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BNT162b2
BLA STN 125742 /0
M 1.11.3 Response to FDA Information Request
PFIZER CONFIDENTIAL
Page 1BNT162b2 (COMIRNATY)
BLA STN 125742/0
Response to CBER 10 August 2021 Information R equest Regarding Post- marketing
Safety Studies
August 2021
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M 1.11.3 Response to FDA Information Request
PFIZER CONFIDENTIAL
Page 2TABLE OF CONTENTS
1. INTRODUCTION ................................ ................................ ................................ ................. 4
2. CBER REQUESTS AND SPONSOR RESPONSES ................................ ............................ 4
2.1. CBER Request 1................................ ................................ ................................ ........ 4
2.2. CBER Request 2................................ ................................ ................................ ........ 6
2.3. CBER Requ est3................................ ................................ ................................ ........ 7
2.4. CBER Request 4................................ ................................ ................................ ........ 7
2.5. CBER Requ est5................................ ................................ ................................ ........ 8
2.6. CBER Request 6................................ ................................ ................................ ........ 8
2.7. CBER Request 7................................ ................................ ................................ ......10
3. APPENDI CES ................................ ................................ ................................ ..................... 12
3.1. Appendix 1 ................................ ................................ ................................ .............. 12
3.2. Appendix 2 ................................ ................................ ................................ .............. 15
4. REFERENCES ................................ ................................ ................................ .................... 16
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Page 3List of Abbreviations and Definitions of Terms
Abbreviation Definition
AESI Adverse events of special interest
CI Confidence interval
DSMB Data Safety Monitoring Board
IRB Institutional Review Board
IRR Incidence rate ratio
PHN Pediatric Heart Netw ork
RR Relative risk
SAP Statistical Analysis Plan
SCCS Self-controlled case series
SCRI Self-controlled risk interval
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Page 41.INTRODUCTION
Reference is made to BLA STN 125742/0 for COVID- 19 mRNA Vaccine (COMI RNATY ),
for active immunization to prevent COVID -19 caused by SARS -CoV -2 in individuals
≥16years of age and to CBER’s Information Request received via email on 10August 2021 .
CBER requests are presented in bold italics followed b y Pfizer -BioNTech response in plain
text.
2.CBER REQUESTS AND SPONSOR RESPONSES
Our review of your pharmacovigilance plan for COMIRNATY (COVID- 19 V accine,
mRNA) under BLA 125742 is ongoing. We are reviewing your response (submitted in
amendment 30 dated August 3, 2021) to our July 28, 20 21 information request regarding
postmarketing safety studies, and have the following comments:
2.1. CBER Request 1
1.The primary analysis in the post -authorization safety study C4591009 protocol synopsis
uses a concurrent unexposed cohort. People without vaccination codes could receive
their COVID vaccinations outside of the system, and exposure misclassification could
bias the results. The self -controlled methods such as self -controlled risk interval
(SCRI) are less susceptible to bias due to exposure misclassification. SCRI with a post -
vaccination control window was proposed as a sensitivity analysis.
Please clarify how you plan to assess the magnitude of exposure misclassification for
the concurrent unexposed cohort and quantify the bias. If the magnitude of the
exposure misclassification is large, please consider using the SCRI as the primary
analysis. The proposed SCRI control window has the same length as the risk interval,
which ma y decrease the risk of time -varying confounding bias but could result in more
limited person time for some AESIs thus impacting the power of the SCRI analysis.
Since SCRI allows the control window to have a different length than the risk window,
please con sider using a longer control window (e.g., multiples of the risk window) in
the primary analysis, while maintaining the shorter control window for a sensitivity
analysis. Please provide length of risk interval for each AESI.
Sponsor Response
Exposure miscl assification is an important consideration for the stud y and this risk will be
addressed in the pre -specified feasibility assessment, which is described in the full protocol
(to be submitted to the agency by Aug ust31, 2021). In Section 9.3.1 of the protoc ol, we
state: “The completeness of exposure data will be assessed in monitoring analy ses before the
end of the stud y by comparing with publicly available estimates of vaccine coverage and/or
estimates based on immunization registry data from select states (if available); if the
coverage estimates differ meaningfully from the “benchmarking” estimates (meaningful
difference to be defined in the Statistical Analy sis Plan [ SAP]), then modifications to the
study approach may be considered. If this happens, the S CRI and the cohort design with
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Page 5historical unexposed comparators may be designated as the primary study designs and/or
linkage to immunization registries may be considered if feasible.”
The length of the control window in the SCRI analy ses will be assessed separatel y for each
outcome. As per Section 9.7.3.1.1, “The control interval will be outcome specific, with the
duration and timing relative to vaccination specified in more detail in the SAP. Control
intervals will be defined during specific periods follo wing vaccination (up to a maximum of
183 day s); pre -vaccination periods will not be used to avoid bias due to healthy vaccinee
effects.”
The risk intervals for each safet y event of interest will be provided in Section 9.3.2.1 of the
full protocol (to be su bmitted to the agency by Aug ust31, 2021). For convenience, Table A
below provides the risk intervals that are described in the protocol .
Table A. General Safety Events to be Assessed in the General Population,
Immunocompromised Individuals, Individuals w ith a History of COVID -19, and
Pregnant Women
Organ System Safety E vent of Interest Risk window (days
following receipt of Pfizer -
BioNTech COVID- 19
Vaccine)a
Neurologic Acute disseminated encephalomyelitis 1-42
Bell’s palsy 1-42
Convulsions 1-42
Encephalomyelitis/encephalitis 1-42
Guillain -Barré syndrome 1-42
Narcolepsy 1-180
Transverse myelitis 1-42
Cardiac Acute myocardial infarction 1-28
Myocarditis/pericarditis 1-21b
Hem atologic Deep vein thrombosis 1-28
Disseminated intravascular coagulation 1-28
Immune hemolytic anemia 1-42
Immune thrombocytopenia 1-42
Pulmonary embolism 1-28
Thromboembolic events associated w ith
thrombocytopenia1-28
Thrombotic thrombocytopenic purpura 1-28
Venous thromboembolism 1-28
Hem orrhagic stroke 1-28
Ischemic stroke 1-28
Respiratory Acute respiratory distress syndrome 1-28
Vaccine -associated enhanced respiratory disease 1-365
Other system Anaphylaxis 0-1
Appendicitis 1-42
Kaw asaki Disease 1-42
Multisystem inflammatory syndrome 1-42
a.Time interval following vaccination when patients will be follow ed for safety events of interest. Day 0
refers to the day of vaccination.
b.Sensitivity analysis will assess alternative risk interval definit ions of 1 -7 days and 1 -14 days .
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Page 62.2. CBER Request 2
2. Table 1 on Page 5 of the Response to Information Request provided the required
number of cases to detect myocarditis under different assumptions with a self -
controlled case series (SCCS) analysis. The study C4591009 protocol synopsis proposed
a SCRI analysis. SCCS samples cases only, SCRI samples vaccinated individuals only,
and the control interval could differ between these two study designs even with the
same length of risk interval. Please clarify the len gth and definition of control interval
in the Table 1 sample size calculation. The choice of risk window is critical for SCRI.
Because the onset of myocarditis was typically within several days after mRNA
COV ID-19 vaccination, please add a 7 -day risk wind ow to the SCRI analysis in
addition to the proposed 14-day and 21- day risk window. Please also provide the
sample size calculation for a 7- day risk window for myocarditis.
For study C4591009 protocol synopsis, the sample size calculation on Page 14 was
based on a true RR=1. Please recalculate the sample size under alternative RRs.
Sponsor Response
We agree that the choice of risk window is critical and plan to conduct sensitivity anal yses
for the m yocarditis/pericarditis endpoint. The leng th of the control window in Table 1 in the
Response to I nformation Request (submitted on 03 August 2021) was assumed to be 2 y ears
(730 day follow up period) minus the risk window ; 709 day s for the 21- day risk window and
706 day s for the 14- day risk window . The required sample size for thisSCRI -based study is
similar to th at predicted in Table 1 ,which is based on the SCCS model ,because the control
window used in the model to determine sample size requirements includes the entire study
period outside of the ris k window rather than a shorter interval, e.g., matched to the duration
of the risk window as is often the case for SCRI -based studies .1 It is estimated that u sing a
7-day risk window, will increase sample size requirements compared to the 14 -day and
21-day risk window respectivel y by approximately 96% to 1.9 fold, given 80% power and
RR=2, for example. This reflects the fact that reducing the at -risk period results in the
expectation of an increased number of cases required for the SCCS design . As reque sted, a
7-day risk period will be incorporated into the protocols.
For stud y C4591009, the sample size calculation in the synopsis was based on a true RR=1
and 1:2 matching. Within the full protocol (to be submitted to the agency by Aug ust31,
2021), the m atching ratio is presented as 1:1 matching. Study size estimates for 1:1 matching
for true RR=1, 1.2 and 1.4 (estimated b y the incidence rate ratio [IRR]) are provided in
Appendix 1.
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Page 72.3. CBER Request 3
3. Please clarify when patient accrual will be completed for study C4591009.
Sponsor Response
Patient accrual for stud y C459100 9will be completed by June 30, 2024.
Given C451009 is a study of secondary data, at the time of data query for the final anal ysis,
all available patients meeting study inclusion criteria will be included. The planned date for
the data query is anticipated to occur during the 3rd quarter of 2024 (August or September
2024, contingent on data partner data refresh schedule and data quality review approval).
2.4. CBER Request 4
4.Please provide the study completion date (in mm/dd/yyyy format) for the following
studies:
a.C4591009
b.C4591022
c.C4591012
d.C459101 5
e.C4591021 an d C4591021 substudy
f.Registry study with Pediatric Heart Network (PHN)
Sponsor Response
The planned stud y completion date (date of end of data collection) for each post -marketing
safet y stud y is listed below. The sponsor assumes that the agency’s reference to “C4591015”
in item d. was intended to refer to study “C4591011”, as C4591015 is the phase 3 study in
pregnant women and not a post -marketing safet y study.
C4591009: 06/30/2025 (this date could be extended based on the extent of validation
activities a nd/or the need for immunization registry linkages)
C4591022: 08/01/2025
C4591012: 06/10/2023
C4591011: 06/10/2023
C4591021 and C4591021 substudy :9/30/2024
Registry study with Pediatric Heart Network (PHN): 12/01/2026
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Page 82.5. CBER Request 5
5.For the registry study with PHN, you have stated that you have identified
approximately 130 patients and plan to enroll additional patients. Please provide a
proposed sample size for this study, and the basis for the sample size calculation. You
have also proposed 1- year prospective follow -up. We request 5 years of follow -up to
capture potential long- term sequelae of myocarditis after vaccination.
Sponsor Response
This study will enroll patients <21 y ears of age who are diagnosed with vaccine -associated
myocarditis within the PHN during the study period and who fulfill study inclusion criteria
(yet to be determined, will include informed consent). A full I RB and DSMB approved
protocol will be shared with the agency by November 30, 2021 and will include sample size
estimates. The estimation of study size in the study protocol will require assumptions about
future approvals of vaccines, numbers of people vaccinated by age, gender, ty pe of vaccine
and dose, effects of each vaccine b y dose, number of participating PHN sites, etc. These
scenarios will be elaborated in a study protocol under preparation with our PHN
collaborators. We will plan for a 5 -year follow -up period. Feasibility discussions with our
PHN collaborators are ongoing; should any issues or unexpected challenges emerge, we will
inform the agency promptly .
2.6. CBER Request 6
6.Please provide the protocol synopses and current status for the study C4591021 and
C4591021 substudy.
Sponsor Response
Study protocol C4591021, Post Conditional Approval Active Surveillance Study Among
Individuals in Europe Receiving the Pfizer -BioNTech Coronavirus Disease 2019 (COVID -
19) Vaccine, was approved by the European Medicines Agency on 24June 2021, in
collaboration with the VAC4EU Consortium Team. The protocol is provided as requested
(Appendix 2).
A substudy ofC4591021 is planned to assess the natural history of post -vaccination my o-
/pericarditis, eg, recovery stat us (medical record review), risk factors, and/or identification of
serious cardiovascular outcomes (structured data) within 1 year of m yo-/pericarditis
diagnosis among individuals vaccinated with COMI RNATY as well as individuals not
vaccinated with a COVID-19 vaccine. A synopsis of the study is provided in Table B. This
substudy is still under development and subject to change based on data availability and
feedback from EMA . The study milestones are listed in Table B below. We will share the
final protocol with FDA following EMA endorsement .
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Page 9Table B. C4591021 Substudy Synopsis
Study title Post Conditional Approval Active Surveillance Study Among Individuals in Europe
Receiving the Pfizer -BioNTech Coronavirus Disease 2019 (COVID -19)
Vaccine (Myo-/pericarditis Substudy)
Research question What are the incidence rates/prevalence of myocarditis and pericarditis outcomes
among individuals vaccinated with the Pfizer -BioNTech COVID -19 vaccine within
selected European data sources compared to people who have not received the
vaccine?
Objectives Primary objective:
To describe the clinical course, for at least one year of follow -up,of Myocarditis
and/or Pericarditis following the administration of a tleast one dose of the Pfizer -
BioNTech COVID -19 vaccine and in individuals with no COVID -19
vaccination.
Secondary objective:
To explore risk factors for myocarditis and pericarditis.
Background The Pfizer -BioNTech COVID -19 vaccine, tozinameran ( Comirnaty®) has been
associated with the occurrence of myocarditis and/or pericarditis. Description of
occurrence and the natural course of these events is needed.
Study design This post -authorization active surveillance study of safety events of interes t
associated with the Pfizer -BioNTech COVID -19 vaccine will usea retrospective
cohort design involving multiple databases.
Within a retrospective cohort design on the safety of the Pfizer Vaccine, a cohort
study of the natural history of Myocarditis / P ericarditis w ill be performed
distinguishing between vaccinated and non -vaccinated subjects
Population The source population w ill comprise all individuals registered in each of the health
care data sources from the parent study C4591021 who meet the myo /peri carditis
case definition.
Inclusion criteria: subjects must meet Brighton Collaboration c ase
(https://brightoncollaboration.us/myocarditis -case-definition -update/). This will
create levels of certainty of the diagnosis.
Data availability for each institution might be affected by third parties or external
circumstances that are independent from the institution involved in the study as
described below in Section 9.9 of the attached approved C4591021 protocol .
Data sources The study will be performed within the following selected data sources:
PHARMO (PHARMO Institute for Drug Outcomes Research) (NL)
ARS Toscana (Agenzia Regionale di Sanita’ della Toscana) (IT)
Pedianet/Health Search Database (HSD) (IT)
EpiChron (EpiChron Research Group on Chronic Dis eases at the Aragon
Health Sciences Institute) (ES)
CPRD (Clinical Practice Research Datalink) (UK), the Norwegian health
registers (NO)
SIDIAP (Sistema d’Informació per el Desenvolupament de la Investigació
en Atenció Primària) [Information System for the Improvement of Research
in Primary Care] (ES)
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Page 10Table B. C4591021 Substudy Synopsis
Inform ation to be
collected at baselineDem ographics and clinical characteristics including comorbidities, comedications,
and concurrent vaccinations, risk factors for myocarditis and pericarditis including:
COVID -19 history, other vaccines, infectious disease comorbidities;
immunocompromising conditions and systemic immune -mediated diseases,
comedication use during the year before time zero (prescripti ons or dispensing, no
over-the-counter medication use).
Method of data
collectionStructured data and medical record review .
Study period The study period w ill start on the date of launch of the Pfizer -BioNTech COVID -19
vaccine and will end on the date of the latest data availability or 31 Dec 2023. It is
expected that follow -up will last for 1 year. Cohort entry: day of
myocarditis/pericarditis diagnosis (time zero)
Inform ation
collected at follow
upTreatments for myocarditis include: symptomatic treatment for viral myocarditis
based on clinical presentation, immunosuppression treatment for autoimmune
myocarditis, heart failure therapy (i.e., beta- blockers, diuretics, angiotensin -
converting enzyme (ACE) inhibitors or angiotensin -II receptor blocker s (ARBs),
aldosterone agonists, cardiac glycosides or calcium -channel blockers); procedural
treatment (i.e., pacemaker, implantable cardiac defibrillator, mechanical circulatory
support and heart transplantation.
Treatments for pericarditis include: Antimi crobial treatment, anti -inflammatory
treatment (Non -steroidal anti -inflammatory drugs (NSAIDs) and colchicine (for
recurrent pericarditis); procedural treatment (i.e., intrapericardial administration of
steroids, pericardioscopy for direct instillation of treatments into the pericardial
space, pericardial drainage. Subdiaphragmatic laparoscopic technique, video -assisted
thoracoscopic technique, and pericardioscopy to easy drainage of effusion,
pericardiocentesis, cardiac catheterisation during pericardiocen tesis, balloon
pericardial w indow form ation, instillation of sclerosing agents. Instillation of
fibrinolytic agents, pericardiectomy.
Outcomes for myocarditis include: recovery, sudden cardiac death, heart failure;
cardiogenic shock, fulminant myocarditis , inflammatory cardiomyopathy, heart
transplant, arrhythmia
Outcomes for pericarditis include: recovery, chronic, restrictive and recurrent
pericarditis
Study timelines and
milestone datesProtocol submission to EMA : 01/31/2022
Final report: 09/30/2024
2.7. CBER Request 7
7.You have proposed to analyze troponin I levels at a central laboratory in 3,000 samples
of stored sera (drawn <1 year ago) in 12 -30-year- old individuals participating in
BNT162b2 studies, prior to receipt of BNT162b2. We acknowledge that the results of
this analysis will help determine what sample size might be required for a prospective
study to assess the incidence of subclinical myocarditis following vaccination. Please
provide projected dates for the Final Protocol Submission, Study Co mpletion, and
Final Report Submission for a prospective study to assess the incidence of subclinical
myocarditis following vaccination.
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Page 11Sponsor Response
Reference is made to Pfizer- BioNTech’s response to the Agency regarding the risk of
myocarditis and per icarditis associated with the Pfizer BioNTech Vaccine submitted to
BB-IND 19,736 on 23 July 2021 (SN 0422).
Specificall y, we propose dto analy ze troponin I levels at a central laboratory in samples of
stored sera (drawn <1 year ago) in 12-30- year-old individuals participating in BNT162b2
studies, prior to receipt of BNT162b2 (ie ,either at baseline, or at any visit for placebo
recipient s). This is planned to include 3000 samples, stratified equally in the 12 -17-, 18-24-
and 25-30- years age groups. This sample size will provide 95% probability of observing one
abnormal result amongst the overall sample if the background rate of abnormalit y is 0.1%
andamongst each age stratum if the background rate is 0.3%. This was to enable us to
determine the background rate of abnormality of a potential non -invasive biomarker in the
relevant population. These data are critical to determining what sampl e size might be
required for a potential future clinical stud y to distinguish a true signal of cardiac findings in
the absence of compatible clinical signs and s ymptoms.
The current status of this work is as follows. A central laboratory that can perform the work
has been identified; contracting and logistical aspects are being prepared: 3000 appropriate
samples need to be identified, retrieved from frozen storage, aliquoted and shipped to the
central laboratory . The samples then need to be analy zed and the data anal yzed and
interpreted. This work is anticipated to be completed by the end of December 2021.
Furthermore, in a response to the Agency ’srecommend ation tocollect and store blood
samples during the time period when s ymptomatic my ocarditis cases have most frequently
been reported (ie, within the first 4 day s post -vaccination), submitted on 4 August 2021
(SN0436), we made the following proposal.
In each case, weproposed to schedule a blood draw to obtain a serum sample for storage, and
potential fut ure troponin testing, at baseline and 2 -5 day s after the second or third dose of
BNT162b2 in two studies.
C4591007: Pfizer/BioNTech propose to add 750 participants 5 to <12 y ears of age
(randomized 2:1 to receive BNT162b2 10 µg or placebo) and 500 particip ants 12 -15 years of
age (open label receipt of BNT162b2 30 µg). These participants would be introduced through
a protocol amendment.
C4591031: Pfizer/BioNTech propose to add a new substudy of 1000 participants with
documented receipt of 2 prior 30 µg doses of BNT162b2 (the second dose received at least 6
months ago), 16 to 30 years of age (randomized 1:1 in a crossover design to receive 30 µg
BNT162b2 or placebo at baseline and the alternate 4 weeks later).
Determination whether to test some or all of these samples for troponins would be predicated
on the anal ysis of background rate of troponin abnormalities in the 3000 existing study
participants (as described above ) and expert advice.
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Page 12Once those results are available, proper consideration can be given to t he design, size and
feasibility of a potential prospective study . Therefore, at this point in time, we are not able to
provide projected dates for the Final Protocol Submission, Study Completion, and Final
Report Submission for a prospective stud y to asses s the incidence of subclinical my ocarditis
following vaccination . Once we have data to inform these decisions, we will share them and
our plans to move forward with the Agency .
3.APPENDI CES
3.1.Appendix 1
In response to Request 2 (Section 2.2 )above, three different Study Size scenarios for Study
C4591009 are provided below; (original incidence rate ratio [I RR]=1.0, alternatives IRR
=1.2 and 1.4) with matching ratio 1:1.
Table 1presents the probability that the upper limit of the 95% confidence interval (CI) for
the observed relative risk will be below 1.5, 2.0, 2.5, and 3.0 for study sizes ranging from
500,000 to 20,000,000 vaccinated individuals (1,000,000 doses to 40,000,000 doses, under
the assumption that each person will receive 2 doses), assuming that the true relative
riskis1.0 and a matching ratio of 1:1. These estimate s are presented to cover a range of
safet y events of interest with respect to rareness, based on background rates in the general
population.
Table 2presents the probability that the upper limit of the 95% CI for the observed relative
risk will be below 1.5, 2.0, 2.5, and 3.0 for stud y sizes ranging from 500,000 to
20,000,000 vaccinated individuals (1,000,000 doses to 40,000,000 doses, under the
assumption that each person will receive 2 doses), assuming that the true relative risk is1.2
and a matching ratio of 1:1. These estimates are presented to cover a range of safet y events of
interest with respect to rareness, based on background rates in the general population.
Table 3 presents the probability that the upper limit of the 95% CI for the observed relative
risk will be below 1.5, 2.0, 2.5, and 3.0 for study sizes ranging from 500,000 to
20,000,000 vaccinated individuals (1,000,000 doses to 40,000,000 doses, under the
assumption that each person will receive 2 doses), assuming that the true relative risk is1.4
and a matching ratio of 1:1. These estimate s are presented to cover a range of safet y events of
interest with respect to rareness, based on background rates in the general population.
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Page 13Table 1.Study Size Calculations - IRR=1.0, Matching Ratio 1:1
Safety event
of interestEstimated
background rate per
100,000 person -years
(Black et al., 2021)Number of
individuals
vaccinatedProbability that the upper confidence limit of
RR will be below the following thresholdsa
1.5 2.0 2.5 3.0
Guillain -
Barré
syndrome1.68 500,000 0.06 0.10 0.14 0.19
1,000,000 0.08 0.16 0.25 0.33
2,500,000 0.14 0.33 0.52 0.68
5,000,000 0.24 0.58 0.81 0.93
10,000,000 0.43 0.86 0.98 1.00
20,000,000 0.71 0.99 1.00 1.00
Bell's palsy 25.2 500,000 0.24 0.58 0.81 0.93
1,000,000 0.43 0.86 0.98 1.00
2,500,000 0.80 1.00 1.00 1.00
5,000,000 0.98 1.00 1.00 1.00
10,000,000 1.00 1.00 1.00 1.00
20,000,000 1.00 1.00 1.00 1.00
Myocardial
infarction 208 500,000 0.95 1.00 1.00 1.00
1,000,000 1.00 1.00 1.00 1.00
2,500,000 1.00 1.00 1.00 1.00
5,000,000 1.00 1.00 1.00 1.00
10,000,000 1.00 1.00 1.00 1.00
20,000,000 1.00 1.00 1.00 1.00
a.Estimates in this table assume a risk window duration of 42 days for Guillain -Barré syndrome, and 28 days
for Bell's palsy and myocardial infarction.
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Page 14Table 2.Study Siz e Calculations - IRR=1.2, Matching Ratio 1:1
Safety event
of interestEstimated
background rate per
100,000 person -years
(Black et al., 2021)Number of
individuals
vaccinatedProbability that the upper confidence limit of
RR will be below the following thresholdsa
1.5 2.0 2.5 3.0
Guillain -
Barré
syndrome1.68 500,000 0.04 0.08 0.11 0.15
1,000,000 0.05 0.11 0.19 0.26
2,500,000 0.07 0.22 0.39 0.56
5,000,000 0.11 0.38 0.66 0.85
10,000,000 0.17 0.65 0.92 0.99
20,000,000 0.30 0.91 1.00 1.00
Bell's palsy 25.2 500,000 0.11 0.38 0.66 0.85
1,000,000 0.17 0.65 0.92 0.99
2,500,000 0.37 0.96 1.00 1.00
5,000,000 0.63 1.00 1.00 1.00
10,000,000 0.90 1.00 1.00 1.00
20,000,000 1.00 1.00 1.00 1.00
Myocardial
infarction 208 500,000 0.55 1.00 1.00 1.00
1,000,000 0.84 1.00 1.00 1.00
2,500,000 1.00 1.00 1.00 1.00
5,000,000 1.00 1.00 1.00 1.00
10,000,000 1.00 1.00 1.00 1.00
20,000,000 1.00 1.00 1.00 1.00
a.Estimates in this table assume a risk window duration of 42 days for Guillain -Barré syndrome, and 28 days
for Bell's palsy and myocardial infarction.
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Page 15Table 3.Study Size Calculations - IRR=1.4, Matching Ratio 1:1
Safety event
of interestEstimated
background rate per
100,000 person -years
(Black et al., 2021)Number of
individuals
vaccinatedProbability that the upper confidence limit of
RR will be below the following thresholdsa
1.5 2.0 2.5 3.0
Guillain -
Barré
syndrome1.68 500,000 0.03 0.06 0.09 0.12
1,000,000 0.03 0.08 0.14 0.21
2,500,000 0.04 0.13 0.28 0.44
5,000,000 0.04 0.22 0.49 0.73
10,000,000 0.05 0.40 0.79 0.95
20,000,000 0.07 0.67 0.97 1.00
Bell's palsy 25.2 500,000 0.04 0.22 0.49 0.73
1,000,000 0.05 0.40 0.79 0.95
2,500,000 0.07 0.76 0.99 1.00
5,000,000 0.11 0.97 1.00 1.00
10,000,000 0.18 1.00 1.00 1.00
20,000,000 0.31 1.00 1.00 1.00
Myocardial
infarction 208 500,000 0.10 0.93 1.00 1.00
1,000,000 0.15 1.00 1.00 1.00
2,500,000 0.32 1.00 1.00 1.00
5,000,000 0.56 1.00 1.00 1.00
10,000,000 0.85 1.00 1.00 1.00
20,000,000 0.99 1.00 1.00 1.00
a.Estimates in this table assume a risk window duration of 42 days for Guillain -Barré syndrome, and 28 days
for Bell's palsy and myocardial infarction.
3.2.Appendix 2
C4591021. Post Conditional Approval Active Surveillance Study Among Individuals in
Europe Receiving the Pfizer -BioNTech Coronavirus Disease 2019 (COVID -19) vaccine.
20May 2021 .
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Page 164.REFERENCES
1LiR, Stewart B,Weintraub E. Evaluating efficiency and statistical power of self -
controlled case series and self -controlled risk interval designs in vaccine safety .
JBiopharm Stat 2016;26(4 ):686-93.
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