of monthly reports complements the submission of 6 monthly PSURs. The
need and frequency of submission of such reports will be re-evaluated based on the available
evidence from post-marketing after 6 months (6 submissions).
 Monthly reports and PSURs will include results of the observed versus expected
analysis for AESI as appropriate, including cases of Bell’s palsy and will present the
results and details of the statistical approach.
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Potential Medication Errors
Large scale public health approaches for mass vaccination may represent changes to standard
vaccine treatment process, thereby potentially introducing the risk of medication errors
related to: reconstitution and administration, vaccination scheme, storage conditions, errors
associated with a multi-dose vial, and once other COVID vaccines are available, confusion
with other COVID vaccines. These potential medication errors are mitigated through the
information in the SmPC and available educational materials for healthcare providers.
 SmPC (section 6.6) contains instructions for reconstitution and administration,

vaccination scheme, and storage conditions of the COVID-19 mRNA vaccine.
 A poster with step-by-step instruction for vaccine storage, dose planning and preparation,
and administration is available, which can be conspicuously displayed in settings where
vaccine is to be administered for ongoing reference.
 Brochures for safe handling of the vaccine and dry ice will accompany vaccine
shipments.
 Medical information call centers will be available for healthcare providers to obtain
information on use of the vaccine.
 Traceability and Vaccination Reminder card (Annex 7) will be provided with the pre-
printed manufacturer name, placeholder spaces for dates of vaccinations and batch/lot
numbers as a mitigation effort for potential confusion between vaccines. (see Traceability
for additional details).
These available resources will inform healthcare providers on the proper preparation and
administration of the vaccine and reduce the potential for medication error in the context of a
mass vaccination campaign. Additionally, the patient information leaflet and Traceability
and Vaccination Reminder card informs patients of the vaccine received so that a series is
completed with the same product.
Traceability
The SmPC, includes instructions for healthcare professionals:
 to clearly record the name and batch number of the administered vaccine to improve
traceability (section 4.4);
 to report any suspected adverse reactions including batch/Lot number if available (section
4.8).
Traceability is available for every shipping container of COVID mRNA vaccine, which are
outfitted with a unique device that provides real-time monitoring of geographic location and
temperature 24 hours per day, 7 days per week. Each device will also trace the batch/lot of
the associated shipment. The device is activated prior to shipment and information is
transmitted wirelessly to Pfizer at a predefined cadence, on behalf of the MAA, until delivery
to the vaccinator’s practice site. A shipment quality report that indicates if the product is
acceptable for immediate use is generated by Pfizer on behalf of the MAA and transmitted to
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the vaccinator’s practice site upon pressing of the stop button on the data logger, or arrival
notification from the carrier in combination with the data loggers location and/or light signal.
Additionally, alarms and escalation/notification for excursions (per pre-defined
specifications) are programmed into the device. These data may be used for the assessment
of a safety signal.
The vaccine carton labelling also contains a 2-D barcode which has the batch/lot and expiry
embedded within, should there be capability at a vaccination site to utilize this as an
information source.
Further, Pfizer on behalf of the MAA, will make available Traceability and Vaccination
Reminder cards (Annex 7) to vaccinators that may be completed at the time of vaccination.
The Traceability and Vaccination Reminder cards contain the following elements:
 Placeholder space for name of vaccinee;

 Vaccine brand name and manufacturer name;
 Placeholder space for due date and actual date of first and second doses, and associated
batch/lot number;
 Reminder to retain the card and bring to the appointment for the second dose of the
vaccine;
 QR code that links to additional information; and
 Adverse event reporting information.
In addition, to the Traceability and Vaccination Reminder cards, two stickers per dose,
containing printed batch/lot information, will be made available to support documentation of
the batch/lot on the Traceability and Vaccination Reminder card and vaccinee medical
records in mass vaccination centers. We also acknowledge that some EU member states may
require utilization of nationally mandated vaccination cards or electronic systems to
document batch/lot number; therefore, the available Traceability and Vaccination Reminder
cards and stickers with printed lot/batch information may not be utilized in all member states.
The following milestones are proposed for the availability of the stickers with printed
lot/batch information:
 Initial vaccine availability: Sufficient quantities of blank “Traceability and Vaccination

Reminder cards” will be made available to vaccinators in the member states where
utilization of a nationally mandated vaccination card is not required.
 31 January 2021: In addition to the blank “Traceability and Vaccination Reminder
cards”, stickers with printed lot/batch information will be made available to vaccinators
at large scale (1000 subjects/day), mass vaccination sites in the member states where the
national authority has not mandated another mechanism for documenting the lot/batch
information.
 Projected 2022: Upon development and approval a of single-dose vials, pre-printed
batch/lot stickers will be available to co-ship with each vaccine shipment.
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Cold-Chain Handling and Storage
Multiple modalities will be utilized for quality assurance throughout shipment due to the
required ultra-cold storage for COVID-19 mRNA vaccine.
 Each shipment of the vaccine is outfitted with a unique device that provides real-time
monitoring of geographic location and temperature 24 hours per day, 7 days per week
until delivery to a vaccinator’s practice site. Alarms and escalation/notification to Pfizer
on behalf of the MAA and/or to the recipient for excursions (per pre-defined
specifications) are programmed into the device. Additionally, a shipment quality report
that indicates if the product is acceptable for immediate use is generated by Pfizer and
transmitted to the vaccinator’s practice site.
 Joint adverse event and product complaint (including available batch/lot information)
trending reviews occur routinely with Global Product Quality.
 Additionally, available educational materials for vaccinators will include information
regarding proper handling of the shipment container as temporary storage, and
handling/disposal of dry ice until the received shipment is either placed into an ultra-low
temperature freezer, or is maintained in accord with pre-defined specifications in the
shipment container as temporary storage (i.e. upon receipt of the shipment quality report
noted above), as appropriate.
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III.2. Additional Pharmacovigilance Activities

The MAA proposes the following 11 studies, of which 1 global, 3 in Europe only, 2 in
Europe and US, and 3 in US only; the countries where 2 studies will be conducted are not
available at this time. There are 6 Interventional studies (C4591001, C4591015, BNT162-01
Cohort 13, C4591018, 1 study in high risk adults and 1 study for vaccine interactions ) and
5 Non-Interventional studies (4 safety and 1 effectiveness), summarized in the table below
and further detailed in Table 27 and Table 28.
Study Number Country Interventional/ Purpose

Non-Interventional
C4591001 Global Interventional Safety
C4591015 Not available at this time Interventional Safety
C4591010 EU Non-Interventional Safety
C4591011 US Non-Interventional Safety
C4591012 US Non-Interventional Safety
ACCESS/VAC4EU EU Non-Interventional Safety
C4591014 EU, US Non-Interventional Effectiveness a
BNT162-01 Cohort 13 EU Interventional Safety
C4591018 US Interventional Safety
Safety and EU, US Interventional Safety
immunogenicity in high
risk adults b
Co-administration study Not available at this time Interventional Safety
with seasonal influenza
vaccine
a. Vaccine effectiveness is not a safety concern;
b. On review of preliminary information from BNT162-01 cohort 13, C4591001 HIV-infected and high-risk
populations and C4591018, a further safety and immunogenicity study is anticipated in up to 150 adult subjects with a
range of primary immunocompromising conditions and/or receiving immunocompromising treatments or in conditions.
Non-Interventional Post Approval Safety Studies (4)
 The MAA proposes 4 complementary studies of real-world safety of COVID-19 mRNA

vaccine that use multiple data sources and study designs. These are described in Table 27
below which includes the proposed post-approval safety studies that will be conducted in
the EU and US.
 Study C4591010 will be conducted in the EU using primary data collection to monitor a
cohort of vaccinees and evaluate risk of safety events of interest reflecting the AESI list.
A draft protocol C4591010 is provided in Annex 2.
 Additionally, Pfizer, on behalf of the MAA, will sponsor one or more PASS using
secondary EHR data sources in Europe based on a master surveillance protocol
developed through the ACCESS project, which is funded by EMA and conducted via the
Vaccine monitoring Collaboration for Europe (VAC4EU) (VAC4EU, 2020). The MAA
has initiated a request for proposal with the VAC4EU secretariat. Pfizer on behalf of the
MAA, understands that the master protocol is under development with the EMA and
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notification will be provided once finalized and will provide draft protocols as soon as
available.
 In addition to the studies planned for EU, in support of the US EUA application, Pfizer
has submitted to the FDA 2 draft protocols for safety surveillance of COVID-19 mRNA
vaccine in populations expected to receive the vaccination under EUA in the US. These
studies include:
 1 study using secondary data from EHR of active military and their families
(C4591011),
 1 study using secondary data from EHR of patients included in the Veterans
Healthcare Administration system (C4591012).
 The draft protocols for the proposed safety studies in the US (C4591011 and C4591012)
are included in Annex 2.
Non-Interventional Post-Approval Safety Studies in Pregnancy
The proposed strategy to assess vaccination during pregnancy will be implemented in

2 stages. It is anticipated that initial use in pregnancy will be subject to local health authority
recommendations regarding which individuals should be vaccinated and likely very limited
intentional vaccination of pregnant women; therefore, initially this information will derive
from 3 of the real-world safety studies (C4591010, C4591011, and ACCESS/VAC4EU),
described in Table 27. Study C4591012 is focused on patients in the Veterans Health
Administration system and is not expected to capture many pregnancies given the
demographics of the source population. The findings from studies’ interim analysis (where
planned) will inform a strategy to assess pregnancy outcomes as vaccination in pregnancy
expands. MAA will consider established EU pregnancy research recommendations such as
CONSIGN (COVID-19 infectiOn aNd medicineS In pregnancy) when developing any
pregnancy related study objectives (currently not listed in Table 27 and Table 28).
The MAA agrees that monitoring vaccine safety in pregnant women is critical. Given that a
pregnancy registry based on primary data collection is susceptible to non-participation,
attrition, small sample size and limited or lack of comparator data, Pfizer, on behalf of the
MAA, would like to propose monitoring vaccine safety in pregnancy using electronic health
care data, which could be conducted in a representative pregnant woman population exposed
to the vaccine and minimize selection bias, follow-up bias, and reporting bias. In addition,
internal comparison groups, such as contemporaneous unvaccinated pregnant women or
women receiving other vaccine(s) to prevent COVID-19 (if available) could be included.
Non-Interventional Post-Approval Effectiveness (1)
Pfizer will conduct, on behalf of the MAA, at least one non-interventional study (test
negative design) of individuals presenting to the hospital or emergency room with symptoms
of potential COVID-19 illness in a real-world setting (C4591014). The effectiveness of
COVID-19 mRNA vaccine will be estimated against laboratory confirmed COVID 19 illness
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requiring admission to the Emergency Department (ED) or hospital where SARS-CoV-2 is

identified. These studies will allow to determine the effectiveness of Pfizer’s vaccine in a
real-world setting and against severe disease, and in specific racial, ethnic, and age groups.
The studies proposed below are under evaluation as potential commitments; studies are
presented by geographical area (US and EU).
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Table 27. Additional Pharmacovigilance Activities

Study Number Study Title Rationale and Study Study design Study populations Milestones
Country (ies) Objectives
Study Type
Study Status
C4591001 A Phase 1/2/3, The objective of the study is Phase 1/2/3, randomized, Healthy men and CSR submission Any time
placebo-controlled, to evaluate the safety, placebo-controlled, observer- women 18-55 and 65-85 upon regulatory
randomized, observer- tolerability, immunogenicity blind, dose-finding, vaccine years of age. request:
Global blind, dose-finding and efficacy of COVID-19 candidate–selection, and Male and female, aged ≥
study to evaluate the mRNA vaccine efficacy study in healthy 12 years of age.
safety, tolerability, individuals.
immunogenicity, and Stable chronic
efficacy of SARS- An unfavorable imbalance conditions including
COV-2 RNA vaccine between the vaccine and stable treated HIV, HBV
candidates against control groups in the and HCV allowed,
COVID-19 in healthy frequency of COVID-19, in excluding
individuals particular for severe immunocompromising
COVID-19, may suggest the conditions and
occurrence of vaccine treatments. CSR submission 6 31-Dec-2021
Interventional associated enhanced months post Dose 2:
Ongoing disease. Surveillance is Final CSR 31-Aug-2023
planned for 2 years submission with
following Dose 2 supplemental follow-
up:
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Study Type
Study Status
C4591011 Safety Surveillance of Assessment of occurrence of Secondary database analysis of Active military and their Interim reports 30-Jun-2021
the Pfizer COVID-19 safety events of interest, observational data to estimate families submission:
Vaccine in the U.S. including severe or atypical incidence rates of safety events 31-Dec-2021
US Department of COVID-19 in a cohort of of interest and other clinically
Defense Population people within the significant events in a cohort 30-Jun-2022
Following Emergency Department of Defense of active military and their
31-Dec-2022
Use Authorization Healthcare System. families who receive the
Non-Interventional COVID-19 mRNA vaccine Final CSR submission: 31-Dec-2023
under EUA in the US
Planned
C4591012 Post-Emergency Use Assessment of occurrence of Secondary database analysis of US Veteran's Interim reports 30-Jun-2021
Authorization Active safety events of interest, observational data to estimate submission:
Surveillance of including severe or atypical incidence rates of safety events 31-Dec-2021
US Adverse Events of COVID-19 in real-world use of interest and other clinically
Special Interest of COVID-19 mRNA significant events in a cohort 30-Jun-2022
among Individuals in vaccine. of US veterans who receive
the Veteran’s Affairs the COVID-19 mRNA vaccine 31-Dec-2022
Health System under EUA in the US
Receiving Final CSR submission: 31-Dec-2023
Pfizer-BioNTech
Coronavirus Disease
2019 (COVID-19)
Vaccine
Non-Interventional
Planned
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Study Type
Study Status
C4591010 A Post-Approval Assessment of occurrence of Primary data collection cohort EU general population Final draft protocol 31-Jan-2021
Active Surveillance safety events in real-world study submission for EMA
Safety Study to use of COVID-19 mRNA review:
EU Monitor Real-World vaccine. Final CSR submission: 31-Mar-2024
Safety of the
Pfizer-BioNTech
COVID-19 vaccine in
the EU
Non-Interventional
Planned
C4591015 A Phase 2/3, Placebo- Planned clinical study to Randomized, placebo- Healthy pregnant women Protocol draft 28-Feb-2021
Controlled, assess safety and controlled, observer-blind 18 years of age or older submission:
Randomized, immunogenicity in pregnant study vaccinated during their
Not available Observer-Blinded women who receive 24 to 34 weeks of
Study to Evaluate the COVID-19 mRNA vaccine gestation
Safety, Tolerability, Safety and immunogenicity
and Immunogenicity of COVID-19 mRNA
of a SARS-CoV-2 vaccine in pregnant women Final CSR submission: 30-Apr-2023
RNA Vaccine
Candidate
(BNT162b2) Against
COVID-19 in Healthy
Pregnant Women 18
Years of Age and
Older
Interventional
Planned
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Study Type
Study Status
C4591014 A test-negative design Estimate the effectiveness of Non-interventional study Adult individuals ≥18 Protocol draft 31-Mar-2021
to evaluate the 2 doses of COVID-19 (test‑negative design) of years of age with acute submission:
effectiveness of mRNA vaccine against individuals presenting with respiratory infection
EU, US BNT162b2 against potential COVID‑19 illness symptoms of potential admitted to the
acute respiratory requiring admission to the COVID-19 illness in a emergency department or
illness due to SARS- ED or hospital where SARS- real‑world setting hospital
CoV-2 infection CoV-2 is identified
among adults Final CSR submission: 30-Jun-2023
≥18 years of age
Non-Interventional
Planned
BNT162-01 Immunogenicity of To assess potentially Dose escalating Use in IA submission: 30-Sep-2021

Cohort 13 COVID-19 mRNA protective immune responses Open uncontrolled immunocompromised
vaccine in in immunocompromised patients
immunocompromised adults
EU subjects, including
assessment of
antibody responses
and cell-mediated
responses Final CSR submission: 31-Dec-2022
Interventional
Ongoing
C4591018 Phase II study of Safety, immunogenicity over Open uncontrolled Immunocompromised Protocol submission: 28-Feb-2021
BNT162b2 in adults 12 months. adults with autoimmune
receiving Description of COVID-19 disease (rheumatoid IA submission: 31-Dec-2021
US immunomodulators cases. arthritis)
for rheumatoid RA activity by Clinical
arthritis (RA) Disease Activity Index.
N-antigen antibodies for
Interventional detection of asymptomatic
infection.
Planned
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Study Type
Study Status
Safety and Phase II study in high Safety, immunogenicity over Open uncontrolled High risk adults Protocol submission: 30-Jun-2021
immunogenicity in
risk adults 12 months in frail elderly, including frail elderly,
high risk adults immunocompromised, those having autoimmune Final CSR submission: 31-Dec-2022
US, EU Interventional autoimmune and other disease, chronic renal
high-risk individuals. disease and
Planned
Description of COVID-19 immunocompromising
cases. conditions
N-antigen antibodies for
detection of asymptomatic
infection.
ACCESS/VAC4EU A Post-Approval Assessment of occurrence of Secondary database analysis of General population Protocol submission: 28-Feb-2021
EU Active Surveillance safety events of interest, observational data to estimate
Safety Study Using including severe or atypical incidence rates of safety events
Secondary Data to COVID-19 in real-world use of interest and other clinically Final CSR submission: 31-Jan- 2024
Monitor Real-World of COVID-19 mRNA significant events in cohorts of
Safety of the vaccine. COVID-19 vaccine recipients
Pfizer-BioNTech in the EU
COVID-19 vaccine in
the EU
Non-Interventional
Planned
Co-administration Co-administration of Safety and immunogenicity Not available at this time General population Protocol submission: 30-Sep-2021
study with seasonal BNT162b2 with of BNT162b2 and Final CSR submission: 31-Dec-2022
influenza vaccine seasonal influenza quadrivalent seasonal
vaccine influenza vaccine when
administered separately or
Not available concomitantly.
Interventional
Planned
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III.3. Summary Table of Additional Pharmacovigilance Activities

III.3.1. On-Going and Planned Additional Pharmacovigilance Activities
Table 28. On-going and Planned Additional Pharmacovigilance Activities

Study (study short Country Summary of Objectives Safety concerns addressed Milestone Due dates
name, and title)
Status
(planned/on-going)
Category 2
C4591001 Global The objective of the study is to Anaphylaxis CSR submission Any time
Ongoing evaluate the safety, tolerability, Vaccine-associated enhanced disease (VAED) including upon regulatory
immunogenicity and efficacy of vaccine-associated enhanced respiratory disease request:
COVID-19 mRNA vaccine (VAERD)
An unfavorable imbalance between Use in patients with co-morbidities (C4591001 subset)
the vaccine and control groups in the
frequency of COVID-19, in Long term safety data. CSR submission 6 31-Dec-2021
particular for severe COVID-19, months post Dose
may suggest the occurrence of 2:
vaccine associated enhanced disease. Final CSR 31-Aug-2023
Surveillance is planned for 2 years submission with
following Dose 2. supplemental
follow-up:
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name, and title)
Status
(planned/on-going)
Category 3
C4591011 US Assessment of occurrence of safety Anaphylaxis Interim reports 30-Jun-2021
Planned events of interest, including severe AESI-based safety events of interest including vaccine submission:
or atypical COVID-19 in a cohort of associated enhanced disease 31-Dec-2021
people within the Department of
Defense Healthcare System. Use in pregnancy
30-Jun-2022
31-Dec-2022
Use in frail patients with co-morbidities (e.g, chronic
obstructive pulmonary disease (COPD), diabetes, chronic Final CSR 31-Dec-2023
neurological disease, cardiovascular disorders) submission:
Use in patients with autoimmune or inflammatory
disorders
Long-term safety data.
C4591012 US Assessment of occurrence of safety Anaphylaxis Interim reports 30-Jun-2021
Planned events of interest, including severe AESI-based safety events of interest including vaccine submission:
or atypical COVID-19 in real-world associated enhanced disease 31-Dec-2021
use of COVID-19 mRNA vaccine.
30-Jun-2022
obstructive pulmonary disease (COPD), diabetes, chronic 31-Dec-2022
neurological disease, cardiovascular disorders)
Final CSR 31-Dec-2023
Use in patients with autoimmune or inflammatory submission:
disorders
Long-term safety data.
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name, and title)
Status
(planned/on-going)
C4591010 EU Assessment of occurrence of safety Anaphylaxis Final draft protocol 31-Jan-2021
Planned events in real-world use of COVID- AESI-based safety events of interest submission for
19 mRNA vaccine. EMA review:
Use in pregnancy
Long-term safety data. Final CSR 31-Mar-2024
submission:
C4591015 Not Planned clinical study to assess Use in pregnancy and while breast feeding. Protocol draft 28-Feb-2021
Planned available safety and immunogenicity in submission:
pregnant women who receive
Final CSR 30-Apr-2023
COVID-19 mRNA vaccine
submission:
Safety and immunogenicity of
COVID-19 mRNA vaccine in
pregnant women
C4591014 EU, US Estimate the effectiveness of 2 doses Not Applicable. Protocol draft 31-Mar-2021
Planned of COVID-19 mRNA vaccine submission:
against potential COVID‑19 illness
Final CSR 30-Jun-2023
requiring admission to the ED or
submission:
hospital where SARS-CoV-2 is
identified
BNT162-01 EU To assess potentially protective Use in immunocompromised patients. IA submission: 30-Sep-2021
Cohort 13 immune responses in
Ongoing immunocompromised adults
submission:
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name, and title)
Status
(planned/on-going)
C4591018 US Safety, immunogenicity over 12 Use in immunocompromised patients Protocol 28-Feb-2021
Planned months. Use in patient with autoimmune or inflammatory submission:
Description of COVID-19 cases. disorders. IA submission: 31-Dec-2021
RA activity by Clinical Disease
Activity Index.
N-antigen antibodies for detection of
asymptomatic infection.
Safety and EU, US Safety, immunogenicity over 12 Use in frail patients with co-morbidities (e.g, chronic Protocol 30-Jun-2021
immunogenicity in months in frail elderly, obstructive pulmonary disease (COPD), diabetes, chronic submission:
high risk adults immunocompromised, autoimmune neurological disease, cardiovascular disorders). Final CSR 31-Dec-2022
Planned and other high-risk individuals. submission:
Description of COVID-19 cases.
N-antigen antibodies for detection of
ACCESS/VAC4EU EU Assessment of occurrence of safety Anaphylaxis Protocol 28-Feb-2021
Planned events of interest, including severe or AESI-based safety events of interest including vaccine submission:
atypical COVID-19 in real-world use associated enhanced disease Final CSR 31-Jan-2024
of COVID-19 mRNA vaccine.
Use in pregnancy submission:
obstructive pulmonary disease (COPD), diabetes, chronic
Use in patients with autoimmune or inflammatory
disorders
Long term safety data.
Co-administration Not Safety and immunogenicity of Interaction with other vaccines. Protocol 30-Sep-2021
study with seasonal available BNT162b2 and quadrivalent submission:
influenza vaccine seasonal influenza vaccine when
Planned administered separately or
submission:
concomitantly.
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PART IV. PLANS FOR POST AUTHORISATION EFFICACY STUDIES

None.
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PART V. RISK MINIMISATION MEASURES (INCLUDING EVALUATION OF

THE EFFECTIVENESS OF RISK MINIMISATION ACTIVITIES)
RISK MINIMISATION PLAN
The safety information in the proposed product information is aligned to the reference
medicinal product.
V.1. Routine Risk Minimisation Measures

The product information is sufficient to mitigate the current identified and potential risks of
COVID-19 mRNA vaccine. The necessary information to ensure appropriate use of the
product is included in the relevant sections of the SmPC. No additional measures for risk
minimisation are considered necessary by the MAA at this time. The proposed minimisation
measures are summarised in the table below for each safety concern.
Table 29. Description of Routine Risk Minimisation Measures by Safety Concern

Safety Concern Routine risk minimisation activities
Important Identified Risk
Anaphylaxis Routine risk communication:
SmPC section 4.4 Special warnings and precautions for use and
section 4.8 Undesirable effects.
Routine risk minimisation activities recommending specific clinical
measures to address the risk:
None.
Other routine risk minimisation measures beyond the Product
Information:
None.
Important Potential Risk
Vaccine-associated enhanced disease Routine risk communication:
(VAED) including Vaccine- None.
associated enhanced respiratory
disease (VAERD)
None.
Information:
None.
Missing Information
Use in pregnancy and while breast Routine risk communication:
feeding SmPC section 4.6 Fertility, pregnancy and lactation
PL section 2. What you need to know before you receive Comirnaty
None.
Information:
None.
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Table 29. Description of Routine Risk Minimisation Measures by Safety Concern

Use in immunocompromised patients Routine risk communication:
SmPC section 4.4 Special warnings and precautions for use and
section 5.1 Pharmacodynamic properties.
None.
Information:
None.
Use in frail patients with co- Routine risk communication:
morbidities (e.g. chronic obstructive SmPC section 5.1 Pharmacodynamic properties.
pulmonary disease (COPD), diabetes,
chronic neurological disease,
None.
Information:
None.
Use in patients with autoimmune or Routine risk communication:
inflammatory disorders None.
None.
Information:
None.
Interaction with other vaccines Routine risk communication:
SmPC section 4.5 Interaction with other medicinal products and
other forms of interaction
None.
Information:
None.
Long term safety data Routine risk communication:
None.
None.
Information:
None.
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V.2. Additional Risk Minimisation Measures Risk Minimisation Measures

Routine risk minimisation activities as described in Part V.1 are sufficient to manage the
safety concerns of the medicinal product.
V.3. Summary of Risk Minimisation Measures

Activities by Safety Concern
Safety Concern Risk Minimisation Measures Pharmacovigilance Activities
Anaphylaxis Routine risk minimisation Routine pharmacovigilance activities beyond

measures: adverse reactions reporting and signal
SmPC sections 4.4. and 4.8. detection:
DCA is intended to facilitate the capture of
Additional risk minimisation clinical details about potential anaphylactic
measures: reactions in individuals who have received the
None. COVID-19 mRNA vaccine (cross. Ref with
Section III.1).
Additional pharmacovigilance activities:

Studies (Final CSR Due Date):
 C4591001 (31-Aug-2023)
 C4591010 (31-Mar-2024)
 C4591011 (31-Dec-2023)
 C4591012 (31-Dec-2023)
 ACCESS/VAC4EU (31-Jan-2024).
Vaccine-associated Routine risk minimisation Routine pharmacovigilance activities beyond
enhanced disease measures: adverse reactions reporting and signal
(VAED) including None. detection:
Vaccine-associated DCA is intended to facilitate the capture of
enhanced respiratory Additional risk minimisation clinical details about the nature and severity of
disease (VAERD) measures: COVID-19 illness in individuals who have
No risk minimisation measures. received the COVID-19 mRNA vaccine and is
anticipated to provide insight into potential
cases of vaccine lack of effect or VAED
(cross. Ref with Section III.1).

Studies (Final CSR Due Date)
 C4591001 (31-Aug-2023)
 C4591011 (31-Dec-2023)
 C4591012 (31-Dec-2023)
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Use in pregnancy and Routine risk minimisation Routine pharmacovigilance activities beyond
while breast feeding measures: adverse reactions reporting and signal
SmPC section 4.6; PL section 2. detection:
None.
Additional risk minimisation
measures:
No risk minimisation measures.
Studies (Final CSR Due Date)
 C4591010 a(31-Mar-2024)
 C4591011 a(31-Dec-2023)
 C4591015 (30-Apr-2023)
 ACCESS/VAC4EU a (31-Jan-2024).
Use in Routine risk minimisation Routine pharmacovigilance activities beyond
immunocompromised measures: adverse reactions reporting and signal
patients SmPC sections 4.4 and 5.1. detection:
None.
measures:
Studies (Final CSR or IA Due Date)
 BNT162-01 Cohort 13 (IA: 30-Sep-2021,
CSR: 31-Dec-2022)
 C4591018 (IA: 31-Dec-2021)
 C4591011 (31-Dec-2023)
 C4591012 (31-Dec-2023)
Use in frail patients with Routine risk minimisation Routine pharmacovigilance activities beyond
co-morbidities (e.g. measures: adverse reactions reporting and signal
chronic obstructive SmPC section 5.1. detection:
pulmonary disease None.
(COPD), diabetes, Additional risk minimisation
chronic neurological measures: Additional pharmacovigilance activities:
disease, cardiovascular No risk minimisation measures. Studies (Final CSR Due Date submission)
disorders)  C4591001 subset (31-Aug-2023)
 C4591011 (31-Dec-2023)
 C4591012 (31-Dec-2023)
 ACCESS/VAC4EU (31-Jan-2024)
 Safety and immunogenicity in high risk
adults (31-Dec-2022).
Use in patients with Routine risk minimisation Routine pharmacovigilance activities beyond
autoimmune or measures: adverse reactions reporting and signal
inflammatory disorders None. detection:
None.
measures: Additional pharmacovigilance activities:
No risk minimisation measures.  C4591011 (31-Dec-2023)
 C4591012 (31-Dec-2023)
 C4591018 (31-Dec-2021)
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Interaction with other Routine risk minimisation Routine pharmacovigilance activities beyond
vaccines measures: adverse reactions reporting and signal
SmPC section 4.5. detection:
None.
No risk minimisation measures.  Co-administration study with seasonal
influenza vaccine (31-Dec-2022).
Long term safety data Routine risk minimisation Routine pharmacovigilance activities beyond
measures: adverse reactions reporting and signal
None. detection:
None.
No risk minimisation measures. Studies (Final CSR Due Date or IA CSR
submission)
 C4591001 (31-Aug-2023)
 C4591010 (31-Mar-2024)
 C4591011 (31-Dec-2023)
 C4591012 (31-Dec-2023)
a. Please note that studies C4591010, C4591011 and ACCESS/VAC4EU address only “Use in pregnancy”.
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PART VI. SUMMARY OF THE RISK MANAGEMENT PLAN

Summary of risk management plan for Comirnaty.
This is a summary of the risk management plan (RMP) for Comirnaty. The RMP details
important risks of Comirnaty, how these risks can be minimised, and how more information
will be obtained about Comirnaty's risks and uncertainties (missing information).
Comirnaty's summary of product characteristics (SmPC) and its package leaflet give essential
information to healthcare professionals and patients on how Comirnaty should be used.
This summary of the RMP for Comirnaty should be read in the context of all this information
including the assessment report of the evaluation and its plain-language summary, all which
is part of the European Public Assessment Report (EPAR).
Important new concerns or changes to the current ones will be included in updates of
Comirnaty's RMP.
I. The Medicine and What It Is Used For

Comirnaty is a vaccine for active immunisation to prevent COVID-19 caused by SARS-
CoV-2 virus, in individuals 16 years of age and older. (see SmPC for the full indication). It
contains nucleoside-modified messenger RNA encapsulated in lipid nanoparticles as the
active substance and it is given intramuscularly.
Further information about the evaluation of Comirnaty’s benefits can be found in

Comirnaty’s EPAR, including in its plain-language summary, available on the EMA website,
under the medicine’s webpage www.ema.europa.eu/en/medicines/human/EPAR/comirnaty .
II. Risks Associated With the Medicine and Activities to Minimise or Further
Characterise the Risks
Important risks of Comirnaty, together with measures to minimise such risks and the
proposed studies for learning more about Comirnaty's risks, are outlined below.
Measures to minimise the risks identified for medicinal products can be:
 Specific Information, such as warnings, precautions, and advice on correct use, in the
package leaflet and SmPC addressed to patients and healthcare professionals;
 Important advice on the medicine’s packaging;
 The authorised pack size — the amount of medicine in a pack is chosen so to ensure
that the medicine is used correctly;
 The medicine’s legal status — the way a medicine is supplied to the patient (e.g. with
or without prescription) can help to minimise its risks.
Together, these measures constitute routine risk minimisation measures.
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In addition to these measures, information about adverse events is collected continuously and
regularly analysed, including PSUR assessment so that immediate action can be taken as
necessary. These measures constitute routine pharmacovigilance activities.
If important information that may affect the safe use of Comirnaty is not yet available, it is
listed under ‘missing information’ below.
II.A List of Important Risks and Missing Information

Important risks of Comirnaty are risks that need special risk management activities to further
investigate or minimise the risk, so that the medicinal product can be safely administered.
Important risks can be regarded as identified or potential. Identified risks are concerns for
which there is sufficient proof of a link with the use of Comirnaty. Potential risks are
concerns for which an association with the use of this medicine is possible based on available
data, but this association has not been established yet and needs further evaluation. Missing
information refers to information on the safety of the medicinal product that is currently
missing and needs to be collected (e.g. on the long-term use of the medicine).
Table 31. List of Important Risks and Missing Information

Important identified risks Anaphylaxis
Important potential risks Vaccine-associated enhanced disease (VAED) including Vaccine-
associated enhanced respiratory disease (VAERD)
Missing information Use in pregnancy and while breast feeding
II.B Summary of Important Risks

The safety information in the proposed Product Information is aligned to the reference.
Table 32. Important Identified Risk: Anaphylaxis

Evidence for linking the Events of anaphylaxis have been reported.
risk to the medicine
Risk factors and risk Known allergy to the vaccine or its ingredients.
groups
Risk minimisation Routine risk minimisation measures
measures SmPC sections 4.4. and 4.8.
Additional risk minimisation measures:
None.
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Table 32. Important Identified Risk: Anaphylaxis

Additional Additional pharmacovigilance activities:
pharmacovigilance  C4591001
activities  C4591010
 C4591011
 C4591012
 ACCESS/VAC4EU
See section II.C of this summary for an overview of the post-authorisation
development plan.
Table 33. Important Potential Risk: Vaccine-associated enhanced disease (VAED)

including Vaccine-associated enhanced respiratory disease (VAERD)
Evidence for linking the VAED is considered a potential risk because it has not been seen in human
risk to the medicine studies with this or other COVID-19 vaccines being studied. It has not been
seen in vaccine studies in animal models of the SARS-CoV-2 virus either.
However, in selected vaccine studies in animal models as well as in some
laboratory studies in animal cells infected with 2 other related coronaviruses
(SARS-CoV-1 and MERS-CoV), abnormalities in immune responses or cellular
responses indicative of VAED were observed. Because of this, VAED is
considered a potential risk. In the past there have been other examples of
particularly respiratory viruses where VAED has been observed. For example,
some children who received an inactivated respiratory syncytial virus vaccine (a
different type of virus), had worse signs of disease when they were subsequently
infected with respiratory syncytial virus.
VAED is thought to occur by several mechanisms where the immune response is
not fully protective and actually either causes the body to have an inflammatory
reaction due to the type of immune response with specific types of T-cells, or the
body does not produce enough strong antibodies to prevent SARS-CoV-2
infection of cells or produces weak antibodies that actually bind to the virus and
help it to enter cells more easily, leading to worse signs of disease.
Risk factors and risk It is thought that the potential risk of VAED may be increased in individuals
groups producing a weak antibody response or in individuals with decreasing immunity
over time.
Risk minimisation Routine risk minimisation measures
measures None.
None.
 C4591012
 ACCESS/VAC4EU
development plan.
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Table 34. Missing Information: Use in pregnancy and while breast feeding
Risk minimisation Routine risk minimisation measures:
measures SmPC section 4.6; PL section 2.
pharmacovigilance  C4591010 a
activities  C4591011 a
 C4591015
 ACCESS/VAC4EU
development plan.
a. Please note that studies C4591010, C4591011 and ACCESS/VAC4EU address only “Use in pregnancy”.
Table 35. Missing Information: Use in immunocompromised patients

measures SmPC sections 4.4 and 5.1.
pharmacovigilance  BNT162-01 cohort 13
 C4591011
 C4501012
 ACCESS/VAC4EU.
development plan.
Table 36. Missing Information: Use in frail patients with co-morbidities (e.g.
chronic obstructive pulmonary disease (COPD), diabetes, chronic
measures SmPC section 5.1.
pharmacovigilance  C4591001 subset
 C4501012
 ACCESS/VAC4EU
 Safety and immunogenicity in high risk adults
development plan.
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Table 37. Missing Information: Use in patients with autoimmune or inflammatory

disorders
measures None.
 ACCESS/VAC4EU
 C4591018
development plan.
Table 38. Missing Information: Interaction with other vaccines

measures SmPC section 4.5.
pharmacovigilance  Co-administration study with seasonal influenza vaccine
activities
development plan.
Table 39. Missing Information: Long term safety data

measures None.
 C4591011
 C4591012
 ACCESS/VAC4EU
development plan.
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II.C Post-Authorisation Development Plan

II.C.1 Studies which are Conditions of the Marketing Authorisation
Study Purpose of the study
C4591001 The objective of the study is to evaluate the safety, tolerability,
immunogenicity and efficacy of COVID-19 mRNA vaccine.
An unfavorable imbalance between the vaccine and control groups in the
frequency of COVID-19, in particular for severe COVID-19, may suggest the
occurrence of vaccine associated enhanced disease. Surveillance is planned
for 2 years following Dose 2.
II.C.2 Other Studies in Post-Authorisation Development Plan

Study Purpose of the study
C4591011 Assessment of occurrence of safety events of interest, including severe or
atypical COVID-19 in a cohort of people within the Department of Defense
Healthcare System.
C4591012 Assessment of occurrence of safety events of interest, including severe or
atypical COVID-19 in real-world use of COVID-19 mRNA vaccine.
C4591010 Assessment of occurrence of safety events in real-world use of COVID-19
mRNA vaccine.
C4591015 Planned clinical study to assess safety and immunogenicity in pregnant
women who receive COVID-19 mRNA vaccine.
Safety and immunogenicity of COVID-19 mRNA vaccine in pregnant
women.
C4591014 Estimate the effectiveness of 2 doses of COVID-19 mRNA vaccine against
potential COVID‑19 illness requiring admission to the ED or hospital where
SARS-CoV-2 is identified.
BNT162-01 To assess potentially protective immune responses in immunocompromised
Cohort 13 adults.
C4591018 Safety, immunogenicity over 12 months; description of COVID-19 cases;
rheumatoid arthritis activity by Clinical Disease Activity Index; N-antigen
antibodies for detection of asymptomatic infection.
Safety and Safety, immunogenicity over 12 months in frail elderly,
immunogenicity in immunocompromised, autoimmune and other high-risk individuals;
high risk adults description of COVID-19 cases; N-antigen antibodies for detection of
ACCESS/ Assessment of occurrence of safety events of interest, including severe or
VAC4EU atypical COVID-19 in real-world use of COVID-19 mRNA vaccine.
Co-administration Safety and immunogenicity of BNT162b2 and quadrivalent seasonal
study with seasonal influenza vaccine when administered separately or concomitantly.
influenza vaccine
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PART VII. ANNEXES TO THE RISK MANAGEMENT PLAN

Table of contents
Annex 2 – Tabulated summary of planned, on-going, and completed pharmacovigilance

study programme
Annex 3 – Protocols for proposed, on-going, and completed studies in the pharmacovigilance
plan
Annex 4 – Specific Adverse Drug Reaction Follow- Up Forms
Annex 5 – Protocols for proposed and on-going studies in RMP Part IV
Annex 6 – Details of Proposed Additional Risk Minimisation Activities (if applicable)
Annex 7 – Other Supporting Data (Including Referenced Material)
Annex 8 – Summary of Changes to the Risk Management Plan over Time
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Vogel AB, Kanevsky I, Che Ye, et al. A prefusion SARS-CoV-2 spike RNA vaccine is
highly immunogenic and prevents lung infection in non-human primates. bioRxiv
2020.09.08.280818.
CONFIDENTIAL
Page 107
Pfizer-BioNTech COVID-19 Vaccine Data Capture Aid
Instructions for use:

This Data Capture Aid (DCA) is intended to capture the available clinical details about the nature and severity of COVID-19 illness
experienced, particularly in relation to potential cases of vaccine lack of effect or vaccine associated enhanced disease (VAED).
Select questions as needed to obtain any DCA-defined information described below that was not included in the initial report.
AER/Manufacturer Report #: ____________________

Suspect product: ____________________
Reported event term prompting special follow-up activities: ____________________
AE onset date (dd-Mmm-yyyy): ____________________
Patient Age (e.g., 65 years): _________________
Patient Gender: Male Female Not Stated
Race: White Black or African American Native American Alaska Native Native Hawaiian Asian Other
Refused or Don’t Know
Ethnic Group: Hispanic/LatinX Non-Hispanic/Non-LatinX
Reporter Information
Name of reporter completing this form (If other than addressee, provide contact information below):
Phone Number: Fax Number: Email Address:
1. Product information (Pfizer-BioNTech COVID-19 Vaccine)
Date Site of injection Route Batch/Lot number

Dose
(dd-Mmm-yyyy)
1st dose
2nd dose
PFIZER GENERAL BUSINESS

The official version of this form is located in the electronic document management system.
Page 1 of 6 Page 114
CONFIDENTIAL
Follow-up Questions
Please provide additional details on a separate page if needed and reference the question number.
1. Does the patient have a positive test for SARS-CoV2? 2. Does the patient have SARS-CoV2 antibodies at diagnosis?
Unknown No Yes  If Yes, please provide details Unknown No Yes  If Yes, please provide details
(and indicate if this is a new infection or a recurrence) Details: (Please specify date of test, whether IgM /IgG or both and the titer if
Details: (Please specify date of test and type of test – e.g., nasal available)
swab reverse transcription–polymerase chain reaction (RT-PCR) test
or nucleic acid amplification–based test (NAAT) or antigen test)
3. Was/Is the patient hospitalized? 4. Was/Is the patient admitted to an Intensive Care Unit?
Unknown No Yes  If Yes, please provide details Unknown No Yes  If Yes, please provide details (e.g.,
(e.g., duration of hospitalization) duration of hospitalization)
Details: Details:
5. Is the patient still hospitalized? 6. If discharged, did the patient have SARS-CoV2 antibodies
Unknown No Yes  If Yes, please provide details at hospital discharge?
(e.g., duration of hospitalization) Unknown No Yes  If Yes, please provide details
Details: Details: (Please specify date of test, whether IgM /IgG or both and the titer if
available)
7. Did the patient display clinical signs at rest indicative 8. Did the patient require supplemental oxygen (including
of severe systemic illness? high flow or ECMO) or receive mechanical ventilation?
Unknown No Yes  If Yes, please provide details Unknown No Yes  If Yes, please provide details (e.g.,
(e.g., Fever, RR ≥30 breaths per minute, HR ≥125 beats per minute, oxygen requirements, pulse oximetry results)
use of vasopressors to maintain BP, SpO2 ≤93% on room air, Details:
PaO2/FiO2 <300 mm Hg)?)
Details:
9. Please provide information on any new or worsened symptoms/signs during the COVID-19 illness experienced (including
date of onset/worsening)
Multiorgan failure Unknown No Yes  If Yes, please indicate which organ systems were affected and provide
information on the applicable systems below
Respiratory Cardiovascular Gastrointestinal/Hepatic Vascular Renal Neurological Hematological Dermatological

Other

CONFIDENTIAL
Respiratory Unknown No Yes  If Yes, please provide details

Dyspnea Unknown No Yes  If Yes, please provide details
Tachypnea Unknown No Yes  If Yes, please provide details
Hypoxemia Unknown No Yes  If Yes, please provide details
COVID-pneumonia Unknown No Yes  If Yes, please provide details
Respiratory failure Unknown No Yes  If Yes, please provide details
Acute Respiratory Distress Syndrome (ARDS) Unknown No Yes  If Yes, please provide details
Other Unknown No Yes  If Yes, please provide details
Details:
Cardiovascular Unknown No Yes  If Yes, please provide details

Heart failure Unknown No Yes  If Yes, please provide details
Cardiogenic shock Unknown No Yes  If Yes, please provide details
Acute myocardial infarction Unknown No Yes  If Yes, please provide details
Arrhythmia Unknown No Yes  If Yes, please provide details
Myocarditis Unknown No Yes  If Yes, please provide details
Details:
Gastrointestinal/Hepatic Unknown No Yes  If Yes, please provide details

Vomiting Unknown No Yes  If Yes, please provide details
Diarrhea Unknown No Yes  If Yes, please provide details
Abdominal pain Unknown No Yes  If Yes, please provide details
Jaundice Unknown No Yes  If Yes, please provide details
Acute liver failure Unknown No Yes  If Yes, please provide details
Details:
Vascular Unknown No Yes  If Yes, please provide details

Deep vein thrombosis Unknown No Yes  If Yes, please provide details
Pulmonary embolism Unknown No Yes  If Yes, please provide details
Limb ischemia Unknown No Yes  If Yes, please provide details
Vasculitis Unknown No Yes  If Yes, please provide details
Other (in particular any other thromboembolic events) Unknown No Yes  If Yes, please provide details
Details:
Renal Unknown No Yes  If Yes, please provide details

Acute kidney injury Unknown No Yes  If Yes, please provide details
Renal failure Unknown No Yes  If Yes, please provide details
Details:
Neurological Unknown No Yes  If Yes, please provide details
Altered consciousness Unknown No Yes  If Yes, please provide details

CONFIDENTIAL
Convulsions/seizures Unknown No Yes  If Yes, please provide details

Encephalopathy Unknown No Yes  If Yes, please provide details
Meningitis Unknown No Yes  If Yes, please provide details
Cerebrovascular accident Unknown No Yes  If Yes, please provide details and indicate if ischemic or hemorrhagic
Details:
Hematological Unknown No Yes  If Yes, please provide details

Thrombocytopenia Unknown No Yes  If Yes, please provide details (see also Q14)
Disseminated intravascular coagulation Unknown No Yes  If Yes, please provide details (see also Q14)
Details:
Dermatological Unknown No Yes  If Yes, please provide details

Chillblains Unknown No Yes  If Yes, please provide details
Erythema multiforme Unknown No Yes  If Yes, please provide details
Details:
OTHER (e.g. multisystem inflammatory syndrome [MIS]) Unknown No Yes  If Yes, please provide details
Details:
10. Did the patient receive any additional therapies for COVID-19?
Date Started Date Stopped

Therapy Dose/Any additional information
(dd-Mmm-yyyy) (dd-Mmm-yyyy)
 Remdesivir
 Hydroxychloroquine/chloroquine
 Azithromycin
 Corticosteroids
 Other (Please Specify)
11. Did the event require the initiation of new medication or other treatment or procedure?
Unknown No Yes  If Yes, please provide details
Details:

CONFIDENTIAL
12. Patient’s outcome with COVID-19:

Recovering Recovered Not recovered Unknown Fatal, Date (dd-Mmm-yyyy): …………………….
If outcome is fatal, was an autopsy performed? Unknown No Yes  If Yes, please provide autopsy findings
Details:
13. How many days from the SARS-CoV2 diagnosis did it take before the SARS-CoV2 antigen test became negative?
14. Were any of the following laboratory tests or diagnostic studies performed? Please specify laboratory data with units, date
of test, and reference ranges; and please provide printouts and photographs if available:
Date Performed Reference Ranges, if applicable (or
Results with units, if
Laboratory Test or Diagnostic Studies please state if abnormal or
(dd-Mmm-yyyy) applicable
elevated/reduced)
Test for SARS-CoV-2 by PCR, or other
commercial or public health assay
Imaging for COVID-Pneumonia
(e.g.CXR, CT)
Other radiological investigations (e.g.

MRI, angiogram, V/Q scan)
Imaging for thrombo-embolic events (e.g.

doppler or CT)
Hematology (e.g. leucocyte count

[including neutrophil and lymphocyte
counts], hemoglobin, platelet count,
coagulation parameters [PT, PTT, D-
Dimer, INR], fibrinogen, B and T cell
function assays)
Clinical chemistry (e.g. serum creatinine,
glomerular filtration rate [GFR], liver
enzymes, bilirubin, albumin, B-type
natriuretic peptide [BNP], troponin)
Inflammatory markers (e.g. CRP, ESR,
procalcitonin, ferritin, LDH, cytokines
[including IL-6])
Urinalysis
Evidence of hypoxemia (e.g. PaO2/FiO2

[P/F ratio], SpO2/FiO2 [S/F ratio]),
hypercapnia (PaCO2) or acidosis (pH)
Other relevant tests (please
specify):______________

CONFIDENTIAL
Past Medical History Questions

Please provide additional details on a separate page if needed and reference the question number.
15. Does the patient have a history of any of the following? 16. Is the patient a smoker/former smoker?
Hypertension Current Smoker Former smoker No
Diabetes
Details:
Heart Disease (please specify)
Lung Disease (please specify)
Liver disease (please specify)
Kidney disease (please specify)
Cancer (please specify)
Immunosuppressive disorder (please specify)
Obesity
Other (please specify)
Details:
17. Was the patient taking any medications routinely prior to the event being reported?
Details:
18. Have any pre-existing diseases worsened during the SARS-CoV2 infection (please specify)
Details:
19. Has the patient been treated with immunomodulating or immunosuppressing medications or received any other vaccines
around the time of COVID-19 vaccination?
Details:
Revision History
Revision Effective Date Summary of Revisions
1.0 07-Dec-2020 New DCA

CONFIDENTIAL

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COVID-19 mRNA VACCINE

RISK MANAGEMENT PLAN (RMP)

For a summary of the RMP, please refer to PART VI.

RMP Version number: 1.0

Data lock point for this RMP: 17 December 2020

Date of final sign off: 21 December 2020

Summary of significant changes in this RMP:

RMP Part/Module Major Change (s)

RMP Part/Module Major Change (s)

RMP Part/Module Major Change (s)

Other RMP versions under evaluation:

QPPV name1: Barbara De Bernardi

Abbreviation Definition of Term

PART III. PHARMACOVIGILANCE PLAN (INCLUDING POST-

Table 25. Long term safety data..........................................................................................72

PART I. PRODUCT(S) OVERVIEW

Pharmacotherapeutic group(s) Not yet assigned

Marketing Authorisation Applicant BioNTech Manufacturing GmbH

Medicinal products to which this 1

Invented name(s) in the European Comirnaty

Dosage in the EEA Proposed:

PART II. SAFETY SPECIFICATION

Active immunisation to prevent COVID-19 caused by SARS-CoV-2 virus, in individuals

Estimates of SARS-CoV-2 incidence change rapidly. As of 9 November 2020, the overall

Figure 1. Age-Gender distribution of COVID-19 Cases as Different Levels of Severity,

Table 1. Distribution and Estimated Cumulative Incidence of Reported

The main existing treatment options:

Natural history of the indicated condition in the untreated population, including

Approximately 17% to 40% of those hospitalized with COVID-19 experience severe

Important comorbidities in hospitalized COVID-19 patients include hypertension, diabetes,

Table 2. Preconditions among COVID-19 Patients in EU/EEA and UK, by Severity

Module SII. Non-Clinical Part of the Safety Specification

Administration of up to 100 µg COVID-19 mRNA vaccine by IM injection to male and

In summary, the nonclinical safety findings related to COVID-19 mRNA vaccine

Table 3. Key Safety Findings and Relevance to Human Usage

Module SIII. Clinical Trial Exposure

Phase 1 of Study C4591001 comprised dose-level–finding evaluations of the 2 selected

 21,937 participants were exposed to BNT162b2 (COVID-19 mRNA vaccine), including

 21,797 participants were exposed to PLACEBO (none from study BNT162-01).

 C4591001: Phase 1/2/3, placebo-controlled, observer-blind, dose-finding, study to

Exposure to COVID-19 mRNA vaccine for participants in 2 ongoing studies by number of

In addition, exposure in clinical studies in special populations is provided in Table 16.

Table 4. Exposure to BNT162b2 by Age Group and Dose (C4591001)

≥16 years to ≤17 years

≥18 years to ≤55 years

Table 4. Exposure to BNT162b2 by Age Group and Dose (C4591001)

Table 5. Exposure to BNT162b2 by Age Group and Dose (BNT162-01)

Table 5. Exposure to BNT162b2 by Age Group and Dose (BNT162-01)

Table 5. Exposure to BNT162b2 by Age Group and Dose (BNT162-01)

Age Group Number of Subjects Total Number of

≥12 years to ≤15 years

Note: 30 μg includes data from phase 1 and phase 2/3.

Table 7. Exposure to BNT162b2 by Dose (Totals) (C4591001)

Dose Number of Subjects Total Number of

Note: 30 μg includes data from phase 1 and phase 2/3.

Table 8. Exposure to BNT162b2 by Dose (Totals) (BNT162-01)

Table 8. Exposure to BNT162b2 by Dose (Totals) (BNT162-01)

Table 9. Exposure to BNT162b2 by Dose, Age Group, and Gender (C4591001)

Number of Subjects Exposed to BNT162b2 Total Number of Vaccine Doses