Document text
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 28 July2021Information Request Regarding Post- marketing
SafetyStudy(ies)
August2021
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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................................ ................................ ................................ ......13
3. REFERENCES ................................ ................................ ................................ .................... 15
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Page 3List of Abbreviations and Definitions of Terms
Abbreviation Definition
DoD Department of Defense
ECG Electrocardiogram
EU European Union
MHS Military Health System
NHLBI National Heart, Lung and Blood Institute
NIH National Institutes of Health
PHN Pediatric Heart Netw ork
PY Person-years
RR Relative risk
TBD To be determined
US United States
VSD Vaccine Safety Datalink
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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 28July2021.
CBER request s are presented in bold italics followed b y Pfizer-BioNTech responsein plain
text.
2.CBER REQUESTS AND SPONSOR RESPONSES
Please include the following information for the postmarketing study(ies) proposal: study
designs, sample sizes and justification of sam ple sizes including number of subjects
≤30years of age, information to be collected at baseline, frequency and methods for
follow-up data collection, plan for duration of long term follow ‐up and information to be
collected in follow ‐up, study timeline and milestone dates (final protocol submission date,
study completion date, and final study report submission date; please provide dates in
mm/dd/yyyy format).
2.1. CBER Request1
1. Please propose postmarketing observational safety study(ies) to assess myo /pericarditis
following administration of COMIRNATY to:
a.Quantify the magnitude of risk by age, sex, and dose
b.Include follow up cases (e.g., via a registry) for recovery status and long -term
sequelae
Sponsor Response
Response to 1A : Quantifying the magnitud e of myocarditis/pericarditis risk
As previously communicated, post -authorization safet y studies C4591009 (US), C4591011
(US), C4591012 (US), and C4591021(EU) use large electronic healthcare databases to assess
increased risk of safet y events of interest, including m yocarditis/pericarditis, following
vaccination with COMIRNATY during a 2 -3 year study period. In these studies, the
incidence of m yocarditis/pericarditis will be described overall, and stratified by age group,
gender, race/ethnicity (if feasibl e), dose, and risk interval using structured information and
following case confirmation via medical record review where feasible. To assess the
magnitude of risk, these studies include comparative methods (self -controlled anal yses, and
analyses involving a separate comparator group). Relative risk (RR) estimates from
comparative anal yses will be obtained overall and stratified by the same factors as described
above when supported by sufficient cell counts.
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Page 5Given the demographics of their source populatio ns, studies C4591009, C4591011, and
C4591021 are expected to capture data on individuals aged 30 years and younger. In
C4591012, the largest sub -population of y ounger individuals includes veterans aged 30-
39years; therefore, individuals 12- 39 years of age will be included in this analy sis.
Table1provides a range of estimates of the numbers of COMIRNATY -exposed persons and
myocarditis cases that would be required to be included in the study in order to have
sufficient power to detect R Rs for various magnitudesof risk of vaccine -associated
myocarditis under different assumptions within a self-controlled case series anal ysis. These
estimates are based estimates of myocarditis/pericarditis background rate sused byCDC in
signal evaluation s, ranging from 1/100,000 (person- years) PY to 10/100,000 PY .1
Table1.Required Number of Cases to Detect Myocarditis Risk Under Different
Assumptions of Background Rates
80%power, alpha = 0.05
Required number
of myocarditis
casesRequired number of
COMIRNATY -exposed
persons, assumed incidence
(1/100,000 PY)Required number of
COMIRNATY -exposed
persons, assumed incidence
(10/100,000 PY)
14-day risk window
RR=2.0
RR=5.0
RR=10.0469
52
1823,008,737
2,414,759
767,5242,300,874
241,476
76,753
21-day risk window
RR=2.0
RR=5.0
RR=10.0319
37
1315,503,995
1,659,091
516,3231,550,400
165,910
51,633
60% power, alpha = 0.05
Required number
of myocarditis
casesRequired number of
COMIRNATY -exposed
persons, assumed incidence
(1/100,000 PY)Required number of
COMIRNATY -exposed
persons, assumed incidence
(10/100,000 PY)
14-day risk window
RR=2.0
RR=5.0
RR=10.0262
28
912,853,495
1,300,255
383,7261,285,350
130,026
38,377
21-day risk window
RR=2.0
RR=5.0
RR=10.0179
20
78,699,734
896,806
278,020869,974
89,681
27,802
Abbreviations: PY=Person -years; RR=Relative risk
In general, studies C4591009, C4591011, C4591012 and C4591021 will include as many
individuals as possible who meet the eligibility criteria during the relevant period of study
without an upper limit (Table2).AsCOMIRNATY is authorized or approved for use
without significant contraindications, the number of persons enrolled in the studies depends
on the following:
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Page 6The number of persons in the source population eligible for the vaccine under current
authorization
The number in eligible source population who get vaccinated with COMIRNATY
vaccine
The proportion of vaccinated, eligible individuals within the source population whose
vaccination is documented in the structured data ; this assumes 50% of vaccines
administered are COMIRNATYand 60% of eligible persons are vaccinated, so 30%
of the source population would be included in the COMIRNATY-exposed sample.
Table2.Source Populations for Safety Surveillance Studies
Protocol
IDTitle Data Source Source Population
(size and type)Estimated
Number of
Individuals
≤30 yearsaEstimated
Proportion
≤30yearsof
Source
Population
Administered
Pfizer Vaccinea
C4591009 A Non-
Interventional
Post-Approval
Safety Study of
Pfizer-BioNTech
COVID-19
Vaccine in the
United StatesFive Data
Research
Partners in US
Sentinel
SystemPfizer-BioNTech
vaccine recipients
among 100+ million
individuals in
general population
captured in Sentinel
system data sources;
includes individuals
<18 years of age~ 47 millionb~14.1 million
C4591011 Active Safety
Surveillance of
the Pfizer-
BioNTech
COVID-19
Vaccine in the
United States
Department of
Defense
Population
Following
Emergency Use
AuthorizationUS
Department of
Defense
(DoD)
Military
Health System
(MHS)
databasePfizer-BioNTech
vaccine recipients
among about 10
million active
military personnel
and families in DoD
MHS; includes
individuals <18
years of age~ 3.5 million ~1.1 millionb
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Page 7Table2.Source Populations for Safety Surveillance Studies
Protocol
IDTitle Data Source Source Population
(size and type)Estimated
Number of
Individuals
≤30 yearsaEstimated
Proportion
≤30yearsof
Source
Population
Administered
Pfizer Vaccinea
C4591012 Post-Emergency
Use
Authorization
Active Safety
Surveillance
Study among
Individuals in
the Veteran’s
Affairs Health
System
Receiving
Pfizer-BioNTech
Coronavirus
Disease 2019
(COVID- 19)
Vaccine US Veterans
Health
Administration
system Pfizer-BioNTech
vaccine recipients
among about 9
million patients in
Veterans’ Health
Administration
system ≤30 years:
~ 350,000
≤39 years:
~ 1.2 millionc≤30 years:
~105,000
≤39 years:
~ 360,000c
C4591021 Post Conditional
Approval Active
Surveillance
Study Among
Individuals in
Europe
Receiving the
Pfizer-BioNTech
Coronavirus
Disease 2019
(COVID- 19)
VaccineElectronic
healthcare
databases in
Netherlands,
Norway, UK,
Italy, SpainPfizer-BioNTech
vaccine recipients
among about 39
million individuals
in general
population; includes
individuals <18
years of age~13.5 million ~4.1 millionb
aEstimates represent the numbers of individuals in the population before study protocol eligibility criteria are
applied.
bEstimates based on assumption that 50% vaccines administered are COMIRNATY and 60% of eligible
persons are vaccinated
cEstimates based on number of actual Pfizer/BioNTech va ccinations as of July 1, 2021.
Given the anticipated number of persons aged ≤30yearsvaccinated with the
Pfizer/BioNTech vaccineexpected to be captured in the studies, the studies thatare expected
to have60% and 80% power to detect risks of different magnitudes assuming a range of rates
of myocarditis temporally unrelated to vaccine and risk windows are summarized in Table3.
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Page 8Table3. Post-Authorization Safety Studies With 60% and 80% Power to Detect
Myocarditis in Persons ≤30 Yearsa, Under Different Assumptions of
Background Rates
80% power, alpha = 0.05
Assumedincidence (1/100,000 PY)Assumedincidence (10/100,000 PY)
14-day risk window
RR=2.0
RR=5.0
RR=10.0None
1009, 1021
1009, 1011, 10211009, 1021
1009, 1011 , 10121021
1009, 1011, 1012, 1021
21-day risk window
RR=2.0
RR=5.0
RR=10.0None
1009, 1021
1009, 1011, 10211009, 1021
1009, 1011, 1012, 1021
1009, 1011, 1012, 1021
60% power, alpha = 0.05
Assumedincidence (1/100,000 PY)Assumedincidence (10/100,000 PY)
14-day risk window
RR=2.0
RR=5.0
RR=10.01009
1009, 1021
1009, 1011, 10211009, 1021
1009, 1011, 1012 1021
1009, 1011, 1012, 1021
21-day risk window
RR=2.0
RR=5.0
RR=10.01009
1009, 1011, 1021
1009, 1011, 1012, 10211009, 1011, 10 21
1009, 1011, 1012, 1021
1009, 1011, 1012, 1021
a. Note: for study 1012 sample size estimates for persons 39 and under w ere used.
Abbreviations: PY=Person -years; RR=Relative risk
Given that governments are making vaccine available at no cost and administration often
occurs outside of t ypical health care delivery s ystems, capture of vaccination within
secondary structured data such as electronic health care records and insurance claims may be
incomplete. Capture is expected to vary by data source and methods to address this potential
limitation will be discussed in each pro tocolas applicable .
Response to 1b: Follow -up of myocarditis/pericarditis cases
Pfizer and BioNTech have been exploring the feasibility of conducting studies using real-
world data sources within the US and EU to identify risk factors for and characterize long-
term outcomes of m yocarditis/pericarditis following vaccination with COMIRNATY.
Within the US, we are conducting a broad feasibility assessment of healthcare data s ystems
and external partnerships that permit the evaluation of long- term prognosis of p atients with
myocarditis/pericarditis temporally associated with COMIRNATYvaccination. As discussed
with CDC and FDA, including Drs. Sara Oliver, Tom Shimabukuro, and Naray an Nair as
well as other colleagues, in an informal meeting on July 19th, we unders tand that the CDC is
conducting enhanced surveillance within the Vaccine Safet y Datalink (VSD) to follow
vaccine-associated my ocarditis/pericarditis cases for 3 -6 months for s ymptomatic recovery .
CDC is also exploring methods to follow cases reported to VA ERs.
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Page 9To complement the CDC’s efforts, we propose the following:
1.Incorporate m yo-/pericarditis -specific anal ytic endpoints in currently planned or ongoing
studies C4591009, C4591011, C4591012, and C4591021 to assess the natural history of
post-vaccination m yo-/pericarditis, e.g., recovery status (medical record review) and/or
identification of serious cardiovascular outcomes (structured data) within 1 year of m yo-
/pericarditis diagnosis among individuals vaccinated with COMIRNATYas well as
individuals not vaccinated with a COVID -19 vaccine.
2.An additional US study to be conducted within the Pediatric Heart Network (PHN), in
collaboration with the National I nstitutes of Health (NIH)/National Heart, Lung and
Blood Institute (NHLBI).
This study is proposed in pa rtnership with the PHN, funded by the NHLBI /NIH. The
PHNis a multi-center consortium of major pediatric cardiovascular academic centers
in the US and Toronto, Canada that has been conducting studies of cardiovascular
disease in children since 2001. The PHN has significant experience with both clinical
trials and observational studies and has done several studies in collaboration with
pharmaceutical companies and under FDA regulation. To date, a convenience sample
of ~130 patients <21 years old with COVID-19 vaccine-associated m yocarditis has
been collected und er waiver of consent. In response to CBER’s urgent request, b elow
is aproposal based on an initial discussion between Pfizer and PHN/NIHscientists.
Details of study design and research agreement are under discussion . We will
promptly notify the Agency ifthere are any challenges encountered with this
proposal.
Specific Aims
AIM 1: To characterize the clinical course of acute post -vaccine m yocarditis in
children and young adults <21 years old
AIM 2: To characterize potential long -term sequelae of post -vaccine myocarditis, and
quality of life in children and y oung adults <21 y ears old
AIM 3: To compare long -term effects of post- vaccine my ocarditis with those of non -
vaccine m yocarditis, including m yocarditis arising in COVI D-infected children and
young adults <21 years old
AIM 4: To identify possible risk factors for post -vaccine m yocarditis in children and
young adults <21 years old including age, sex, race, ethnicity , obesity, and other
factors.
Study Population and Testing
AIM 1: ~130 patients, alread y identified, who presented to PHN main and auxiliary
sites after receiving a first or second dose of aCOVID-19 vaccine and were
diagnosed with my ocarditis. Additional patients continue to present and could be
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Page 10enrolled. In patien ts presenting with clinical s ymptoms suggesting m yocarditis, all
had elevated troponin levels, which led to additional investigations including ECG,
echocardiograph y, and cardiac MRI.
AIM 2: Myocarditis patients identified in AIM 1 will be followed prospe ctively for
one year to collect data from assessments, such as lab testing , ECG, Holter or Zio
patch, echocardiogram, cardiac MRI with gadolinium, and exercise stress test s.
Standard, age -appropriate tools to assess quality of life and ps ychosocial functi oning
will also be administered.
AIM 3: Unvaccinated my ocarditis comparator group: I dentify through EHR search
of approximately previous 3 y ears about 100 patients with confirmed non- vaccine
myocarditisand obtain clinical course and long -term sequelae. Parameters for
comparison (descriptive) will include age at diagnosis, sex, co- morbidities, clinical
features of acute event (need for pressors, day s in ICU, presence and character of
dysrhythmias, time to discharge, discharge cardiac meds) , long-term sequelae and
time to recovery .
COVID Myocarditis sub -group: Identify through EHR search of previous y ear
available patients with confirmed SARS -CoV-2 infection and confirmed
myocarditis (but not MI S-C)
AIM 4: Prospective patients aged 12-21 years who were vaccinated but did not have
myocarditis.
Summary of C urrent and P roposed S tudies
Table4summarizes the study design of the current and proposed studies. Pfizer/BioNTech
believe the sestudies provide a comprehensive plan to satisfy the above CBER requests.
Formal protocols will be submitted to FDA when available.
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Page 11Table4. Current and Proposed Post-marketing Safety Surveillance Studies
C4591009 C4591011 C4591012 C4591021 C4591021 substudy Pediatric Heart
Network Study
Study title A Non-Interventional
Post-Approval Safety
Study of Pfizer -
BioNTech COVID-19
Vaccine in the United
StatesActive Safety
Surveillance of the
Pfizer-
BioNTech COVID-19
Vaccine in the United
States Department of
Defense Population
Following Emergency
Use Authori zationPost-Emergency Use
Authorization Active
Safety Surveillance
Study among
Individuals in the
Veteran’s Affairs
Health System
Receiving
Pfizer-BioNTech Coron
avirus Disease 2019
(COVID-19) VaccinePost Conditional
Approval Active
Surveillance Study
Among Individuals in
Europe Receiving the
Pfizer-
BioNTech Coronavirus
Disease 2019 (COVID -
19) VaccinePost Conditional
Approval Active
Surveillance Study
Among Individuals in
Europe Receiving the
Pfizer-
BioNTech Coronavirus
Disease 2019 (COVID -
19) Vaccine (Substudy)TBD
Study design Retrospective cohort
studyRapid-cycle,
longitudinal,
observational cohort
studyRapid-cycle,
longitudinal,
observational cohort
studyRetrospective cohort
studyNatural history cohort
study withina
retrospective cohort
studyProspective cohort
study
Comparator group Risk:unvaccinated
comparator
Follow up:myocarditis
in unvaccinated
comparatorRisk:Self-controls,
unvaccinated
comparator and
influenza vaccine
comparator
Follow up:myocarditis
/pericarditis casesRisk:Self-controls,
unvaccinated
comparator and
influenza vaccine
comparator
Follow up:myocarditis
/pericarditis casesRisk:unvaccinated
comparator
Follow up:myocarditis
in unvaccinated
comparatorRisk:unvaccinated
comparator
Follow up:myocarditis
in unvaccinated
comparatorRisk: unvaccinated
comparator
Follow up: myocarditis
in unvaccinated
comparator
Suitability for
identifying risk factors
(Y/N)Y TBD TBD N Y Y
Suitability to assess
change in risk over time
(Y/N)Y Y Y Y Y Y
Information to be
collected at baselineDemographics and
clinical characteristics
includinghealth care
utilization, comorbiditie
s,comedications, andco
ncurrentvaccinationsDemographics andclini
cal characteristics
includinghealth care
utilization,
comorbidities, and
concurrent vaccinationsDemographics and
clinical characteristics
includinghealth care
utilization,
comorbidities, and
concurrent vaccinationsDemographics and
clinical characteristics
includinghealth care
utilization, comorbiditie
s,comedications, andco
ncurrentvaccinationsDemographics and
clinical characteristics
including comorbidities,
comedications, and
concurrent vaccinationsDemographics and
clinical characteristics
including comorbidities,
comedications, and
concurrent vaccinations
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Page 12Table4. Current and Proposed Post-marketing Safety Surveillance Studies
C4591009 C4591011 C4591012 C4591021 C4591021 substudy Pediatric Heart
Network Study
Frequency of data
collectionRetrospective Retrospective Retrospective Retrospective Retrospective 3, 6, and 12 months
after diagnosis of
myocarditis
Method of data
collectionRisk:structured data
Follow up:structured
dataRisk:structured data
Follow up:medical
recordsRisk:structured data
Follow up:medical
recordsRisk:structured data
Follow up:medical
recordsRisk:structured data
Follow up:medical
recordsPrimary data collection
Length of follow up Up to 1 year Up to 30 months Up to 30 months Up to 2 years 1 year 1 year
Information collected at
follow upClinical outcomes Clinical outcomes, labs,
imagingClinical outcomes, labs,
imagingClinical outcomes, labs,
imagingTreatment for
myocarditis and
pericarditis, clinical
outcomes, recoveryClinical outcomes (eg,
resolution, long term
sequelae), labs,
imaging, quality of life
parameters
Assessment of impact
on daily life (Y/N)N N N N TBD Y
Study timelines and
milestone datesProtocol: 08/31/2021
Monitoring report:
10/31/2022
Interim report:
10/31/2023
Final study report:
10/31/2025Protocol: 01/29/2021
Interim report 1:
12/31/2021
Interim report 2:
06/30/2022
Interim report 3:
12/31/2022
Final study report:
12/31/2023Protocol: 01/29/2021
Interim report 1:
06/30/2021
Interim report 2:
12/31/2021
Interim report 3:
06/30/2022
Interim report 4:
12/31/2022
Final study report:
12/31/2023Protocol: 05/20/2021
Progress report:
09/30/2021
Interim report 1:
03/31/2022
Interim report 2:
09/30/2022
Interim report 3:
03/31/2023
Interim report 4:
09/30/2023
Interim report 5:
03/31/2024
Final study report:
09/30/2024Protocol: 12/31/ 2021
Final report:
09/30/2024Protocol: 11/30/2021
Final report: 10/ 31/2025
Abbreviations: TBD=To be determined; Y=Yes; N=No.
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Page 132.2. CBER Request2
3.Please also provide your plans to characterize subclinical cases of myocarditis.
Sponsor Response
Myocarditis and pericarditis are inflammatory conditions of the my ocardium and the
pericardium respectively . A definitive diagnosis of my ocarditis requires histological or
immunohistological confirmation of an endom yocardial biopsy or other tissue specimen (e.g.
from an autops y). Due to their invasive nature, biopsies are rarel y obtained, and therefore a
diagnosis of m yocarditis is often based upon a compatible clinical scenario associated with
noninvasive biomarker and imaging feat ures.2This results in case definitions that are very
complex, potentially based on multiple parameters (e.g. Brighton Collaboration definitions).3
Abnormal ECG, echocardiogram, or troponin findings consistent with my ocarditis with no
cardiac symptoms have been reported in association with SARS -CoV-2 infection4but are not
well characterized phenomena , and there is no widely accepted definition of subclinical
myocarditis.
Many different ECG a bnormalities can occur in sy mptomatic m yocarditis, none of which a re
pathognomonic for the condition.5Similarly, troponin levels can be elevated in a number of
cardiac and non -cardiac conditions, as well as spuriously .6One study , in 1993 patients 0 to
21 years of age without history of cardiac disease, evaluated tropon in T levels in those with
both cardiac and noncardiac presentations. Troponin was elevated in 9% of patients overall,
only 60% of whom had a cardiac diagnosis; furthermore, a cardiac diagnosis was made in
12% of those with a normal troponin level.7Hence neither is specific to symptomatic
myocarditis, and certainly not subclinical m yocarditis, which makes them unsuitable to serve
as screening tests for a rare entity like myocarditis.The background incidence of troponin
abnormalities in vaccine recipients i s unknown and likely heterogeneous.
In this context, a prospective study to detect subclinical my ocarditis is not practicall y feasible
at this time, as it would need to enroll a large number of participants, and if performed,
would not y ield clearl y interpretable data. Furthermore, spurious findings from non- specific
positive laboratory results could undermine vaccine uptake and cause unnecessary work ups
and vaccinee anxiety .
We therefore propose to anal yze troponin I levels at a central laboratory in samplesof stored
sera (drawn <1 year ago) in 12-30- year-old individuals participating in BNT162b2 studies,
prior to receipt of BNT162b2 (i.e. either at baseline, or at an y visit for placebo recipients).
This is planned to include 3000 samples, stratified equ ally 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 abnormality is 0.1%, amongst
each age stratum if the background rate is 0.3%, as follows ( Table5).
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Page 14Table5.Probability of Observing 1 Abnormal Result with Given Abnormal
Result Rates (%)
Abnormal Result Rate (%) N=1000 N=3000
0.01 9.5 25.9
0.05 39.4 77.7
0.1 63.2 95.0
0.2 86.5 99.8
0.3 95.0 100.0
0.4 98.2 100.0
0.5 99.3 100.0
Once we have ascertained timelines in which this can be performed, we will communicate
them to the Agency .
This will 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 sample size might be required for a potential future clinical study to distinguish a true
signal of cardiac findings in the absence of compatible clinical signs and s ymptoms.
In the meantime, we areaddingmyocarditis and pericarditis as AESI s in all protocols with
ongoing administration of study vaccines, as well as the following requi rement:
“Any study participant who reports acute chest pain, shortness of breath, palpitations, or
any other symptom(s) that might be indicative of my ocarditis or pericarditis within
4weeks of a study vaccination should be specifically evaluated, preferab ly by a
cardiologist, for possible my ocarditis or pericarditis.”
In addition to a clinical evaluation, the following should be performed:
Electrocardiogram (ECG)
Troponin level
If myocarditis or pericarditis are suspected based upon the initial evaluation, the
following should also be performed:
Cardiac echocardiogram, and/or
Cardiac magnetic resonance study
Results of these investigations will be recorded in the Case Report Form.”
In addition, we are including routine ECGs in the Study BNT162-17 (submitted to BB-I ND
19736 on 22 July 2021; SN 0416), which will start shortly, evaluating versions of BNT162b2
encoding the delta variant S protein, or the alpha and delta variants. This study consists of two
parts, Part A and Part B, and will evaluate the safety and immunogenicity of a third injection of
the multivalent vaccine BNT162b2 (B.1.1.7 + B.1.617.2), and the safety and immunogenicity
of a third injection of the monovalent vaccin
e BNT162b2 (B.1.617.2), in
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Page 15participants who have received two doses of the parent vaccine BNT162b2 at 30 µg, at least
6 months after the second dose of BNT162b2. In addition, it will evaluate the safet y and
immunogenicit y of a two -dose regimen (21- days apart) of BNT162b2 (B.1.1.7 + B.1.617.2)
in participants who have not r eceived prior COVID -19 vaccination. Part A will include ~120
participants 18 to 55 y ears of age: 100 will have been previousl y vaccinated, 80 of whom
will receive a 3rd dose and 20 of whom will receive a 3rd and 4th dose; 20 vaccine-naïve
participants will receive 2 primary doses. Part B will include ~1125 participants: 750 will
have been previousl y vaccinated and will receive a 3rd dose; 375 vaccine -naïve participants
will receive 2 primary doses. ECGs will be obtained for all participants at screening, on the
day of each vaccination and 1 week after each vaccination.
Finally, Pfizer/BioNTech is also propos ing (in response to a separate CBER information
request received on 30 July2021)to include blood draws in Studies C4591007 and
C4591031 to obtain serum samples for potential future troponin testing . 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 study participants and expert advic e.
3.REFERENCES
1VRBPAC Vaccine Safety Updates (slide 17) . 10June2021. Accessed on
03 August 2021 at https://www.fda.gov/media/150054/download
2Bozkurt B, Colvin M, Cook J, et al.American Heart Association Committee on Heart
Failure and Transplantation of the Council on Clinical Cardiology; Council on
Cardiovascula r Disease in the Young; Council on Cardiovascular and Stroke Nursing;
Council on Epidemiology and Prevention; and Council on Quality of Care and
Outcomes Research. Current Diagnostic and Treatment Strategies for Specific Dilated
Cardiomy opathies: A Scienti fic Statement From the American Heart Association.
Circulation. 2016 Dec 6;134(23):e579 -e646.
3Myocarditis/Pericarditis Case Definition: www.brightoncollaboration.us . Accessed on
20 July 2021
4Daniels CJ, Rajpal S, Greenshields JT, et al.; Big Ten COVID -19 Cardiac Registry
Investigators. Prevalence of Clinical and Subclinical My ocarditis in Competitive
Athletes With Recent SARS -CoV-2 Infection: Results From the Big Ten COVID -19
Cardiac Registry . JAMA Cardiol. 2021 May 27:e212065.
5Buttà C, Zappia L, Laterra G, et al. Diagnostic and prognostic role of
electrocardiogram in acute my ocarditis: A comprehensive review. Ann Noninvasive
Electrocardiol. 2020 May ;25(3):e12726. doi: 10.1111/anec.12726.
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Page 166Roongsritong C, Warraich I , Bradley C. Common causes of troponin elevations in the
absence of acute m yocardial infarction: incidence and clinical significance. Chest.
2004 May ;125(5):1877 -84.
7Dionne A, Kheir JN, Sleeper LA, et al. Value of Troponin Testing for Detection of
Heart Disease in Previous ly Healthy Children. J Am Heart Assoc. 2020 Feb
18;9(4):e012897.
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