Document text
Pfizer -BioNTech COVID -19 Vaccine
C4591022 NON -INTERVENTIONAL STUDY PROTOCOL SYNOPSIS
14April 2021
PFIZER CONFIDENTIAL
Page 1of 12NON- INTERVENTIONAL (NI) STUDY PROTOCOL SYNOPSIS
Study information
Title Pfizer -BioNTech COVID-19 Vaccine Exposure
during Pregnancy : A Non-Interventional Post -
Approval Safet y Study of Pregnancy and Infant
Outcomes in the Organization of Teratology
Information Specialists (OTI S)/MotherToBab y
Pregnancy Registry
Protocol number C4591022
Date 14April 2021
EU Post Authoriz ation Study (PAS)
register numberTo be registered before the start of data
collection
Active substance COVID -19 mRNA Vaccine is single -stranded,
5’-capped messenger RNA (mRNA) produced
using a cell -free in vitro transcription from the
corresponding DNA templates, encoding the
viral spike (S) protein of SARS -CoV -2
Medicinal product Pfizer -BioNTech COVID- 19 Vaccine
(BNT162b2)
Research question and objectives Are the incidence rates of pregnancy and infant
safet youtcomes among pregnant women
vaccinated with the Pfizer- BioNTech COVID 19
vaccine in the Organization of Teratology
Information Specialists (OTI S)/MotherToBaby
Pregnancy Registry (“OTIS Pregnancy
Registry ”)increased as compared with rates of
these outcomes in pregnant women who did not
receive the Pfizer -BioNTech COVID -19
vaccine?
Primary Objective
To assess whether pregnant women in the
OTIS Pregnancy Registry receiving the
Pfizer -BioNTech COVID- 19 vaccine
experience increased risk of pregnancy
andinfant safety outcomes, including
090177e196cb44c5\Approved\Approved On: 15-Apr-2021 16:57 (GMT)
FDA-CBER-2021-5683-0780481
Pfizer -BioNTech COVID -19 Vaccine
C4591022 NON -INTERVENTIONAL STUDY PROTOCOL SYNOPSIS
14April 2021
PFIZER CONFIDENTIAL
Page 2of 12major congenital malformations,
spontaneous abortion, stillbirth, preterm
delivery , small for gestational age, and
small for age postnatal growth to one
year of age.
Secondary Objective
To characterize utilization patterns of the
Pfizer -BioNTech COVID- 19 vaccine
among pregnant women in the OTIS
Pregnancy Registry , including the
proportion who completed the 2- dose
vaccine schedule, the trimester of vaccine
administration, and the distribution of
time gaps between the first and second
dose.
Author Christina Chambers, PhD, MPH
Professor of Pediatrics
School of Medicine
University of California San Diego
9500 Gilman Drive, MC 0828
La Jolla, CA 92093
Tel: +1 858-246-1704
Email: [email protected]
Renu Garg, PhD, MPH
Safety Surveillance Research Scientist
Worldwide Medical and Safety
Pfizer, I nc.
235 East 42nd Street
New York, NY 10017
Tel: +1 212-733-0254
Email: [email protected]
090177e196cb44c5\Approved\Approved On: 15-Apr-2021 16:57 (GMT)
FDA-CBER-2021-5683-0780482
Pfizer -BioNTech COVID -19 Vaccine
C4591022 NON -INTERVENTIONAL STUDY PROTOCOL SYNOPSIS
14April 2021
PFIZER CONFIDENTIAL
Page 3of 12TABLE OF CONTENTS
LIST OF TABLES ................................ ................................ ................................ ..................... 3
1. RATIONALE AND BAC KGROUND ................................ ................................ .................. 4
2. RES EARCH QUESTION AND O BJECTI VES ................................ ................................ ...4
3. RESEARCH METHODS ................................ ................................ ................................ ......5
3.1. Study design ................................ ................................ ................................ .............. 5
3.2. Setting ................................ ................................ ................................ ........................ 5
3.3. Variables ................................ ................................ ................................ .................... 6
3.3.1. Vaccine Exposures ................................ ................................ ........................ 6
3.3.2. Pregnancy and Infant Safet y Outcomes ................................ ........................ 6
3.3.3. Demographic and Clinical Characteristics ................................ ................... 6
3.4. Data Source ................................ ................................ ................................ ............... 7
3.4.1. Materna l Interviews ................................ ................................ ...................... 8
3.4.2. Medical Records and General Pediatric Evaluation ................................ .....9
3.5. Study Size ................................ ................................ ................................ ................ 10
3.6. Data Anal ysis................................ ................................ ................................ .......... 10
3.7. L imitatio ns of the Research Methods ................................ ................................ ......10
4. MILESTONES ................................ ................................ ................................ ..................... 11
5. REFERENCES ................................ ................................ ................................ .................... 12
LIST OF TABLES
Table 1. Timing of Cohort Enrollment, I nterviews, Examinations, and
Medical Records ................................ ................................ ......................... 9
090177e196cb44c5\Approved\Approved On: 15-Apr-2021 16:57 (GMT)
FDA-CBER-2021-5683-0780483
Pfizer -BioNTech COVID -19 Vaccine
C4591022 NON -INTERVENTIONAL STUDY PROTOCOL SYNOPSIS
14April 2021
PFIZER CONFIDENTIAL
Page 4of 121.RATIONALE AND BACKGR OUND
Despite public health efforts, the incidence of coronavirus disease 2019 (COVID -19) due to
the severe acute respiratory syndrome coronavirus 2 (SARS -CoV -2)has continued to rise .
COVID -19 largel y affect smiddle -aged persons with worsening clinical sequelae linked to
increasing age and comorbid conditions (e.g., cardiovascular disease, diabetes ,and chronic
lung disease). As of 23 March 202 1, over 29.8million COVI D-19 cases and 542,991 deaths
have been reported in the United States (US) alone (Johns Hopkins University , 202 1).
Pfizer and BioNTech have partnered to develop a novel messenger RiboNucleic Acid
(mRNA )vacci ne against SARS -CoV -2 for the prevention of COVID -19 (Candidate
BNT162b2). On 11 December 2020, the US Food and Drug Administration ( FDA )granted
Emergency Use Authorization ( EUA )for the Pfizer -BioNTech COVID-19 vaccine for
individuals 16 y ears of age and older.
Available data suggest that pregnant women who become infected with COVID -19may be
more likely to be hospitalized and may be at increased risk of preterm delivery (MMWR ,
2020 ). The Pfizer- BioNTech COVID -19 vaccine is likely to be utilized by pregnant women
when they and their healthcare providers believe that risk/benefit considerations favor its use,
however, h uman pregnancy exposure data for the vaccine is lacking. While the current
product labeling communicates that data are insufficient, Pfizer is conducting a n ongoing
Phase 2/3 clinical trial of the safet y and immunogenicity of the Pfizer -BioNTech COVID-19
vaccine in pregnant women .Also, given the frequency of unplanned pregnancies,
information regarding the safet y of the COVID -19 vaccine in human pregnancy is essential
from a public health perspective. Here, we provide a s ynopsis of the proposed study, which is
intended t o monitor rates of pregnancy and infant safet y outcomes in pregnancies exposed to
the Pfizer -BioNTech COVID-19 vaccine among women enrolled in an established North
American pregnancy registry .This proposed non-interventional study is designated as a Post -
Authoriz ation Safety Study (PASS) and is anticipated as a commitment to the FDA .
2.RESEARCH QUESTION AND OBJECTIVES
The research question for the study is: Are the incidence rates of pregnancy and infant safety
outcomes among pregnant women vaccinated with the Pfizer -BioN Tech COVID 19 vaccine
in the Organization of Teratology Information Specialists (OTI S)/MotherToBaby Pregnancy
Registry (“OTIS Pregnancy Registry ”)increased as compared with rates of these outcomes in
pregnant women who did not receive the Pfizer- BioNTech COVID -19 vaccine ?
Primary objective
To assess whether pregnant women in the OTIS Pregnancy Registry receiving the
Pfizer -BioNTech COVID- 19 vaccine experience increased risk of pregnancy and
infant safet y outcomes, including major congenital malformations, spontaneous
abortion, stillbirth, preterm delivery , small for gestational age, and small for age
postnatal growth to one year of age.
090177e196cb44c5\Approved\Approved On: 15-Apr-2021 16:57 (GMT)
FDA-CBER-2021-5683-0780484
Pfizer -BioNTech COVID -19 Vaccine
C4591022 NON -INTERVENTIONAL STUDY PROTOCOL SYNOPSIS
14April 2021
PFIZER CONFIDENTIAL
Page 5of 12Secondary objective
To characterize utilization patterns of the Pfizer -BioNTech COVID -19 vaccine
among pregnant women in the OTI S Pregnancy Registry ,including the proportion
who completed the 2 -dose vaccine schedule, the trimester of vaccine administration,
and the distribution of time gaps between the first and second dose.
3. RESEARCH METHODS
3.1.Study design
This proposed st udy is a prospective, observational cohort study of pregnancy and infant
safet y outcomes in pregnant women with expos ureto the Pfizer -BioNTech COVID-19
vaccine using data from the OTIS Pregnancy Registry .The comparator groups are 1)
pregnant women who received an influenza or Tdap (i.e., tetanus, diphtheria, and acellular
pertussis) vaccine during pregnancy and 2) pregnant women who received no vaccines
during pregnancy .
3.2. S etting
The study population includes pregnant women aged18 years or older resid ing in the US or
Canada who are enrolled in the OTI S Pregnancy Registry during the study period 01 May
2021 – 30 April 2024. To participate in the stud y, women must provide consent indicating
that the y have been informed of all pertinent aspects of the study , including the conditions
and requirements of the study such as the interview schedule and release of medical records .
The study will include t hree groups of participants followed for pregnancy and infant
outcomes:
Pfizer -BioNTech COVID -19 Vaccine -Exposed
–Pregnant women with exposure to at least one dose of the Pfizer- BioNTech
COVID -19 vaccine within onemonth prior to the first day of the last menstrual
period (LMP) or during pregnancy
Influenza or TDAP Vaccine Exposed ( Active Comparator )
–Pregnant women with exposure to an influenza or Tdap vaccine but no exposure
to a COVID -19 vaccine within one month prior to the first day of LMP or
during pregnancy
Vaccine Unexposed ( Unexposed Comparator )
–Pregnant women who have not had exposure to any vaccine within one month
prior to the first day of LMP or during pregnancy .
Women with a known pregnancy outcome at the time of study entry (e.g., positive prenatal
diagnostic test results for a major congenital malformation prior to study entry )are not
eligible for study entry .
090177e196cb44c5\Approved\Approved On: 15-Apr-2021 16:57 (GMT)
FDA-CBER-2021-5683-0780485
Pfizer -BioNTech COVID -19 Vaccine
C4591022 NON -INTERVENTIONAL STUDY PROTOCOL SYNOPSIS
14April 2021
PFIZER CONFIDENTIAL
Page 6of 123.3.Variables
Variables for the exposures, outcomes, demographics, and clinical characteristics of interest
are included below .Data on these variables will be collected via maternal interview and
medical record review per standard process within the registry infrastructure .Detailed
operational definitions will be provided in the full protocol and the Statistical Anal ysis Plan
(SAP) .
3.3.1. Vaccine Exposure s
Pfizer -BioNTech COVID-19 v accine (Exposure)
Influenza and Tdap vaccines (Active Comparator)
3.3.2. Pregnancy and Infant Safety Outcomes
Pregnancy Outcome s
oMajor congenital malformations
oSpontaneous abortion/miscarriage
oStillbirth
oPreterm delivery
oSmall for gestational age at birth
InfantOutcome
oSmall for age p ostnatal growth to oneyear of age .
3.3.3. Demographic and Clinical Characteristics
Demographic characteristics
oAge
oRace
oEthnicity
oGeographic area of residence
oEducation
oSocioeconomic category
090177e196cb44c5\Approved\Approved On: 15-Apr-2021 16:57 (GMT)
FDA-CBER-2021-5683-0780486
Pfizer -BioNTech COVID -19 Vaccine
C4591022 NON -INTERVENTIONAL STUDY PROTOCOL SYNOPSIS
14April 2021
PFIZER CONFIDENTIAL
Page 7of 12Clinical characteristics
oHeight
oPre-pregnancy body weight
oPre-pregnancy BMI
oNumber of prior pregnancies
oNumber of previous live birth or stillbirth deliveries
oNumber of previous pregnancies ending in spontaneous abortion
oNumber of previous pregnancies ending in elective termination
oGesta tional age at enrollment
oReferral source
oPrenatal vitamin, multivitamin, or folic acid use in pregnancy
oAlcohol use in pregnancy
oTobacco use in pregnancy
oOther vaccine exposure during pregnancy
oPrenatal diagnostic tests prior to study enrollment
oPrenatal diagnostic tests on or after study enrollment
oMaternal pregnancy exposure to another known human teratogen
oComorbid maternal medical history
oCovid -19 infection sy mptoms and/or positive test
3.4.Data Source
This study will use data that are collected as part of the OTIS Pregnancy Registry . The OTIS
Pregnancy Registry was established in 1999 and is conducted b y the OT IS Research Group ,a
network of university and health department based telephone information centers serving
pregnant women and healthcare providers throughout the US and Canada (Leen -Mitchell et
al, 2000 ). Pregnant women who call are recruited for the OTIS Pregnancy Registry , and the
healthcare providers are requested to contact the OTIS Pregnancy Registry to provide patient
referrals. A ctive recruitment strategies are also used, e.g., direct mailings to healthcare
providers , website, and professional meetings.
090177e196cb44c5\Approved\Approved On: 15-Apr-2021 16:57 (GMT)
FDA-CBER-2021-5683-0780487
Pfizer -BioNTech COVID -19 Vaccine
C4591022 NON -INTERVENTIONAL STUDY PROTOCOL SYNOPSIS
14April 2021
PFIZER CONFIDENTIAL
Page 8of 12As part of the registry protocol , data are collected using maternal interview(s), medica l
record r eview (obstetric, delivery hospital, pediatric, vaccine provider, and/or other specialty
provider if applicable) , and the pregnancy exposure diary (see Table 1Schedule of Follow -
up).
3.4.1. Maternal Interview s
Intake/Enrollment Interview : Astructured maternal intake telephone interview is
conducted at enrollment by a trained Research Associate from the OTI S Research
Center . This interview includ esquestions on the following: pregnancy history ;
current health history ; pre-pregnancy weight and height; socioeconomic and
demographic information including maternal and paternal occupation, education and
ethnicity ; income category , current medication use, both prescripti onand over the
counter; other environmental or occupational exposures, alcohol, tobacco, caffeine
and illicit drug use; current pregnancy complications including illnesses; names and
addresses of health care providers; and vaccine use .
Interim Interviews I and II : Telephone interviews areconducted at 20- 22 and 32 -34
weeks’ gestation ( ifenrolled at those times ) by a trained Research Associate from the
OTIS Research Center . This interview is intended to update records of pregnancy
exposures (medications, vaccinations, vitamins, etc.) , results of prenatal tests, and
events of interest since last interview; to supplement this interview and improve
recall, participants aregiven a pregnancy exposure diary after the Enrollment
Interview to record related information.
Pregnancy Outcome Interview : Astructured telephone interview will be conducted
at 0 to six weeks after the expected due date, or at an interim interview point if
pregnancy has ended ,by a trai ned Research Associate from the OTI S Research
Center to elicit information based on t ype of birth :
oFor women with live born infants: date of delivery , hospital location and
mode of delivery ; sex, birth weight, length and head circumference; Apgar
scores; description of delivery or birth complications including
malformations; type and length of hospital stay for mother and infant;
delivering ph ysician’s and infant phy sician’s names and addresses; method of
infant feeding; pregnancy weight gain; and additiona l exposures and results of
prenatal tests occurring since the previous interview.
oFor women with spontaneous abortions: date and ty pe of outcome; hospital
location if applicable; prenatal diagnosis; pathology results if available; and
additional exposures and results of prenatal tests occurring since the previous
interview.
oFor women with stillborn infants :all of the abov e for women with
spontaneous abortions, plus sex, delivery or birth complications including
malformations, and autopsy results if available.
090177e196cb44c5\Approved\Approved On: 15-Apr-2021 16:57 (GMT)
FDA-CBER-2021-5683-0780488
Pfizer -BioNTech COVID -19 Vaccine
C4591022 NON -INTERVENTIONAL STUDY PROTOCOL SYNOPSIS
14April 2021
PFIZER CONFIDENTIAL
Page 9of 123.4.2. Medical Records and General Pediatric Evaluation
The mother’s and infant’s medical records are captured at birth an d again for the infant at 1
yearof age . Medical records are reviewed by trained abstractors to confirm information self -
reported b y the participant related to vaccine exposure, outcomes, prenatal tests, and medical
history .A standard phy sical evaluation form is also mailed to each pediatrician or other
physician responsible for the care of each live born in fantto complemen tthe medical record
which may not be complete . This form includes information on infant size at the time of the
latest examination an d an open-ended question about postnatal complications and congenital
anomalies.
At one y ear of age, a second standard ph ysical evaluation form is sent to the health care
provider to request updated information on growth, and major congenital malformations.
Table 1. Timing of Cohort Enrollment, Interviews, Examinations, and Medical
Records
Any time
In
Pregnancy20-22
Weeks’
Gestationb32-34
Weeks’
Gestationc0-6
Weeks
Post-
Delivery0-12
Months
Post-
Delivery1 Year
Post-
Delivery
Referrala√
Enrollment and
Consenta√
Enrollment Interviewa√
Interim Interview I √
Interim Interview II √
Pregnancy Outcome
Interview and Request
for Medical Records√
Medical Record
Acquisition and Review√
Pediatric 1- Year
Medical Records
Request and Review √
a.Participants may enroll in the study any time during pregnancy.
b.If subject is enrolled and Intake Interview is conducted after 18 w eeks’ gestation, only one interim
interview is conducted during pregnancy at 32 -34 w eeks gestation.
c.If subject is enrolle d and Intake Interview is conducted at 30 weeks’ gestation or after, no Interim
Interview is collected.
090177e196cb44c5\Approved\Approved On: 15-Apr-2021 16:57 (GMT)
FDA-CBER-2021-5683-0780489
Pfizer -BioNTech COVID -19 Vaccine
C4591022 NON -INTERVENTIONAL STUDY PROTOCOL SYNOPSIS
14April 2021
PFIZER CONFIDENTIAL
Page 10of 123.5.Study Size
Thestudy will aim to enroll 1800 pregnant women in the cohort study over a 3 -year
recruitment period : 900 in the Pfizer -BioNTech COVID- 19 vaccine group, 600 in the
flu/Tdap vaccine group (active comparator) ,and 300 in the vaccine unexposed group
(unexposed comparator) .
The relative risk (RR) for safet y endpoints between the exposed and comparator groups will
be estimated as feasible (eg, sufficient case counts) . Thefullprotocol will include sample
size and power calculations forthe minimum detectable RRs with 80% power and two-sided
alpha level of 0.05 for the range of background risks of the outcomes of interest .
3.6.Data Analysis
The distributions of demographic and baseline characteristics will be summarized within
each exposure group .Birth prevalence rates and incidence rates will be calculated for the
pregnancy and infant outcomes, respectivel y.Foreach outcome, risk estimates will be
described separatel y foreach cohort and , where feasible, will be compared between the
Pfizer -BioNTech COVID-19 vaccine- exposed group and 1) the influenza/Tdap vaccinated
cohort and 2) the unvaccinated cohort using methods to control potential confounding.
Descriptive statistics will be used to summarize utilization patterns of the Pfizer -BioNTech
COVID -19 vaccine.
Detailed methodology for summary and statistical anal yses of data collected in this study will
be docum ented in the full protocol and statistical analy sis plan (SAP) .
3.7.Limitations of the R esearch M ethods
This study will use data from the well -established OTI S Pregnancy Registry which collects
detailed data on prenatal/birth exposures (including timing of exp osures during pregnancy )
and outcomes. However, potential selection bias is the primary limitation of a cohort study
utilizing volunteer participants; women who agree to enroll in the cohort study may represent
particularl y high or low risk pregnancies ( Johnson, 2001 ).
Another limitation of the study design relates to the evaluation of spontaneous abortion rates.
Rates of early spontaneous abortion, i .e., at 7- 9 weeks post -LMP or less, will not be
measured in a stud y that e nrolls women after recognition of pregnancy . Therefore,
spontaneous abortion will be defined as late first -trimester and earl y second- trimester
pregnancy loss. Anal ysis of spontaneous abortion will be restricted to those who enroll prior
to 20.0 weeks’ ge station. In addition, if a high proportion of women enroll later in pregnancy ,
other survival biases may be introduced. A sensitivity anal ysis by gestational age at
enrollment will be performed in order to address these questions. Anal yses will be stratifi ed
by gestational age at enrollment to help address the potential selection bias.
Because earl y prenatal t esting is so prevalent in the U.S. and Canada , it may be difficult to
achieve adequate numbers of participant s if all pregnancies with prenatal test ing prior to
enrollment are excluded from the anal ysis. Therefore, the study will include pregnant
women enrolled prior to outcome but after a prenatal test has been performed as long as the
090177e196cb44c5\Approved\Approved On: 15-Apr-2021 16:57 (GMT)
FDA-CBER-2021-5683-0780490
Pfizer -BioNTech COVID -19 Vaccine
C4591022 NON -INTERVENTIONAL STUDY PROTOCOL SYNOPSIS
14April 2021
PFIZER CONFIDENTIAL
Page 11of 12testdoes not indicate the presence of a major congenital malfor mation . The FDA guidance
document ( FDA Postapproval Pregnancy Safet y Studies Draft Guidance for Industry , 2019 )
acknowledges that such an approach may be necessary to accrue adequate numbers.
However, this practice could poten tially bias the r esults by lowering the overall estimate of
the prevalence of major congenital malformations ( Honein, 1999).
4.MILESTONES
The full protocol will be submitted for FDA review by 01 July2021. Proposed milestones are
listed below.
Milestone Planned date
Registration in the EU PAS register To be registered before the start of data collection
Start of data collection 01 November 20211
Interim Reports 31 January 2022
31 January 2023
31 January 2024
31 January 2025
End of data collection 31 December 20242
Final study report 01December 2025
1To meet sample size goals, enrollment of participants into study cohort is planned to begin 01 May
2021. The start of data collection is defined as start date of data extraction for the first interim report.
2The end of data collection is defined as the date that the analytic dataset is available for analysis .
090177e196cb44c5\Approved\Approved On: 15-Apr-2021 16:57 (GMT)
FDA-CBER-2021-5683-0780491
Pfizer -BioNTech COVID -19 Vaccine
C4591022 NON -INTERVENTIONAL STUDY PROTOCOL SYNOPSIS
14April 2021
PFIZER CONFIDENTIAL
Page 12of 125.REFERENCES
FDA. Postapproval Pregnancy Safet y Studies Draft Guidance for Industry . Mary land, May
2019
Honein MA, Paulozzi L J, Cragan JD, Correa A. Evaluation of selected characteristics of
pregnancy drug registries. Teratology 1999; 60:356 -64.
Johns Hopkins University. Coronavirus Resource Center. Available at:
https://coronavirus.jhu.edu/. Accessed March 23 , 202 1.
Johnson KA, Weber PA, Jones KL , Chambers CD. Selection bias in Teratology Information
Service pregnancy outcome studies. Teratology 2001; 64:79 -82.
Leen -Mitchell M, Martinez L , Gallegos S, Robertson J, Carey JC. Mini- review: hi story of
organized teratology information services in North America. Teratology 2000;
61:314 -7.
MMWR Morb Mortal Wkly Rep. Birth and Infant Outcomes Following Laboratory -
Confirmed SARS -CoV -2Infection in Pregnancy —SET-NET, 16 Jurisdictions,
March 29 –Octo ber 14 . 2020 Nov 6;69(44):1635-1640.
090177e196cb44c5\Approved\Approved On: 15-Apr-2021 16:57 (GMT)
FDA-CBER-2021-5683-0780492