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COVID -19 Vaccine (BNT162, PF -07302048)
BB-IND 19736
M 1.11.3 Response to FDA Information Request
PFIZER CONFIDENTIAL
Page 1COVID -19 Vaccine (BNT162, PF -07302048)
IND 19736
Response to 30 June 2021 Information Request Regarding Updating Informed Consent
Documents and Investigator's Brochure with I nformation R elated to Myocarditis and
Pericarditis
July 2021
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M 1.11.3 Response to FDA Information Request
PFIZER CONFIDENTIAL
Page 2TABLE OF CONTENTS
LIST OF TABLES ................................ ................................ ................................ ..................... 2
LIST OF ABBREVIATION S................................ ................................ ................................ ....3
1. INTRODUCTION ................................ ................................ ................................ ................. 4
2. CBER REQUEST ................................ ................................ ................................ .................. 4
2.1. CBER Comment 1 ................................ ................................ ................................ .....4
2.1.1. Response to CBER Comment 1 ................................ ................................ ....5
2.2. CBER Comment 2 ................................ ................................ ................................ .....5
2.2.1. Response to CBER Comment 2 ................................ ................................ ....5
2.3. CBER Comment 3 ................................ ................................ ................................ .....6
2.3.1. Response to CBER Comment 3 ................................ ................................ ....6
2.4. CBER Comment 4 ................................ ................................ ................................ .....8
2.4.1. Res ponse to CBER Comment 4 ................................ ................................ ....8
2.5. CBER Comment 5 ................................ ................................ ................................ .....9
2.5.1. Response to CBER Comment 5 ................................ ................................ ....9
2.6. CBER Comment 6 ................................ ................................ ................................ .....9
2.6.1. Respons e to CBER Comment 6 ................................ ................................ ..10
LIST OF TABLES
Table 1. Status of I nformed Consent for Ongoing Studies ................................ ................... 6
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PFIZER CONFIDENTIAL
Page 3LIST OF ABBREVIATIONS
Abbreviation Term
20vPnC 20-valent pneumococcal conjugate vaccine
BB-IND Biological Investigational New Drug
CBER Center for Biologics Evaluation and Research
CDC Centers for Disease Control and Prevention
CFR Code of Federal Regulations
COVID -19 Coronavirus Disease 2019
EC Ethics Committee
ECG/EKG electrocardiogram
EUA Emergency Use Authorization
FDA Food and Drug Administration
ICD Informed consent document
IRB Institutional Review Board
mRNA messenger ribonucleic acid
PCR Polymerase chain reaction
RNA ribonucleic acid
SARS -CoV -2 Severe Acute Respiratory Syndrome Coronavirus 2
SOP Standard operating procedure
SUSAR Suspected unexpected serious adverse reaction
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Page 41.INTRODUCTION
Reference is made to BB- IND 19736 for the COVID -19 vaccine (BNT162; PF -07302048),
which Pfizer and BioNTech are developing for the indication of active immunization to
prevent COVID -19 caused by SARS -CoV -2. The IND was effective on 29 April 2020.
Further reference is made to CBER’s 30June 2021 Information Request regarding updating
Informed Consent Documents a nd Investigator's Brochure with information related to
myocarditis and pericarditis.
CBER’s comments/requests in bold italics are followed b y Pfizer/BioNTech’s responses
below.
2.CBER REQUEST
Available data regarding myocarditis or pericarditis reported in i ndividuals vaccinated
with the Pfizer- BioNTech COVID -19 V accine strongly support a plausible causal
relationship to the vaccine and have warranted revision of the EUA Fact Sheets to include
a warning statement and other information about these events. We a lso consider it
necessary to adequately inform investigators and study participants in ongoing clinical
trials with the Pfizer -BioNTech COVID -19 Vaccine, and modified formulations thereof
(e.g., for different presentations or to address SARS -CoV-2 variants ), about the risk of
myocarditis or pericarditis associated with the vaccine.
2.1.CBER Comment 1
Please update informed consent documents to include information about the risk of
myocarditis and pericarditis. This information should include that:
a. Myocarditis or pericarditis have been reported in greatest numbers in males under
the age of 30 years following the second dose, but cases have been reported in older
males and in females as well, and also following the first dose.
b.Symptoms of myocarditis or pericarditis include chest pain, shortness of breath, or
feelings of having a fast-beating, fluttering, or pounding heart, with onset of
symptoms most commonly reported within a few days following vaccination. Study
participants should seek medical atte ntion and also notify study site staff if any of
these symptoms occur following vaccination.
c.While some severe cases have been reported, most cases have been associated with
full resolution of symptoms in the short term. However, long- term follow -up is
limited.
d.It is not known whether the risk of myocarditis or pericarditis is increased
following additional doses of the vaccine (e.g., following a booster dose).
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Page 52.1.1. Response to CBER Comment 1
Pfizer -BioNTech acknowledge sCBER’s comments regarding the need to inform
investigators and stud y participants in ongoing clinical trials with the Pfizer -BioNTech
COVID -19 Vaccine, and modified formulations thereof (e.g., for different presentations or to
address SARS -CoV -2 variants), about the risk of my ocarditis or perica rditis associated with
the vaccine. Pfizer -BioNTech agrees to add the requested information to ICDs as follows :
Myocarditis (inflammation of the heart muscle) and pericarditis (inflammation of the
lining outside the heart) have occurred in some people who have received BNT162b2.
Cases have mainl y been reported in males under 30 y ears of age and following the
second vaccination ;however, there have been some cases reported in older males and
females as well as following the first vaccination. The chance of having this occur is
very low and, in most of these people, s ymptoms began within a few day s to a week
following vaccination. As a precaution, y ou should seek medical attention right away if
you have an y of the following s ymptoms after receiving the vaccine:
Chest pain
Shortness of breath
Feelings of having a fast- beating, fluttering, or pounding heart
Please also notify study staff, when appropriate, if y ou have any of these s ymptoms.
Whilst some severe ca ses have been reported, most cases have been associated with
full resolution of sy mptoms in the short term ; however, long- term follow -up is limited.
It is not known whether the risk of m yocarditis or pericarditis is increased following
additional doses of the vaccine, e.g. following a booster dose.
If you have had m yocarditis (inflammation of the heart muscle) or pericarditis
(inflammation of the lining outside the heart) previously , please tell y our study doctor.
2.2.CBER Comment 2
We note that you have submit ted revised informed consent documents for several ongoing
studies addressing myocarditis and pericarditis, and that these revisions state, “…it is not
clear that it is due to the vaccine.” We do not agree with this statement, as there is a
substantial bas is to believe there is a causal relationship to vaccination. Please further
revise your informed consent documents for all ongoing clinical trials to remove this
statement and according to items 1a- 1d above.
2.2.1. Response to CBER Comment 2
Pfizer -BioNTech ackno wledge sCBER’s comment and hasrevised this part of the ICD as
indicated in response to Comment 1 above . Updated I CDsfor all studies will be submitted in
parallel to BB -IND 19736 on 06 July 2021.
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Page 62.3.CBER Comment 3
While we would agree that the balance of benefits vs. risks remains favorable for
completion of the 2-dose vaccination regimen in most individuals (excepting, for example,
individuals who are recovering from myocarditis or pericarditis following the first dose),
study participants who are awaiting their second dose should be re -consented after being
provided information about myocarditis and pericarditis as described above.
2.3.1. Response to CBER Comment 3
Pfizer -BioNTech agrees that study participants who are a waiting their second dose should be
re-consented after being provided with information about my ocarditis and pericarditis. On
the same day that Pfizer -BioNTech received the request from CBER to include language in
the EUA factsheet, Pfizer -BioNTech alread yupdated I CDs for all ongoing BNT162b2
studies to include reference to cases of m yocarditis and pericarditis after vaccination. Given
the time needed to obtain the required IRB/EC approvals for the updated ICDs across
countries and sites, so as not to dela y second doses (which could result in partial protection ,
particularl y in the context of emerging variants ), and in accordance with Pfizer SOPs, any
participants due for their second dose were provided this information verbally , informed of
the right to withdraw from the clinical study at any time, and asked if they are agreeable to
continue with the study following receipt of the new information. This interaction isto be
documented in a Pfizer Provision of Critical Safety Form, as well as in the participant source
documents at the site . The status of informed consent for ongoing studies is presented in
Table 1. This verbal process is only utilized during the time period in which the I CD is being
updated and approved. Once the updated ICD is approved, these participants will also be
required to sign the updated I CD.
In light of CBER comments and our commitment to re -update the ICD (per response to
Comment 1), once approved by IRB/ECs ,we will utilize the updated ICDwith CBER -
requested text for re -consenting.
Table 1.Status of Informed Con sent for Ongoing Stu dies
Study Number Brief Title Interim Verbal
Provision of Safety
Inform ation Used for
Second or Subsequent
Doses (Yes/No)aDate for Updated ICDb
C4591001 A Phase 1/2/3 Study to
Evaluate the Safety,
Tolerability,
Immunogenicity, and
Efficacy of RNA
Vaccine Candidates
Against COVID -19 in
Healthy IndividualsYes Week commencing 05
July 2021
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Page 7Table 1.Status of Informed Con sent for Ongoing Stu dies
Study Number Brief Title Interim Verbal
Provision of Safety
Inform ation Used for
Second or Subsequent
Doses (Yes/No)aDate for Updated ICDb
C4591007 A Phase 1/2/3 Study to
Evaluate the Safety,
Tolerability, and
Immunogenicity
of an RNA Vaccine
Candidate Against
COVID -19 in Healthy
Children <12 Years of
AgeYes Week commencing 05
July 2021
C45910 15 A Phase 2/3 Study to
Evaluate the Safety,
Tolerability, and
Immunogenicity of a
SARS -CoV- 2 RNA
Vaccine Candidate
(BNT162b2) Against
COVID -19 in Healthy
Pregnant Women 18
Years of Age and OlderYes Week comm encing 05
July 2021
C4591017 A Phase 3 Study to
Evaluate the Safety,
Tolerability, and
Immunogenicity of
Multiple Production Lots
and Dose Levels of
BNT162b2 RNA -Based
COVID -19 Vaccines
Against COVID -19 in
Healthy ParticipantsNo Week commencing 05
July 2021
C4591020 A Phase 3 Study to
Evaluate the Safety,
Tolerability, and
Immunogenicity of
Multiple Formulation of
BNT162b2 Against
COVID -19 in Healthy
AdultsNo Week commencing 05
July 2021
C4591024 Phase 2b, Open -Label
Study to Evaluate Safety,
Tolerability, and
Immunogenicity of
Vaccine Candidate
BNT162b2 in
Immunocompromised
Participants
≥2 Years of AgeNo Week commencing 05
July 2021
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Page 8Table 1.Status of Informed Con sent for Ongoing Stu dies
Study Number Brief Title Interim Verbal
Provision of Safety
Inform ation Used for
Second or Subsequent
Doses (Yes/No)aDate for Updated ICDb
C4591031 A Study to Evaluate
Additional Dose(s) of
BNT162b2 in Healthy
Individuals Previously
Vaccinated With
BNT162b2No Week commencing 05
July 2021
B7471026cA Phase 3 Safety and
Immunogenicity Study
of 20vPnC When
Coadm inistered With a
Booster Dose of
BNT162b2No Week commencing 05
July 2021
a.Based on w ording in the updated EUA fact sheet .
b.3subjects in StudyC4591007 and16 subjects in Study C4591031 were consented and dosed on the
updated ICD that CBER asked us to modify. These subjects will be re- consented using the new and approved
ICD.
c. ICD for Study B7471026 will be filed under PCV20 IND 17039 .
2.4.CBER Comment 4
Please describe how study materials (including the Investigator’s Brochure) and
procedures for ongoing clinical trials will ensure adequate detection and reporting, as well
as appropriate diagnosis and management, of cases of m yocarditis or pericarditis that
occur in study participants. Please also describe what circumstances would represent a
significant and unreasonable risk related to myocarditis or pericarditis and result in
halting of study vaccinations in participants for whom the vaccine is not yet authorized for
use.
2.4.1. Response to CBER Comment 4
The Investigator’s Brochure is in the process of being updated and will include information
regarding the occurrence of cases of my ocarditis and pericarditis. The updated final
document is planned to be available b y 14 July 2021 and will be submitted to BB-IND 19736
in parallel with distribution to I nvestigators and IRBs and/or ECs .
In a Dear Investigator letter sent to sites (24 June 2021) ,the following guidance was alread y
provided to investigators:
If any stud y participants report s ymptoms that could represent m yocarditis or
pericarditis, please follow the CDC Clinical Considerations for m yocarditis and
pericarditis following COVID -19 vaccination published on 28 May 2021:
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Page 9For initial evaluation, consider an ECG, troponin level, and inflammatory
markers such as C -reactive protein and ery throcy te sedimentation rate. In the
setting of normal ECG, troponin, and inflammatory markers, m yocarditis or
pericarditis is unlikely .
Consider consultation with:
oCardiology for assistance with cardiac evaluation and management.
oInfectious disease and/or rheumatology to assist in this evaluation.
Where available, evaluate for potential etiologies of my ocarditis and pericarditis,
particularl y acute COVID -19 infection (e.g., PCR testing), prior SARS- CoV -2
infection (e.g., detection of SARS -CoV -2 nucleocapsid- binding antibodies), and
other viral etiologies (e.g., enterovirus PCR and comprehensive respiratory viral
pathogen testing).
With respect to halting of study vaccinations in participants for whom the vaccine is not y et
authorized for use (interpreted as individuals <12 years of age or pregnant women), we
believe that is not possible to identify a priori what circumstances would represent a
significant and unreasonable risk related to m yocarditis or pericarditis. Rather, we propose to
carefully review the details of each new case identified in clinical studies (including
frequency , severity and outcome/sy mptoms resolution) , as well as cumulatively , to identify
whether to halt stud y vaccinations. Additionally, our external Data Monitoring Committee
will be alerted about all suspected m yocarditis/pericarditis cases in real time .
2.5.CBER Comment 5
We expect that cases of myocarditis or pericarditis occurring in temporal association with
vaccination of study participants, if occurring at greater frequency or severity than as
described in the Investigator’s Brochure, would be reported as SUSARs as required by 21
CFR 312.32. Please confirm.
2.5.1. Resp onse to CBER Comment 5
Pfizer -BioNTech acknowledges CBER’s comment. Pfizer -BioNTech will carefully review
the details of each new case of m yocarditis or pericarditis identified in clinical studies and
willreport case sof my ocarditis or pericarditis as a S USAR per 21 CFR 312.32.
2.6.CBER Comment 6
Please describe your plans to further understand the risk of myocarditis or pericarditis
associated with the Pfizer -BioNTech Vaccine, including but not necessarily limited to:
a.The frequency of these events attributable to vaccination in various demographic
subgroups classified by age, gender, race, and ethnicity;
b. The biological mechanism responsible for these events;
c.The long-term prognosis for post-vaccination myocarditis and pericarditis;
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Page 10d.Whether initially subclini cal cases occur (e.g., as detected through routine baseline
and post -vaccination cardiac enzymes and/or EKGs in relevant populations), and if
so at what frequency and with what long- term prognosis; and
e.Whether myocarditis or pericarditis, including initial ly subclinical cases, are
associated with other mRNA vaccines manufactured using the same platform and
in clinical development for non -COVID indications.
2.6.1. Response to CBER Comment 6
Pfizer -BioNTech is actively working to understand the risk of my ocarditis and pericarditis
associated with the Pfizer -BioNTech vaccine andwill provide a thorough response with
regards to parts b, d, and e, by 02August2021 .
At this time, several hy potheses for the biological mechanism of vaccine-associated
myocarditis and pericarditis are under discussion, including secondary to vaccine -elicited
non-specific immune stimulation (e.g., exacerbation of subclinical autoimmun e my ocarditis),
antigen -specific immune -mediated m yocarditis (e.g., antigen mimicry), and hypersensitivity.
There is no nonclinical evidence of direct cardiotoxicity ,and there was no vaccine -related
myocardial or pericardial inflammation identified in nonclinical toxicity studies in rats or in
vaccine efficacy studies in rhesus macaques . Although there are animal models of
myocarditis, without further clarity around the underly ing cause of the m yocarditis observed
clinically in vaccine rec ipients , the translatability of animal study results to the mechanism of
putative vaccine -related my ocarditis in humans w ould be quite opaque . Therefore, no animal
model studies are proposed at this time.
Response to CBER Comment 6a
Our planned post -authorization safety studies involving large -scale electronic health care
databases (protocols C4591009, C4591011, and C4591012 ) are designed to measure the
incidence of m yocarditis and pericarditis events occurring within 42 day s of a vaccination
dose. Incidence estimates will be based on structured data, stratified b y dose, age group,
gender, and race/ethnicity . In addition, the se stratified incidence estimates will be calculated
for shorter risk intervals, e .g.,7 day s post -vaccination. Results will be available within the
first interim reports (due in October 2023 for C4591009, and in December 2021 for
C4591011 and C4591012).
Response to CBER Comment 6c
Post-authorization safety studies C4591011 and C4591012 follow vaccinated individuals for
up to approximately 2 years. These studies aredesigned to use structured information to
identify signals and use information from individual medical records to further evaluate
events that exhibit a signal. Given that my ocarditis and pericarditis have generated a signal
outside of these studies, any myocarditis or pericarditis events identified, i.e., by presence of
corresponding ICD codes in electronic medical records , will be prioritized for review to
confirm diagnosis and to obtain information on prognosis (e .g., time to resolution).
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Page 11Further plans to evaluate long term prognosis of myocarditis or pericarditis in other real -
world secondary data sources, such as the Senti nel Data Research partners included within
the planned post -authorization safet y study C4591009, and in clinical trial participants will
be included in the 02 August 2021 proposal .
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