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 13 August2021 Information Request Regarding
Safety-RelatedPostmarketing Requirement/Postmarketing Commitment S tudies
16 August 2021
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M 1.11.3 Response to FDA Information Request
PFIZER CONFIDENTIAL
Page 2TABLE OF CONTENTS
1. INTRODUCTION ................................ ................................ ................................ ................. 3
2. CBER REQUESTS AND SPONSOR RESPONSES ................................ ............................ 3
2.1. CBER Request 1 -Postmarketing Requirements ................................ ...................... 3
2.2. CBER Request 2 –Postmarketing Commitments ................................ ..................... 6
2.3. CBER Request 3 –Study Milestones................................ ................................ ........8
2.4. CBER Request 4 ................................ ................................ ................................ ......11
2.5. CBER Request 5 ................................ ................................ ................................ ......11
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Page 31.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 13August2021.
CBER requests are presented in bold italics followed b y Pfizer-BioNTech response in plain
text.
2.CBER REQUESTS AND SPONSOR RESPONSES
Our revie w of your pharmacovigilance plan for COMIRNATY (COVID- 19 Vaccine,
mRNA) under BLA STN 125742/0 is ongoing.
Should this product be approved, we have determined that an analysis of spontaneous
postmarketing adverse events reported under section 505(k)(1) of the Federal Food, Drug,
and Cosmetic Act (FDCA) will not be sufficient to identify:
known serious risks of myocarditis and pericarditis
an unexpected serious risk of subclinical myocarditis
2.1.CBER Request 1 - P ostmarketing Requirements
Furthermore, the pharm acovigilance system that FDA is required to maintain under
section 505(k)(3) of the FDCA is not sufficient to assess these serious risks. Therefore,
should this product be approved, we have determined that you will be required to conduct
the following stu dies as postmarketing requirements (PMRs) under Section 505(o) of
FDCA:
1. Epidemiologic studies using large electronic healthcare databases to evaluate the
occurrence of myocarditis and pericarditis following administration of COMIRNATY
a.US –Sentinel system (C4591009)
b.EU active surveillance study (C4591021)
c.EU active surveillance substudy (C4591021)
Sponsor Response
Pfizer/BioNTech acknowledge s CBER’s request and will conduct the following studies as
postmarketing requirements (PMRs) under Section505(o) of F DCA:
a.Study C4591009 entitled,“A Non-interventional PostApproval Safety Study of the
Pfizer-BioNTech COVID- 19 mRNA Vaccine in the United States ” is a planned PMR
to assess the occurrence of safet y events of interest in the general US population of all
ages, pregnant women, the immunocompromised and persons with a prior history of
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Page 4COVID-19 within selected data sources participating in the US Sentinel System.
Individuals receiving the vaccine since receipt of EUA on 11 December 2020 will be
captured. Protoc ol submission is planned for 31 August 2021. A monitoring r eport
will be submitted by 31 October 2022 ; an interim report by 31 October 2023; and a
final study reportby 31 October 2025.
b.StudyC4591021, Post Conditional Approval Active Surveillance Study Among
Individuals in Europe Receiving the Pfizer -BioNTech Coronavirus Disease 2019
(COVID-19) Vaccine, conducted in collaboration with the VAC4EU Consortium
Team, is a commitment made to EMA. The final protocol was approved by the
European Medicines Agen cy on 24 June 2021. The final protocol was submitted to
CBER on 11 August 2021 as part of the Response to 10 August 2021 Information
Request Regarding Post -Marketing Safet y Studies.
c.A substudy of C4591021 is planned to describe the natural history of post-vaccination
myocarditis/pericarditis, including recovery status (medical record review), risk
factors, and/or identification of serious cardiovascular outcomes (structured data)
within 1 y ear of myocarditis/pericarditis diagnosis among individuals vac cinated with
COMIRNATY as well as individuals not vaccinated with a COVID -19 vaccine. A
synopsis of the study was provided as part of the Response to CBER 10 August 2021
Information Request Regarding Post-M arketingSafety Studies,which was submitted
on 11August 2021 . This substudy is still under development and subject to change
based on data availability and feedback from EMA. Pfizer /BioNTech will share the
final protocol with FDA following EMA endorsement.
2.A prospective cohort study with at least 5 years of follow -up for potential long -term
sequelae of myocarditis after vaccination (in collaboration with Pediatric Heart
Network)
Sponsor Response
This study will enroll patients <21 y ears of age who are diagnosed with vaccine -associated
myocarditis wit hin the Pediatric Heart Network ( PHN)during the study period and who
fulfill study inclusion criteria (y et to be determined, will include informed consent). A full
IRB and DSMB approved protocol will be shared with the agency by 30 November 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 b y
age, gender, t ype of vaccine and dose, effects of each vaccine b y dose, number of
participating PHN sites, etc. These scenarios will be elaborated in a stud y protocol under
preparation with our PHN collaborators. Pfizer/BioNTech will plan for a 5 -year follow-up
period. Feasibility discussions with our PHN collaborators are ongoing; sho uld any issues or
unexpected challenges emerge, Pfizer/BioNTech will inform the agency promptly .
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PFIZER CONFIDENTIAL
Page 53. A prospective study to assess the incidence of subclinical myocarditis following
vaccination
Regarding the study to further characterize subclinical myocarditi s, we acknowledge that
you are in the process of analyzing Troponin I levels in serum samples to determine the
background rate of abnormality of this biomarker in the relevant population. We
acknowledge the challenge in projecting a definitive sample size or dates for a future study
to assess the incidence of subclinical myocarditis. However, we request that you propose
your plans for a future prospective study to assess the incidence of subclinical myocarditis,
including projected study milestone dates.
Sponsor Response
Reference is made to our most recent correspondence with the Agency on this topic, as
described in Response to CBER 10 August 2021 Information Request Regarding Post -
marketing Safet y Studies submitted to BLA on 11 August 2021.
As noted, we proposed to anal yze troponin I levels at a central laboratory in samples of
stored sera (drawn <1 year ago) in 12-30- year-old individuals participating in the C4591001
study, prior to receipt of BNT162b2 (ie, either at baseline, or at an y visit for plac ebo
recipients prior to cross -over). This is planned to include 3000 samples, stratified equall y in
the 12-17-, 18-24-, and 25-30-years age groups.
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 have been identified, retrieved from frozen storage, aliquoted and shipped to the
central laboratory . The samples then need to be tested and the data anal yzed and interpreted.
This work is anticipated to be completed b y the end of December 2021.
Furthermore, in a response to the Agency ’s recommendation to collect 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 to BB-IND 17936 on
04August 2021 ( SN0436), we made the following proposal but have not received feedback
on this proposal at this time.
We proposed to schedule a blood draw to obtain a s erum sample for storage and potential
future troponin testing, at baseline and 2 -5 days after the second or third dose of BNT162b2
in two studies.
C4591007: Pfizer/BioNTech propose dto add 750 participants 5 to <12 y ears of age
(randomized 2:1 to receive BNT162b2 10 µg or placebo) and 500 participants 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 dto add a new substudy of 1000 participants w ith
documented receipt of 2 prior 30 µg doses of BNT162b2 (the second dose received at least
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Page 66months 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 alternat ive4 weeks later).
Wereiterate our caution, which the Agency has acknowledged, that there is no widely
accepted definition of subclinical my ocarditis. Neither ECG abnormalities, nor elevated
troponin levels, arespecific to sy mptomatic m yocarditis, and certainly not to subclinical
myocarditis. Therefore, there remain many unknowns with respect to the feasibility and
design of an y potential prospective study of subclinical my ocarditis. In light of that, our
current proposal for a prospective study to assess the incidence of subclinical my ocarditis
following vaccination in individuals ≥16 years:
Analysis of baseline troponin I test results will be available by the end of December
2021.
During this same period of time we will prep are to start enrol lment of 1000
participants into the C4591031 substudy in January 2022.
Assuming that subclinical my ocarditis can be defined on the basis of elevated
troponin I , and that the baseline anal ysis indicates that such a study is feasible, we
will consider C4591031 to be the prospective study to assess the incidence of
subclinical my ocarditis following vaccination in individuals ≥16 years. If the sample
size of 1000 is insufficient, it will be increased through a protocol amendment .
Projected stu dy milestone dates (if sample size were to be increased to 3000) would
be as follows:
oFinal protocol submission: 30 November 2021 ;
oStudy completion: 30 June 2022 ;
oInterim reports: not applicable ;
oFinal study report: 31 December 2022 .
2.2.CBER Request 2 – Postmarketing Commitments
Additionally, should this product be approved, your proposed studies listed below will be
postmarketing commitments (PMCs) as agreed upon between FDA and the applicant:
1.A pregnancy registry for COMIRNATY to assess pregnancy and infant outcomes after
exposure of COMIRNATY during pregnancy in the Organization of Teratology
Information Specialists (OTIS)/Mother to Baby Pregnancy Registry (C4591022)
Sponsor Response
Pfizer/BioNTech acknowledges CBER ’s request and will conduct Study C4591022, “Pfizer-
BioNTech COVID -19 Vaccine Exposure during Pregnancy : A Non-Interventional Post-
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Page 7Approval Safet y Study of Pregnancy and Infant Outcomes in the Organization of Teratology
Information Specialists (OTI S)/MotherToBaby Pregnancy Registry,” as a PMC.
This prospective, observational cohort studywill assess pregnancy and infant outcomes after
exposure toCOMIRNATY during pregnancy amongpregnant women aged18 years orolder
who reside in the US or Canada . Pregnant women who participate in the OTI S Pregnancy
Registry and receive the vaccine on or after 11 December 2020 (i e, date FDA granted EUA
for the Pfizer -BioNTech COVID -19 vaccine) will be captured. The protocol was submitted
on 01 July 2021. Annualinterim report swill be submitted on 31 January 2022, 31 January
2023, 31 January 2024, and 31 January 2025. A f inal study reportwill be submitted by 01
December 2025.
2.A placebo -controlled, randomized, observer -blind study to evaluate the safety,
tolerability, and immunogenicity of BNT162b2 in healthy pregnant women ≥18 years
of age (C4591015)
For study C4591015, please comment on recruitment and retention of study participants to
date, including any barriers that you have encountered. Please comment on the feasibility
of completing the trial, as planned, considering CDC’s recommendation of COVID -19
vaccination for all people 12 years and older, including people who are pregnant
(https://www.cdc.gov/coronavirus/2019 -
ncov/vaccines/recommendations/pregnancy.html#anchor_1628692562866 ).
Sponsor Respon se
C4591015 is a global Phase 2/3, randomized, placebo -controlled, observer -blind study
evaluating the safet y, tolerability, and immunogenicity of 30 µg of BNT162b2 or placebo
administered in 2 doses, 21 day s apart, in approximately 700 healthy pregnant wo men
18years of age or older vaccinated at 24 to 34 weeks’ gestation. Participants are being
randomized 1:1 to receive BNT162b2 or placebo (saline). Participating countries are US,
Spain, UK, S outh Africa, Brazil andMozambique . All countries are active, w ith the
exception of Mozambique where enrollmentis due to start in October 2021.
Enrollmenthas been challenging due to recommendations for immunization of pregnant
womenin all participating countries, except Mozambique ,where such a recommendation is
anticipated shortl y. As of 13August 2021,enrollmentwas 259out of the planned 700 .
Anticipated enrollmentby December is approximately 450 participants. Retention does not
appear problematic once participants are enrolle d, with approximately 6% withdraw nfrom
the study due to request by participant , almost all participants in Phase2 having received a
second dose and 124having already delivered their infants .
An Internal Review Committee met on 0 5August 2021 to review the Phase 2 reactogenicity
andsafetydata through 7 day s after thesecond dose ,and recommended that the study
continue.
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PFIZER CONFIDENTIAL
Page 8There is concern that the study may have trouble reaching the full enrollment. At present the
intention is to complete the study if at all possible , because of the importance of a placebo -
controlled safet y assessment in pregnancy .
3. An active safety surveillance study among individuals in the Veteran’s Affairs Health
System (C4591012)
Sponsor Response
Study C4591012: “ Post-emergency UseAuthorization Active Safety Surveillance Study
Among Individuals in the Veteran’s Affairs Health Sy stem Receiving Pfizer -BioNTech
Coronavirus Disease 2019 (COVID -19) Vaccine”is an ongoing active surveillance PMC to
assess whether individuals in the US Veteran’s Affairs Health S ystem overall and in
subcohorts of interest experience an increased risk of safet y events of interest, following
receipt of the Pfizer-BioNTech COVID- 19 Vaccine. The study period will be approximately
30 months following availability of vaccine under EUA. A study protocol was submitted to
FDA on 29 January 2021. A protocol amendment to address anal yses requested by CBER on
12 May and 10 August 2021 will be submitted to the FDA b y 31 August 2021. A first
interim report was submitted to BB -IND 19736 (SN 0386) and EUA 27034 on 30 June 2021.
Additional interim reports are planned for 31 December2021, 30 June 2022 and 31
December2022. A final study report will be submitted by 31 December2023.
4.Study C4591014, Pfizer -BioNTech COVID -19 BNT162b2 Vaccine Effectiveness Study
-Kaiser Permanente Southern California
For Study C4591014, please comment on the feasibility of revising or amending the
protocol to also collect information on the incidence of myocarditis and pericarditis and to
include individuals 12 through 15 years of age.
Sponsor Response
Study C4591014 will be amended to include individuals 12 through 15 y ears of age in
vaccine effectiveness calculations. Safet y endpoints, however, will not be collected in this
study and are better -suited to be collected in other ongoing post -authorization safety studies.
2.3.CBER Request 3 – Study Milestones
Please confirm the study milestone dates (mm/dd/yyyy) in the tables below, and populate
the projected study milestone dates for PMR#3 (subclinical myocarditis) as per the above
request.
Note that we have also included dates for interim reports when applicable.
Sponsor Response
Study milestones have been updated (in boldfont)in the below tables.
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PFIZER CONFIDENTIAL
Page 9Milestone
datesPMR #1a:
C4591009
(Sentinel)PMR #1b: C4591021
(EU)PMR #1c:
C4591021
substudy (EU)PMR#2: PHN
registryPMR#3:
subclinical
myocarditis
Final protocol
submission 08/31/2021 08/11/2021 Subsequent to
EMA approval,
estimated
01/31/202211/30/2021 11/30/2021
Study
completion06/30/2025 09/30/2024 09/30/2024 12/01/2026 06/30/22
Interim reports Monitoring
report:
10/31/2022
Interim report:
10/31/2023Progress 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:
03/31/2024Not applicable
Final study
report10/31/2025 09/30/2024 09/30/2024 05/01/2027 12/31/2022
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Page 10Milestone dates PMC #1: C4591022
pregnancy registryPMC#2: C4591015 RCT
pregnant w omenPMC#3: C4591012
VA studyPMC #4: C4591014
Kaiser study
Final protocol
submission 07/01/2021 12/22/2020 1/29/2021 3/22/2021
Study completion 06/01/2025 10/31/2022 06/10/2023
Interim reports Interim report 1:
01/31/2022
Interim report 2:
01/31/2023
Interim report 3:
01/31/2024
Interim report 4:
01/31/2025Interim 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 12/01/2025 5/31/2023 12/31/2023 06/30/2023
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Page 112.4.CBER Request 4
Please also propose study(ies) in adolescents 12 through 17 years of age to evaluate the
safety and immunogenicity of lower doses of COMIRNATY.
Sponsor Response
Pfizer/BioNTech submitted protocol amendment 2 to BB-IND 19736 for Study C4591007 to
the Agency on 10 August 2021 (SN 0443).
This protocol amendment includes Phase 1 evaluation of dose levels of 3 µg and 10 µg in
individuals 12 to <16 yearsof age and 16 to <30 yearsof age(32 participants per dose level
and age group) .Based on the results from Phase 1, one dose level will be selected for each
age group for Phase 3 evaluation of s afety and immunogenicit y in 300 participants per age
group.
2.5.CBER Request 5
Voluntary sponsor studies
For the following voluntary sponsor studies, please provide study status updates in your
periodic safety reports:
C4591011: Active safety surveillance of the Pfizer- BioNTech COVID -19
vaccine in the U.S. Department of Defense population following Emergency
Use Authorization
C4591008: HERO Together: A post -Emergency Use Authorization
observational cohort study to evaluate the safety of the Pfizer- BioNTech
COVID-19 Vaccine in U.S. healthcare workers, their families, and their
communities
Sponsor Response
Pfizer/BioNTech will provide study status updates regarding Study C4591011 and Study
C4591008 in periodic safety reports.
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