Document text
Pfizer -BioNTech COVID -19 Vaccine
C4591022 NON -INTERVENTIONAL STUDY PROTOCOL
Version 4.0, 09 May 2022
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 3.0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
20-May-2021
Page 1 of 50NON -INTERVENTIONAL (NI) STUDY PROTOCOL
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)/MotherToBaby
Pregnancy Registry
Protocol number C4591022
Protocol version identifier 4.0
Date 09 May 2022
EU Post Authorization 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 Is the risk of pregnancy and infant safet y
outcomes increased among pregnant women
in the Organization of Teratology
Information Specialists
(OTIS)/MotherToBab y Pregnancy Registry
who were vaccinated with the Pfizer -
BioNTech COVID -19 vaccine during
pregnancy compared wit h those who did not
receive an y COVID -19 vaccine during
pregnancy ?
Study Objective
090177e19a3ab0c5\Approved\Approved On: 17-May-2022 21:36 (GMT)
FDA-CBER-2022-5812-0236185
Pfizer -BioNTech COVID -19 Vaccine
C4591022 NON -INTERVENTIONAL STUDY PROTOCOL
Version 4.0, 09 May 2022
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 3 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
20-May-2021
Page 2of 50To assess whether pregnant women
who received the Pfizer -BioNTech
COVID -19 vaccine during pregnancy
experienced increased risk of
pregnancy and infant safety
outcomes, inclu ding major
congenital malformations,
spontaneous abortion, elective
termination/abortion, stillbirth,
preterm delivery , small for
gestational age, and small for age
postnatal growth atone year of age,
relative to pregnant women who
received no COVID -19 vaccines
during pregnancy .
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]
This document contains confidential information belonging to Pfizer. Except as otherw ise agreed to in w riting,
by accepting or reviewing this document, you agree to hold this information in confidence and not copy or
disclose it to others (except where required by applicable law) or use it for unauthorized purposes. In the event
of any actual or suspected breach of this obligation, Pfizer must be promptly notified.
090177e19a3ab0c5\Approved\Approved On: 17-May-2022 21:36 (GMT)
FDA-CBER-2022-5812-0236186
Pfizer -BioNTech COVID -19 Vaccine
C4591022 NON -INTERVENTIONAL STUDY PROTOCOL
Version 4.0, 09 May 2022
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 3 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
20-May-2021
Page 3of 501.TABLE OF CONTENTS
1. TABLE OF CONTENTS ................................ ................................ ................................ .......3
2. LIST OF ABBREVIAT IONS ................................ ................................ ................................ 5
3. RESPONSIBLE PARTI ES................................ ................................ ................................ ....7
4. ABSTRACT ................................ ................................ ................................ ........................... 8
5. AMENDMENTS AND UP DATES ................................ ................................ ..................... 11
6. MILESTONES ................................ ................................ ................................ ..................... 14
7. RATIONALE A ND BACKGROUND ................................ ................................ ................ 15
8. RESEARCH QUESTION AND OBJECTI VES ................................ ................................ .16
9. RESEARCH METHODS ................................ ................................ ................................ ....16
9.1. Study Design ................................ ................................ ................................ ........... 16
9.2. Setting ................................ ................................ ................................ ...................... 17
9.2.1. I nclusion Criteria ................................ ................................ ........................ 17
9.2.2. Exclusion Criteria ................................ ................................ ....................... 17
9.2.3. Follow -Up................................ ................................ ................................ ...18
9.3. Variables ................................ ................................ ................................ .................. 18
9.3.1. I dentif ication of Exposure and Comparator ................................ ............... 18
9.3.2. Classification of Pregnancy and Infant Outcomes ................................ ......19
9.3.2.1. Major Congenital Malformations ................................ .............. 20
9.3.2.2. Spontaneous abortion ................................ ................................ 21
9.3.2.3. Elective termination/abortion ................................ .................... 21
9.3.2.4. Stillbirth ................................ ................................ ..................... 21
9.3.2.5. Preterm delivery ................................ ................................ ........ 21
9.3.2.6. Small for gestational age at birth ................................ ............... 21
9.3.2.7. Small for age postnatal growth at one year of age .................... 21
9.3.3. Demographic and Clinical Characteristics ................................ ................. 23
9.4. Data Source ................................ ................................ ................................ ............. 26
9.4.1. Modalities of Recruitment ................................ ................................ .......... 28
9.4.2. Maternal Interviews................................ ................................ .................... 29
9.4.3. Medical Records and General Pediatric Evaluation ................................ ...30
9.4.4. Scientific Advisory Board ................................ ................................ .......... 31
090177e19a3ab0c5\Approved\Approved On: 17-May-2022 21:36 (GMT)
FDA-CBER-2022-5812-0236187
Pfizer -BioNTech COVID -19 Vaccine
C4591022 NON -INTERVENTIONAL STUDY PROTOCOL
Version 4.0, 09 May 2022
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 3 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
20-May-2021
Page 4of 509.5. Study Size ................................ ................................ ................................ ................ 31
9.6. Data Management ................................ ................................ ................................ ...34
9.7. Data Anal ysis................................ ................................ ................................ .......... 34
9.7.1. Sta tistical Methods......................................................................................34
9.7.2. Primary Anal yses................................ ................................ ........................ 35
9.7.3. Secondary Anal yses................................ ................................ .................... 38
9.7.3.1. Stratified/Subgroup Analy ses................................ .................... 38
9.7.3.2. I ndividual Dose Effects ................................ ............................. 38
9.7.3.3. Evaluation for a Pattern of Major Congenital
Malformations ................................ ................................ ................... 39
9.7.3.4. L ost to Follow -Up................................ ................................ .....39
9.7.4. Sensitivity Analy ses................................ ................................ .................... 39
9.7.5. Missing Data ................................ ................................ ............................... 40
9.7.6. Analy sis Software ................................ ................................ ....................... 40
9.8. Quality Control ................................ ................................ ................................ ........ 40
9.9. L imitations of the Research Methods................................ ................................ ......41
9.10. Other Aspects ................................ ................................ ................................ ........ 43
10. PROTECTI ON OF HUMAN SUBJECTS ................................ ................................ ........ 44
10.1. Patient I nformation ................................ ................................ ................................ 44
10.2. Participant Consent ................................ ................................ ............................... 44
10.3. I nstitutional Review Board (IRB)/Independent Ethics Committee (I EC)............ 44
10.4. Ethical Conduct of the Study ................................ ................................ ................ 44
11. MANAGEMENT AND R EPORTI NG OF ADVERSE EVENTS /ADVERSE
REACTI ONS ................................ ................................ ................................ ...................... 44
12. PL ANS FOR DI SSEM INATING AND COMMUNI CATING STUDY RESUL TS........ 45
13. REFERENCES ................................ ................................ ................................ .................. 46
14. LIST OF TA BLES ................................ ................................ ................................ ............. 50
15. LIST OF FIGURES ................................ ................................ ................................ ........... 50
ANNEX 1. LIST OF STAND ALONE DOCUMENTS .........................................................50
ANNEX 2. ADDITIONAL INFORMATION ................................ ................................ ......... 50
090177e19a3ab0c5\Approved\Approved On: 17-May-2022 21:36 (GMT)
FDA-CBER-2022-5812-0236188
Pfizer -BioNTech COVID -19 Vaccine
C4591022 NON -INTERVENTIONAL STUDY PROTOCOL
Version 4.0, 09 May 2022
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 3 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
20-May-2021
Page 5of 502. LIST OF ABBREVIATIONS
Abbreviation Definition
AE adverse event
BMI body mass index
CBER Center for Biologics Evaluation and Research
CDC Centers for Disease Control and Prevention
CI confidence interval
COVID -19 Coronavirus disease 2019
EUA Emergency Use Authorization
EU PAS European Union Post Authorization Study
FDA Food and Drug Administration
HCP health care provider
HIPAA Health Insurance Portability and Accountability Act
HR hazard ratio
IEC independent ethics committee
IRB Institutional Review Board
IPTW inverse probability of treatment weighting
LMP last menstrual period
MACDP Metropolitan Atlanta Congenital Defects Program
MI multiple imputation
MICE multivariate imputation by chained equations
mRNA messenger ribonucleic acid
NCHS National Center for Health Statistics
OTIS Organization of Teratology Information Specialists
090177e19a3ab0c5\Approved\Approved On: 17-May-2022 21:36 (GMT)
FDA-CBER-2022-5812-0236189
Pfizer -BioNTech COVID -19 Vaccine
C4591022 NON -INTERVENTIONAL STUDY PROTOCOL
Version 4.0, 09 May 2022
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 3 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
20-May-2021
Page 6of 50Abbreviation Definition
PASS Post-Authorization Safety Study
PDA patent ductus arteriosus
PFO patent foramen ovale
PMC postmarketing commitment
RR risk ratio
SAP Statistical Analy sis Plan
SARS -CoV -2 severe acute respiratory syndrome coronavirus 2
SOP standard operating procedure
Tdap tetanus, diphtheria, and acellular pertussis
UCSD University of California San Diego
US United States
VAMPSS Vaccines and Medications in Pregnancy Surveillance
System
WHO World Health Organization
090177e19a3ab0c5\Approved\Approved On: 17-May-2022 21:36 (GMT)
FDA-CBER-2022-5812-0236190
Pfizer -BioNTech COVID -19 Vaccine
C4591022 NON -INTERVENTIONAL STUDY PROTOCOL
Version 4.0, 09 May 2022
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 3 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
20-May-2021
Page 7of 503.RESPONSIBLE PARTIES
Principal Investigator(s) of the Protocol
Nam e, degree(s) Job Title Affiliation Address
Christina
Chambers, PhD,
MPHPrincipal
Investigator, OTIS
Mother to Bab yUniversity of
California, San
Diego9500 Gilman Dr. #0828
La Jolla, CA, 92093 -
0828
Kenneth Ly ons
Jones, MDCo-Investigator,
OTIS Mother to
BabyUniversity of
California, San
Diego9500 Gilman Dr. #0828
La Jolla, CA, 92093
Renu Garg, PhD,
MPHNon-Interventional
(NI) Stud y LeadPfizer, I nc. 235 East 42nd Street
New York, NY
10017
090177e19a3ab0c5\Approved\Approved On: 17-May-2022 21:36 (GMT)
FDA-CBER-2022-5812-0236191
Pfizer -BioNTech COVID -19 Vaccine
C4591022 NON -INTERVENTIONAL STUDY PROTOCOL
Version 4.0, 09 May 2022
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 3 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
20-May-2021
Page 8of 504.ABSTRACT
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)/MotherToBaby Pregnancy
Registry
Main author: Christina Chambers, University of California S an Diego (UCSD) and the
Organization of Teratology Information Specialists (OTI S)
Rationale and background: In December 2019, a novel coronavirus (severe acute
respiratory syndrome coronavirus 2 [SARS -CoV -2]) was first identified by public health
official s in China. The World Health Organization (WHO) declared the SARS -CoV -2
outbreak and associated disease (Coronavirus disease 2019 [COVID -19] a global pandemic
in March 2020. Despite public health efforts, the incidence of COVID -19 has continued to
rise, la rgely affecting middle -aged persons with worsening clinical sequelae linked to
increasing age and comorbid conditions (e.g., cardiovascular disease, diabetes and chronic
lung disease). As of 17 May 2021, over 32.9 million COVI D-19 cases and 586,330 deaths
have been reported in the United States (US) alone ( The Center for S ystems Science and
Engineering at Johns Hopkins University , 2021 ).The Food and Drug Administration ( FDA )
initially granted Emergency Use Authorization (EUA) for the Pfizer -BioNTech COVID -19
vaccine two-dose primary series on 11 December 2020 in individuals 16 y ears of age and
older ,and approved the vaccine for this population on 23 August 2021 ( FDA, 2021a ;FDA,
2021b ).FDA expanded the EUA on 10 May 2021 to include children 12 -15 years of age ,and
on 29 October 2021 to include lower -dose vaccine administration for children 5- 11 years of
age(FDA, 2021 c;FDA, 2021 d).The EUA was further amended on 12 August 2021 to
include the administration of a third primary series dose in certain immunocompromised
individuals 12 y ears of age and older , and on 22 September 2021 to allow for use of a single
booster dose at least six months after completion of the primary series in certain populations
(FDA, 2021 e).
Available data suggest that pregnant women who become infected with COVID -19 may be
more likely to be hos pitalized and may be at increased risk of preterm delivery (MMWR,
2020 ).Pfizer is conducting a Phase 2/3 clinical trial of the safety and immunogenicity of the
Pfizer -BioNTech COVID- 19 vaccine in pregnant women. Interim analy ses of Pfizer’s Phase
3 clinical trial for vaccine candidate BNT162b2 were reported in December 2020 and
showed that the two -dose regimen had 95% efficacy in the prevention of COVID -19 among
individuals without evidence of prior SARS -CoV -2 infection. While the current product
labeling communicates that data are insufficient, the Pfizer -BioNTech COVID- 19 vaccine
may be received by pregnant women when they and their healthcare providers believe that
risk/benefit considerations favor its use. As of 25 October 2 021, more than 169,000 women
reported to the Centers for Disease Control and Prevention ’s (CDC ) V-safe surveillance
system that they were vaccinated during pregnancy (CDC, 2021a ). Therefore, information
regarding the real -world safet y of vaccination during pregnancy is essential from a public
health perspective.
090177e19a3ab0c5\Approved\Approved On: 17-May-2022 21:36 (GMT)
FDA-CBER-2022-5812-0236192
Pfizer -BioNTech COVID -19 Vaccine
C4591022 NON -INTERVENTIONAL STUDY PROTOCOL
Version 4.0, 09 May 2022
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 3 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
20-May-2021
Page 9of 50This non- interventional study is designated as a Post -Authorization Safety Study (PASS) and
isa postmarketing commitment (PMC) to the FDA .
Research question and objectives : Is the risk of pregnancy and infant safety outcomes
increased among pregnant women in the Organization of Teratology Information Specialists
(OTIS)/MotherToBab y Pregnancy Registry (OTIS Pregnancy Registry )who were vaccinated
with the Pfizer -BioNTech COVID -19 vaccine during pregnancy compared with those who
did not receive an y COVID -19 vaccine during pregnancy ?
Study Objective
To assess whether pregnant women who receiv edthe Pfizer -BioNTech COVID-19
vaccine during pregnancy experience dincrease d risk of pregnancy and infant safet y
outcomes, including major congenital malformations, spontaneous abortion, elective
termination/abortion, stillbirth, preterm delivery , small for gestational age, and small
for age postnatal growth at one year of age , relative to pregnant women who receiv ed
no COVID -19vaccine sduring pregnancy .
Study design: This proposed study is a prospective, observational cohort study of pregnancy
and infant safety outcomes in pregnant women with exposure to the Pfizer -BioNTech
COVID -19 vaccine using data from the OTIS Pregnancy Registry . The birth
prevalence /incidence rat esof pregnancy outcomes and incidence proportion of the infant
outcome for women exposed to an y dose of the Pfizer -BioNTech COVID-19 within one
month prior to the first day of the last menstrual period (LMP) to end of pregnancy will be
compared to those o bserved in a comparator cohort unexposed to any COVID -19 vaccine
during this period.
Population: The study population includes pregnant women of all ages participating in the
OTIS Pregnancy Registry on or after 11 December 2020 (i.e., date FDA granted EUA for the
Pfizer -BioNTech COVID -19 vaccine ). The OTIS Pregnancy Registry includes women who
resid ein the US or Canada. Women with a known pregnancy outcome at the time of study
enrollment (e.g., positive prenatal diagnostic test results for a major congenit al malformation
prior to study entry ), exposure to known human teratogens during pregnancy, or receipt of
anyvaccine during pregnancy other than the Pfizer -BioNTech COVID- 19 vaccine, influenza
vaccine, or Tdap vaccine are not eligible for stud y entry.
Variables: Exposure will be defined as receipt of the Pfizer -BioNTech COVID- 19 vaccine
obtained by maternal report and/or medical record, with information on the gestational
timing and date(s) of vaccination captured. A copy of the COVID -19 vaccine record is
requested to supplement maternal report of vaccination. Pregnancy outcomes of interest
include major congenital malformations, spontaneous abortion, elective termination/abortion
for an y reason, stillbirth, preterm delivery , and small for gestational age . The infant outcome
of interest is small for age postnatal growth of live born infants at one year of age. Each
pregnancy and infant outcome will be anal yzed separatel y, and the following exposed cohort
and unexposed cohort will be defined for each outcome analysis (depending on a
090177e19a3ab0c5\Approved\Approved On: 17-May-2022 21:36 (GMT)
FDA-CBER-2022-5812-0236193
Pfizer -BioNTech COVID -19 Vaccine
C4591022 NON -INTERVENTIONAL STUDY PROTOCOL
Version 4.0, 09 May 2022
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 3 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
20-May-2021
Page 10of 50participant’s timing of vaccination/study enrollment as it relates to the at -risk period for an
outcome) :
Pfizer -BioNTech COVID -19 Vaccine -Exposed
–Pregnant women with exposure to at least one dose of the Pfizer- BioNTech
COVID -19 vaccine within one month before the first day of LMP up to and
including end of pregnancy
COVID -19 Vaccine -Unexposed (Comparator)
–Pregnant women with no exposure to any COVID -19 vaccine within one month
before the first day of LMP up to and including end of pregnancy .
Information on study outcomes will be obtained by maternal report and /ormedical record
review. Potential confounders or covariates to be collected include maternal age,
race/ethnicity, socioeconomic status, pregnancy and health history , lifest yle factors,
comorbidities ,medication use, vaccine exposures ( including COVID -19 vaccination prior to
and during pregnancy ),vitamin/mineral exposures, and prenatal tests .Forwomen who
received the Pfizer -BioNTech COVID -19 vaccine, information will also be collected on the
specific doses ( i.e., 1st, 2nd, 3rd,and booster) of the vaccine received .
Data source: This study will use data collected as part of the OTIS Pregnancy Registry from
maternal interviews, medical records (obstetric , delivery hospital, pediatric, vaccine provider,
and/or other specialty provider if applicable), and pregnancy exposure diary .
Study size: The target sample size for the study is 2000 pregnant women: 1100 pregnant
women in the Pfizer -BioNTech COVID- 19 vac cine exposure cohort and 9 00 pregnant
women in the COVID -19 vaccine- unexposed comparator cohort.
Data analysis: The distributions of demographic and baseline characteristics will be
summarized within the exposure and comparator cohort. The following measures will be
calculated for the pregnancy and infant outcomes: birth prevalence of major congenital
malformations; incidence rates of spontaneous abortion, elective termination/abortion,
stillbirth, and preterm delivery ;and incidence pr oportions of small for gestational age and
small for age postnatal growth at one y ear of age . For each outcome, risk estimates will be
described separatel y for the Pfizer -BioNTech COVID- 19 vaccine exposure cohort and the
comparator cohort. The outcomes wil l be compared between the Pfizer -BioNTech COVID-
19 vaccine -exposed and vaccine -unexposed cohort s.Where feasible, comparisons will also
be made using methods to control potential confounding and to evaluate outcomes following
receipt of specific doses ( i.e., 1st, 2nd, 3rd, booster) in pregnancy .
Milestones: Pregnant women participat ingin the OTI S Pregnancy Registry on or after 11
December 2020 (date of EUA for the Pfizer -BioNTech COVID -19 vaccine )areeligible for
study enrollment . The start of data collection (defined as start date of data extraction for the
first interim report) will be 01 October 2021. Four annual interim reports will be submitted.
The final study report and anal ysis is projected for December 202 4.
090177e19a3ab0c5\Approved\Approved On: 17-May-2022 21:36 (GMT)
FDA-CBER-2022-5812-0236194
Pfizer -BioNTech COVID -19 Vaccine
C4591022 NON -INTERVENTIONAL STUDY PROTOCOL
Version 4.0, 09 May 2022
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 3 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
20-May-2021
Page 11of 505.AMENDMENTS AND UPDAT ES
Amendment
NumberDate Protocol
Section(s)
ChangedSummary of Amend ment(s) Reason
1 20 August
20216 Changed the date for “Final study
report” from 01 December 2025 to 31
December 2025.Information Request from Center
for Biologics Evaluation and
Research (CBER) received on 27
July 2021 ; CBER follow -up
request on 19 August 2021.
6 Changed the date for “End of data
collection” from 01 August 2025 to 30
June 2025.Allows for a 6 -month period
after end of data collection to
conduct analyses and prepare
final study report.
9.3.1 ,
9.4.3 ,
Table 1Added clarification that aparticipant is
classified as exposed if she reports in
the maternal interviews that she
received the Pfizer -BioNTech COVID -
19 vaccine orif there is supporting
documentation in the medical record for
receipt of the Pfizer -BioNTech COVID -
19 vaccine.To clarify the use of maternal
interviews and medical records in
the classification of Pfizer -
BioNTech COVID -19 vaccine
exposure status.
9.3.2.1 Added information on the expert
dysmorphologist who review sand
classif ies major congenital
malformations including the
qualifications and rationale for selection
of the revie wer.Information Request from Center
for Biologics Evaluation and
Researc h(CBER) received on 27
July 2021 .
Table 2 ,
9.4.2Added clarifications on data elements
that are collected as part of existing
registry procedures .Information Request from CBER
received on 27 July 2021 .
9.4.1 Provided additional information on
patient -initiated recruitment efforts and
retention plans , including recruitment
and retention strategies for diverse
populations.Information Request from CBER
received on 27 July 2021 .
9.5 Added rationale for the target sample
size.Information Request from CBER
received on 27 July 2021 .
Table 4 Added sample size and pow er
calculations for the infant outcome of
small for age postnatal growth atone
year of age ;Information Request from CBER
received on 27 July 2021 .
090177e19a3ab0c5\Approved\Approved On: 17-May-2022 21:36 (GMT)
FDA-CBER-2022-5812-0236195
Pfizer -BioNTech COVID -19 Vaccine
C4591022 NON -INTERVENTIONAL STUDY PROTOCOL
Version 4.0, 09 May 2022
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 3 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
20-May-2021
Page 12of 50Amendment
NumberDate Protocol
Section(s)
ChangedSummary of Amend ment(s) Reason
Added detail s on how the exposed and
comparator sample sizes for each of the
study endpoints were derived.
Corrected sample sizes for comparator
cohort Ns in Table 4.Error w as made in transferring
sample size estimates of
comparator c ohort to Table 4 in
the previously submitted
protocol .
2 29 November
20214,
6,
7Updated milestones. To reflect current recruitment
timelines.
7 Updated Rationale and Background. 1) To reflect the current approval
and authorization status of the
Pfizer -BioNTech COVID -19
vaccine in the United States, and
2) to update the number of
women who reported to the
Centers for Disease Control and
Prevention V -safe surveillance
system that th ey received the
vaccine during pregnancy.
9.1,
9.5,
9.7.3.1,
Table 2,
Table 4,
Table 5Increased sample size to allow for
increased capture of women receiving a
booster dose of the Pfizer -BioNTech
COVID -19 vaccine during pregnancy ;
added 3rdand booster doses to the
variable for specific dose of Pfizer -
BioNTech COVID -19 vaccine; added
subgroup analysis to include 3rdand
booster doses.To add safety assessment of 3rd
and booster doses after
authorization.
9.3.1 Added clarification based on ACOG
guidelines how gestational weeks are
defined if first day of LMP is unclear or
if ultrasound dates differ from LMP -
derived dates.To clarify how gestational weeks
are calculated.
3 09 May 2022 4,
9.2.1,
Table 2Removed inclusion criteria of maternal
age 18 or olderTo allow for enrollment of
individuals who are <18 years of
age as per CBER request given
vaccine authorization/approval in
younger ages.
Table 2 Change definition of g estational age at
vaccination/study enrollment from 13, To align with the SAP and
definitions used for the study
090177e19a3ab0c5\Approved\Approved On: 17-May-2022 21:36 (GMT)
FDA-CBER-2022-5812-0236196
Pfizer -BioNTech COVID -19 Vaccine
C4591022 NON -INTERVENTIONAL STUDY PROTOCOL
Version 4.0, 09 May 2022
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 3 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
20-May-2021
Page 13of 50Amendment
NumberDate Protocol
Section(s)
ChangedSummary of Amend ment(s) Reason
13-19.9, ≥20 w eeks gestation to ≤13,
13.1-19.9, ≥20
090177e19a3ab0c5\Approved\Approved On: 17-May-2022 21:36 (GMT)
FDA-CBER-2022-5812-0236197
Pfizer -BioNTech COVID -19 Vaccine
C4591022 NON -INTERVENTIONAL STUDY PROTOCOL
Version 4.0, 09 May 2022
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 3 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
20-May-2021
Page 14of 506.MILESTONES
Milestone Planned Date
Registration in the EU PAS register 29 September 2021
Start of data collection 01 October 20211
Interim Annual Reports131 January 2022
31 January 2023
31 January 2024
End of data collection 30 June 20242
Final study report 31 December 2024
1Pregnant women participa tinginthe OTIS Pregnancy Reg istry on or after 11 December 2020 after EUA
for the Pfizer -BioNTech COVID -19 vaccine are eligible for study inclusion . The start of data collection is
defined as the planned date for starting data extraction for the first interim report.
2The end of data co llection is defined as the planned date on which the analytic dataset will be first
completely available ; the analytic dataset is the minimum set of data required to perform the statistical
analysis for the primary objective(s) .
090177e19a3ab0c5\Approved\Approved On: 17-May-2022 21:36 (GMT)
FDA-CBER-2022-5812-0236198
Pfizer -BioNTech COVID -19 Vaccine
C4591022 NON -INTERVENTIONAL STUDY PROTOCOL
Version 4.0, 09 May 2022
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 3 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
20-May-2021
Page 15of 507.RATIONALE AND BACKGR OUND
In December 2019, a novel coronavirus (severe acute respiratory syndrome coronavirus 2
[SARS -CoV -2]) was first identified by public health officials in China. The World Health
Organization (WHO) declared the SARS -CoV -2 outbreak and associated disease
(Coronavirus disease 2019 [ COVI D-19 ] a global pandemic in March 2020. Despite public
health efforts, the incidence of COVID -19 has continued to rise, largel y affecting middle -
aged persons with worsening clinical sequelae linked to increasing age and comorbid
conditions (e.g., cardiovascular d isease, diabetes and chronic lung disease). As of 17 May
2021, over 32.9 million COVID -19 cases and 586,330 deaths have been reported in the
United States (US) alone ( The Center for S ystems Science and Engineering at Johns Hopkins
University , 2021 ).
Pfizer and BioNTech have partnered to develop a novel (messenger ribonucleic acid) mRNA
vaccine against SARS- CoV -2 for the prevention of COVID-19 (Candidate BNT162b2).
Pfizer is conducting a Phase 1/2/3, randomized, placebo -controlled, observer -blind, dose -
finding, vaccine candidate- selection, and efficacy study among healthy individuals
(NCT04368728). Interim anal yses of Pfizer’s Phase 3 clinical trial for vaccine candidate
BNT162b2 were reported in December 2020 and showed t hat the two- dose regimen had 95%
efficacy in the prevention of COVID -19 among individuals without evidence of prior SARS-
CoV -2 infection. Based on the safet y and efficacy data, as well as a review of manufacturing
information regarding product quality and consistency , the Food and Drug Administration
(FDA) determined that the known and potential benefits of the vaccine outweighed the
known and potential risks for the prevention of COVID -19 in individuals 16 y ears of age and
older ( FDA, 2021 a). The FDA initiallygranted Emergency Use Authorization (EUA) for the
Pfizer -BioNTech COVID- 19 vaccine two-dose primary series on 11 December 2020 in
individuals 16 y ears of age and older ,and approved the vaccine for this population on 23
August 2021 (FDA, 2021a ;FDA, 2021b ). FDA expanded the EUA on 10 May 2021 to
include children 12 -15 years of age , and on 29 October 2021 to include lower- dose vaccine
administration for children 5- 11 years of age (FDA, 2021 c;FDA, 2021 d).The EUA was
further amended on 12 August 2021 to include the administrat ion of a third primary series
dose in certain immunocompromised individuals 12 y ears of age and older, and on 22
September 2021 to allow for use of a single booster dose at least six months after completion
of the primary series in certain populations (FDA, 2021 e).
Studies in women with COVID -19 infection are limited. The available data suggest that
pregnant women who become infected with COVID -19 may be more likely to be
hospitalized and may be at increased risk of preterm deli very (MMWR, 2020 ). The COVID -
19 vaccine is likel y to be utilized by pregnant women when they and their healthcare
providers believe that risk/benefit considerations favor its use. Also, given the frequency of
unplanned pregnancies, information regarding the safet y of the COV ID-19 vaccine in human
pregnancy is essential from a public health perspective. As of 25 October 2021 , more than
169,000 women reported to the Centers for Disease Control and Prevention (CDC) V-safe
surveillance s ystem that they were vaccinated during pre gnancy (CDC, 2021a ).Therefore,
information regarding the real -world safet y of vaccination during pregnancy is essential from
a public health perspective.
090177e19a3ab0c5\Approved\Approved On: 17-May-2022 21:36 (GMT)
FDA-CBER-2022-5812-0236199
Pfizer -BioNTech COVID -19 Vaccine
C4591022 NON -INTERVENTIONAL STUDY PROTOCOL
Version 4.0, 09 May 2022
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 3 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
20-May-2021
Page 16of 50The current Pfizer- BioNTech COVID -19 vaccine product label for healthcare providers
specifies that safet y data are insufficient or not available to assess vaccine -associated risks in
pregnant or lactating women. However, Pfizer is conducting an ongoing Phase 2/3 clinical
trial of the safety and immunogenicit y of the vaccine in pregnant women. In addition, this
protocol proposes an observational stud y to evaluate pregnancy and infant safet y outcomes
among pregnant women enrolled in an established North American pregnancy registry who
were exposed to the Pfizer -BioNTech COVID -19 vaccine .
This non- interventional study is designated as a Post -Authorization Safety Study (PASS) and
isa postmarketing commitment (PMC) to the FDA .
8.RESEARCH QUESTION AND OBJECTIVES
Is the risk of pregnancy and infant safet y outcomes increased among pregnan t women in the
Organization of Teratology Information Specialists (OTI S)/MotherToBaby Pregnancy
Registry (OTI S Pregnancy Registry )who were vaccinated with the Pfizer- BioNTech
COVID -19 vaccine during pregnancy compared with those who did not receive any COVID-
19 vaccine during pregnancy ?
Study Objective
To assess whether pregnant women who receiv edthe Pfizer -BioNTech COVID-19
vaccine during pregnancy experience dincreased risk of pregnancy and infant safet y
outcome s,including major congenital malformations, spontaneous abortion, elective
termination/abortion, stillbirth, preterm delivery , small for gestational age, and small
for age postnatal growth at one year of age , relative to pregnant women who receiv ed
no COVID -19vaccine sduring pregnanc y.
9. RESEARCH METHODS
9.1.Study Design
This proposed study is a prospective, observational cohort study of pregnancy and infant
safet y outcomes in pregnant women of all ages in the OTI S Pregnancy Registry who received
the Pfizer -BioNTech COVID- 19 vaccine any time from one month before the first day of the
last menstrual period (LMP) to the end of pregnancy . The comparator cohort includes
pregnant women who received no COVID -19 vaccines within one month before the first day
of LMP to end of pregnancy . The pregn ancy outcomes are major congenital malformations,
spontaneous abortion, elective termination/abortion, stillbirth, preterm delivery , and small for
gestational age ; the infant outcome is small for age postnatal growth at one y ear of age. The
target sample size for the study is 2000 pregnant women: 1 100pregnant women in the
Pfizer -BioNTech COVID-19 vaccine exposure cohort and 900 pregnant women in the
COVID -19 vaccine- unexposed comparator cohort .The main measures of effect are
unadjusted and adjusted risk r atios (RRs) and 95% confidence intervals (CIs) comparing the
Pfizer -BioNTech COVID- 19 vaccine exposed cohort to the comparator cohort for the
outcomes of major congenital malformations, small for gestational age, and postnatal growth;
and unadjusted and ad justed hazard r atios (HRs) and 95% CI scomparing the Pfizer -
090177e19a3ab0c5\Approved\Approved On: 17-May-2022 21:36 (GMT)
FDA-CBER-2022-5812-0236200
Pfizer -BioNTech COVID -19 Vaccine
C4591022 NON -INTERVENTIONAL STUDY PROTOCOL
Version 4.0, 09 May 2022
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 3 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
20-May-2021
Page 17of 50BioNTech COVID -19 vaccine exposed cohort to the comparator cohort for the outcomes of
spontaneous abortion, elective termination /abortion , stillbirth, and preterm delivery .
9.2. Setting
This study will use data that are collected as part of the existing OTI S Pregnancy Registry
(described further in Section 9.4Data Source) and converted to a structured database for
analysis. The registry includes pregnant women who reside in the US or Canada and allows
for direct capture of information from participants through various health interviews. To
obtain information provided by thetreating ph ysicians, data are collected from medical
records for pregnant women and their infant s.
When pregnant women are in contact with the OTIS Research Center, enrollment in the
OTIS Pregnancy Registry is voluntary and requires informed consent of the pregnant woman.
The study encourages enrollment as earl y as possible in the pregnancy before an y prenatal
testing results are known. This is accomplished by encouraging clinicians to refer patients,
and patients who contact an OTIS service or who self -refer, to enroll upon first positive
pregnancy test. These efforts reduce possible bias based on prior knowledge of a normal or
abnormal ultrasound and allow for better estimation of risk of spontaneous abortion.
9.2.1. Inclusion Criteria
Individuals must meet all of the following inclusion criteria to be eligible for inclusion in the
study :
Residence in the US or Canada
Enrolled in the OTIS Pregnancy Registry and c urrently pregnant on or after 11
December 2020 (i.e., date of EUA for the Pfizer -BioNTech COVID -19 va ccine)
9.2.2. Exclusion Criteria
Individuals meeting any of the following criteria will not be included in the study :
Previous entry into th isstudy for a prior pregnancy
Receipt of an y vaccine other than the Pfizer -BioNTech COVID -19 vaccine, influenza
vaccine, o r Tdap vaccine (e.g., Moderna or Johnson & Johnson COVI D-19 vaccines,
human papillomavirus vaccine, hepatitis B vaccine, etc.) from one month before the
first day of LMP up to and including end of pregnancy
Exposure to known human teratogens during pregnancy within one month before the
first day of LMP up to and including end of pregnancy
Known pregnancy outcome at time of study enrollment (e.g., positive prenatal
diagnostic test results for a major congenital malformation prior to study entry )
090177e19a3ab0c5\Approved\Approved On: 17-May-2022 21:36 (GMT)
FDA-CBER-2022-5812-0236201
Pfizer -BioNTech COVID -19 Vaccine
C4591022 NON -INTERVENTIONAL STUDY PROTOCOL
Version 4.0, 09 May 2022
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 3 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
20-May-2021
Page 18of 509.2.3. Follow -Up
Pregnant women are entered in a cohort at the time of enrollment into the OTI S Pregnancy
Registry . Information is collected on their pregnancy to date and they are then followed for
the duration of their pregnancy . In addition, infants will be fo llowed for potential safet y
events through their first y ear of life. Follow -up will end at the earliest of the following
events:
Lost to follow -up, i.e., an enrolled individual who withdraws or who fails to complete
the outcome interview despite a standard number of telephone attempts and attempt to
contact b y mail as per study procedure manual within one year of the participant’s
estimated due date.
Receipt of an y vaccine other than the Pfizer -BioNTech COVID -19 vaccine, influenza
vaccine, or Tdap vaccine ( e.g., Moderna or Johnson & Johnson COVI D-19 vaccines,
human papillomavirus vaccine, hepatitis B vaccine, etc.) during pregnancy
Occurrence of spontaneous abortion, elective termination/abortion, or stillbirth
End of follow -up (i.e., one -year post -partum)
End of study period
Infant death
Maternal death during pregnancy .
9.3.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 an d
medical record review per standard process described in the OTIS Pregnancy Registry
protocol. Detailed operational definitions will be provided in the Statistical Analy sis Plan
(SAP) .
9.3.1. Identification of Exposure and Comparator
Vaccine exposure data are ob tained b y maternal report and/or medical record to classify
Pfizer -BioNTech COVID -19 vaccine exposure status .The two sources of information are
used in order to minimize misclassification of exposure status. Detailed information
regarding vaccine exposure status of participants is obtained through the maternal interviews
including at enrollment, at interim timepoints during pregnancy, and at pregnancy outcome
interview (0 to 6 weeks after the expected due date or end of pregnancy ).Participants are
directl y queried about the specific vaccines they received, including information on the
gestational timing, dates of exposure, and brand. Vaccine exposures are coded using the
Slone Drug Dictionary . Maternal report that a COVID -19 vaccine was received is
complem ented b y requesting a cop y of the COVID -19 vaccine record. In addition, medical
090177e19a3ab0c5\Approved\Approved On: 17-May-2022 21:36 (GMT)
FDA-CBER-2022-5812-0236202
Pfizer -BioNTech COVID -19 Vaccine
C4591022 NON -INTERVENTIONAL STUDY PROTOCOL
Version 4.0, 09 May 2022
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 3 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
20-May-2021
Page 19of 50records from the obstetric provider, hospital of delivery , and any specialt y provider are
reviewed (when available) for all participants.
A participant is classified as unexpos ed if she reports that she did not receive an y COVID -19
vaccine and her medical record (when available) shows no indication that she received an y
COVID -19 vaccine. A participant is classified as exposed if she reports in the maternal
interviews that she re ceived the Pfizer -BioNTech COVID-19 vaccine or if there is supporting
documentation in the medical record for receipt of the Pfizer -BioNTech COVID-19 vaccine .
If maternal report indicates no receipt of a COVID -19 vaccine but the medical record
indicates discordance such that the Pfizer -BioNTech COVID -19 vaccine was administered,
the medical record would supersede maternal report and the participant would be classified
asPfizer -BioNTech COVID -19 vaccine- exposed. Moreover , where maternal report indicates
that the Pfizer -BioNTech COVID -19 vaccine was received but documentation in the medical
record is discordant (i.e., no indication in medical record that COVID -19 vaccine was
administered), the maternal repor t would supersede medical record for classification as
exposed.
The estimated gestational weeks to qualify participants for the study for exposure and to
classify outcomes is based on weeks from the first day of LMP which is counted as day 0. In
circumstan ces where the date of LMP is not available or uncertain, or when a prenatal
ultrasound estimates a gestational week that is discrepant according to obstetric guidelines,
gestational week of pregnancy will be assigned based on the earliest available ultrasound
(ACOG, 2017).
Table 1below provides a description of variables for exposures to be included in this study .
Each pregnancy and infant outcome will be anal yzed separatel y, and the following exposure
and comparator cohorts will be defined separately for each outcome anal ysis ( depending on a
participant’s timing of vaccination/study enrollment as it relates to the at -risk peri od for an
outcome ):
Pfizer -BioNTech COVID -19 Vaccine (Exposure)
–Receipt of at least one dose of the Pfizer- BioNTech COVID -19 vaccine during
the study period at any time from one month before the first day of LMP up to
and including end of pregnancy
COVID -19 Vaccine -Unexposed (Comparator)
–Receipt of no COVID -19 vaccines during the study period within one month
before the first day of LMP up to and including end of pregnancy
9.3.2. Classification of Pregnancy and Infant Outcomes
The following pregnancy and in fant outcome variables (refer to Table 1) are obtained by
maternal report and /ormedical record review (when available) as part of existing procedures
for the pregnancy registry .
090177e19a3ab0c5\Approved\Approved On: 17-May-2022 21:36 (GMT)
FDA-CBER-2022-5812-0236203
Pfizer -BioNTech COVID -19 Vaccine
C4591022 NON -INTERVENTIONAL STUDY PROTOCOL
Version 4.0, 09 May 2022
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 3 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
20-May-2021
Page 20of 509.3.2.1. Major Congenital Malformations
The method for classify ing major congenital malformations for purpose of anal ysis has been
described b y the stud y investigators and the OTIS Research Group ( CDC, 2000 ;Olsen et al.,
2010 ) and has been used in previous studies conducted b y OTIS.
A major congenital malformation is defined as a defect that has either cosmetic or functional
significance to the child (e.g., a cleft lip). Major congenital malformations diagnosed during
pregnancy and up to 1 y ear of age are reported b y participants or the healthcare provider, or
are identified through medical record review. Independent confirmation of certain defects is
required via medical record review. For example, a heart murmur thought to represent a
ventricular septal defect prior to 1 y ear of age will be included if it is confirmed as a heart
defect b y cardiac ultrasound. Similarly , a midline cutaneous marker at L2- L3 noted will be
included as occult spinal dy sraphism only if confirmed by appropriate imaging studies.
Classification of major defects is performed uniformly across cohorts according to the CDC
Metropolitan Atlanta Congenital Defects Program (MACDP) coding criteria ( CDC, 2017).
Some major congenital malformations are known consequences of pregnancy events,
such as preterm delivery , and are therefore not directly due to vaccine exposure. For
example, isolated patent ductus arteriosus or isolated inguinal hernia in an infant
delivered before 36 weeks’ gestation are considered consequences of prematurity , and
therefore, using CDC coding criteria, none of these defects are counted as major
congenital malformations. Other structural defects, such as club foot or cranial
synostosis, could be due to position of the infant in the uterus or could be primary
defects initi ated earlier in pregnancy . In most cases, it is not possible to know the true
onset or etiology of the defect. Therefore, using CDC coding criteria, these anomalies
are counted as major congenital malformations uniformly across all cohorts.
One exception to using the CDC coding criteria is that chromosomal anomalies will
not be counted as major congenital malformations as it is unlikely that a vaccine
exposure could cause a chromosomal defect.
The uniform coding reduces differences in outcome definitions be tween studies for a better
interpretation of results in the event they are compared. It is anticipated that the occurrence of
defects that are unrelated to vaccine exposure in the proposed stud y population will be
nondifferential across cohorts. Therefore, their inclusion, when indicated, represents part of
the baseline risk for major congenital malformations in each cohort. This should not impact
the risk estimates and measures of association.
Major congenital malformations identified by prenatal ultrasou nd or examination of the
products of conception following elective termination/abortion or spontaneous abortion will
not be included in the primary anal ysis due to potential bias involved in non -uniform use of
prenatal diagnosis and pathology evaluation for all abortuses .
090177e19a3ab0c5\Approved\Approved On: 17-May-2022 21:36 (GMT)
FDA-CBER-2022-5812-0236204
Pfizer -BioNTech COVID -19 Vaccine
C4591022 NON -INTERVENTIONAL STUDY PROTOCOL
Version 4.0, 09 May 2022
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 3 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
20-May-2021
Page 21of 50As per recommend ations in the FDA draft Guidance for Industry Postapproval Pregnancy
Safety Studies (May 2019) ,an expert d ysmorphologist and co -investigator for OTIS
Pregnancy Registry studies , Dr. Kenneth Ly ons Jones, reviews all the med ical records and
reports of major congenital malformations. The review is done blinded to exposure status and
performed in the same manner for exposed and comparator cohort s.Dr. Jones is a
pediatrician and the leading authorit y on environmental causes of congenital anomalies . He is
the author of the main textbook in this field titled Smith’s Recognizable Patterns of
Malformation, 8thEdition ( Jones et al ., 2021 ).
9.3.2.2. Spontaneous abortion
Defined as non -deliberate fetal death which occurs prior to 20 weeks from the first day of
LMP.
9.3.2.3. Elective termination/abortion
Defined as deliberate termination of pregnancy at any time in gestation. Reasons for elective
termination/abortion are captured a nd are classified as due to medical reasons or social
reasons.
9.3.2.4. Stillbirth
Defined as non -deliberate fetal death any time in gestation at or after 20 weeks from the first
day of LMP.
9.3.2.5. Preterm delivery
Defined as live birth prior to 37 weeks ’gestation as counted from the first day of LMP.
9.3.2.6. Small for gestational age at birth
Defined separately for weight, length, and head circumference (binary endpoints) asbirth
sizeless than or equal to the 10th centile for sex and gestational age using stan dard pediatric
CDC growth curves for full term or preterm infants ( CDC, 2000; Olsen et al., 2010).
9.3.2.7. Small for age postnatal growth at one year of age
Defined separately for weight, length, and head circumference (binary endpoints) as
postnatal size less than or equal to the 10th centile for sex and age using National Center for
Health Statistics (NCHS) pediatric growth curves, and adjusted postnatal age for preterm
infants if the postnatal measuremen t is obtained at less than 1 y ear of age ( CDC, 2000).
Table 1. Exposure, Comparator, Exclusion, and Outcome Variables
Variable Role Data Source(s) Operational Definition
Exposure to the
Pfizer -
BioNTech Exposure Maternal report Maternal report of exposure to the Pfizer -
BioNTech COVID -19 vaccine of at least one dose
any time from one month prior to the first day of
LMP to end of pregnancy
090177e19a3ab0c5\Approved\Approved On: 17-May-2022 21:36 (GMT)
FDA-CBER-2022-5812-0236205
Pfizer -BioNTech COVID -19 Vaccine
C4591022 NON -INTERVENTIONAL STUDY PROTOCOL
Version 4.0, 09 May 2022
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 3 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
20-May-2021
Page 22of 50Table 1. Exposure, Comparator, Exclusion, and Outcome Variables
Variable Role Data Source(s) Operational Definition
COVID -19
vaccineVaccine record (e.g.,
COVID -19 vaccine
or yellow card)
Medical record
Gestational
timing of the
Pfizer -
BioNTech
COVID -19
vaccine useExposure Maternal report
Vaccine record (e.g.,
COVID -19 vaccine
or yellow card)
Medical recordDates of the Pfizer -BioNTech COVID -19 vaccine
administration one month prior to the first day of
LMP up to and including end of pregnancy
No vaccine
exposure during
pregnancyCom parator Maternal report
Medical recordMaternal report of no exposure to any vaccines at
any time from one month prior to the first day of
LMP to end of pregnancy
Exposure to
non-study
vaccines during
the pregnancy
window up to
study
enrollmentExclusion
criterionMaternal report
Vaccine record (e.g.,
COVID -19 vaccine
or yellow card)
Medical recordMaternal report of exposure to any vaccine other
than the Pfizer -BioNTech COVID -19 vaccine,
influenza vaccine, or Tdap vaccine (e.g., Moderna
or Johnson & Johnson COVID- 19 vaccines,
human papill omavirus vaccine, hepatitis B
vaccine, etc.)
Maternal
pregnancy
exposure to a
known human
teratogenExclusion
criteri onMaternal report
Medical recordMaternal pregnancy exposure to a known human
teratogen (e.g., Type I Diabetes)
Major
congenital
malformationPregnancy
outcomeMaternal report
Medical record
OTIS investigator
reviewA major structural or chromosomal defect that has
either cosmetic or functional significance to the
child (e.g., a cleft lip). Classified using the CDC
Metropolitan Atl anta Congenital Defects Program
(MACDP) coding criteria ( CDC ,2017 )
According to the CDC MACDP guidelines, the
following do not qualify as major congenital
malformations:
oThose findings that are present in infants
with outcomes at <36 weeks gestational
090177e19a3ab0c5\Approved\Approved On: 17-May-2022 21:36 (GMT)
FDA-CBER-2022-5812-0236206
Pfizer -BioNTech COVID -19 Vaccine
C4591022 NON -INTERVENTIONAL STUDY PROTOCOL
Version 4.0, 09 May 2022
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 3 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
20-May-2021
Page 23of 50Table 1. Exposure, Comparator, Exclusion, and Outcome Variables
Variable Role Data Source(s) Operational Definition
age or if gestational age is unavailable,
weighing <2500 grams, and are attributed
to prematurity alone, such as patent ductus
arteriosus (PDA), patent foramen ovale
(PFO), a nd inguinal hernias
oInfants with only transient or infectious
conditions, or biochemical abnormalities,
are classified as being without major
congenital malformations unless there is a
possibility that the condition reflects an
unrecognized major congenita l
malformation
Spontaneous
abortionPregnancy
outcomeMaternal report
Medical recordNon-deliberate embryonic or fetal death that
occurs prior to 20 weeks’ gestation (CDC, 2021 b)
Stillbirth Pregnancy
outcomeMaternal report
Medical recordA non-deliberate fetal death that occurs at or after
20 w eeks’ gestation but prior to delivery (Prager S
et al., 2021 )
Preterm
deliveryPregnancy
outcomeMaternal report
Medical record A spontaneous or induced delivery at
<37gestational weeks (as counted from the first
day of LMP) (CDC, 2021 c)
Small for
gestational ageInfant
outcomeMaternal report
Medical recordBirth size (w eight, length, or head circumf erence)
≤10thpercentile for sex and gestational age using
NCHS pediatric growth curves for full term
infants. Prenatal growth curves specific to preterm
infants are used for preterm infants ( Olsen et al.,
2010 ;Schlaudecker EP et al ., 2017 )
Small for age
postnatal
grow th at one
year of ageInfant
outcomeMedical record Postnatal size (weight, length or head
circumference) ≤10thpercentile for sex and age
using NCHS pediatric grow th curves and adjusted
postnatal age for preterm infants
Abbreviations: CDC, Centers for Disease Control and Prevention;
LMP, last menstrual period; MACDP, Metropolitan Atlanta Congenital Defects Program; NCHS, National
Center for Health Statistics
9.3.3. Demographic and Clinical Characteristics
Potential confounders and other covariates to be collected include maternal age,
race/ethnicity, socioeconomic status, pregnancy and health history , lifest yle factors,
comorbidities, medication, vaccine and vitamin/mineral expo sures, and prenatal tests.
Table 2provides a description of corresponding variables to be included in this study . The
SAP will provide greater detail on covariable definitions, such as a listing of known human
teratogens.
090177e19a3ab0c5\Approved\Approved On: 17-May-2022 21:36 (GMT)
FDA-CBER-2022-5812-0236207
Pfizer -BioNTech COVID -19 Vaccine
C4591022 NON -INTERVENTIONAL STUDY PROTOCOL
Version 4.0, 09 May 2022
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 3 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
20-May-2021
Page 24of 50Table 2.Demographic and Clinical Variables
Variable Role Data Source(s) Operational Definition
Age Confounder Maternal report Maternal age (years) at due date, continuous
and categorical (<18, 18 -25, 25- 29, 30 -34,
>34)
Race Confounder Maternal report Maternal/Paternal race (Caucasian/White,
Black, Asian/Pacific Islander, Native
American, Other)
Ethnicity Confounder Maternal report Maternal/Paternal ethnicity (H ispanic, Non -
Hispanic)
Education Confounder Maternal report Maternal Educational Category (years of
completed education <12, 12 -15, >15)
Socioeconomic
categoryConfounder Maternal report Hollingshead Socioeconomic Category based
on maternal and paternal occupation and
education (1 -5)(Hollingshead A, 1975)
Geographic area of
residenceConfounder Maternal report Geographic area of residence (e.g., US,
Canada)
Referral source Confounder Maternal report Source options: S ponsor, OTIS service, health
care provider ( HCP ), Internet, Other, UC Rely
Gestational age at
vaccination/study
enrollmentConfounder Maternal report
Medical recordWeeks of pregnancy at time of enrollment,
continuous and categorical ( ≤13,13.1-19.9,
≥20): gestational age is calculated from the
first date of LMP
Trim ester of
vaccination/study
enrollmentConfounder Maternal report
Medical record1st, 2nd, or 3rdtrimester categorization based on
gestational age at vaccination/study
enrollment
Height Confounder Maternal report Maternal height (cm)
Pre-pregnancy body
weightConfounder Maternal report
Medical recordMaternal pre- pregnancy body weight (kg)
Pre-pregnancy body
mass index ( BMI)Confounder Maternal report Maternal pre- pregnancy BMI (<18.5, 18.5 -
24.9, 25 -29.9, ≥30)
Number of prior
pregnanciesConfounder Maternal report
Medical recordNumber of times ever pregnant (1, 2 -3, 4-5,
≥6)
Number of previous
live birth or stillbirth
deliveriesConfounder Maternal report
Medical recordNumber of previous live birth or stillbirth
deliveries (0, 1 -2, 3-4, ≥5)
Previous pregnancies
with a major
congenital
malformation Confounder Maternal report ≥1previous pregnanc ywith a major structural
or chromosomal defect diagnosed in utero or
post-partum –Yes/No
090177e19a3ab0c5\Approved\Approved On: 17-May-2022 21:36 (GMT)
FDA-CBER-2022-5812-0236208
Pfizer -BioNTech COVID -19 Vaccine
C4591022 NON -INTERVENTIONAL STUDY PROTOCOL
Version 4.0, 09 May 2022
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 3 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
20-May-2021
Page 25of 50Table 2.Demographic and Clinical Variables
Variable Role Data Source(s) Operational Definition
Type of major
congenital
malformation in
previous pregnanciesConfounder Maternal report A major structural or chromosomal defect that
has either cosmetic or functional significance
to the child (e.g., a cleft li p)classified using
CDC coding criteria
Number of previous
pregnancies ending in
spontaneous abortionConfounder Maternal report
Medical recordNumber of previous pregnancies ending in
spontaneous abortion (0, 1, 2, ≥3)
Number of previous
pregnancies ending in
elective
termination/abortionConfounder Maternal report
Medical recordNumber of previous pregnancies ending in
elective termination/abortion (0, 1, 2, ≥3)
Previous pregnancies
ending in preterm
deliveryConfounder Maternal report ≥1previous pregnanc yending in preterm
delivery – Yes/No
Previous pregnancies
ending in fetal growth
restrictionConfounder Maternal report ≥1 previous pregnancy ending in fetal growth
restriction –Yes/No
Number of previous
ectopic pregnanciesConfounder Maternal report
Medical recordNumber of previous pregnancies ending in
ectopic pregnancy (0, 1, 2, ≥ 3); ectopic
pregnancy is defined as a pregnancy in which
the fetus develops outside the uterus, typically
in a fallopian tube .
Family history of
genetic disorders and
major congenital
malformationsConfounder Maternal report Any family history of amajor structural or
chromosomal defect that has either cosmetic
or functional significance to the child as
defined using the CDC coding criteria –
Yes/No
Prenatal vitam in,
multivitamin, or folic
acid use in pregnancyConfounder Maternal report Prenatal, Multivitamin or Folic Acid
supplement use by timing (began prior to
conception, post -conception only, not taken at
all)
Alcohol use in
pregnancyConfounder Maternal report Yes/No; dose and frequency are captured
Tobacco use in
pregnancyConfounder Maternal report Yes/No
Prenatal diagnostic
tests prior to
enrollmentConfounder Maternal report
Medical recordTests performed prior to enrollment
(Ultrasound level 1, Ul trasound level 2,
Chorionic Villus Sampling, Amniocentesis)
Prenatal diagnostic
tests any time during
pregnancyConfounder Maternal report
Medical recordTests performed any time in pregnancy
(Ultrasound level 1, Ultrasound level 2,
Chorionic Villus Sampling, Amniocentesis)
090177e19a3ab0c5\Approved\Approved On: 17-May-2022 21:36 (GMT)
FDA-CBER-2022-5812-0236209
Pfizer -BioNTech COVID -19 Vaccine
C4591022 NON -INTERVENTIONAL STUDY PROTOCOL
Version 4.0, 09 May 2022
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 3 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
20-May-2021
Page 26of 50Table 2.Demographic and Clinical Variables
Variable Role Data Source(s) Operational Definition
Pregnancy
complicationsConfounder Maternal report
Medical recordPregnancy induced hypertension
Preeclampsia
Gestational diabetes
Com orbid m aternal
medical historyConfounder Maternal report
Medical recordCom orbid m aternal medical history (e.g.,
chronic hypertension, asthma)
Current medication
useConfounder Maternal report Prescription and over -the-counter medications
are captured for the period of time from the
first day of LMP through the end of
pregna ncy. Dose, frequency, duration, and
indication including stop and start dates are
collected
Exposure to the
influenza or Tdap
vaccineConfounder Maternal report
Medical recordMaternal report of exposure to an influenza or
Tdap vaccine any time from one month prior
to the first day of LMP up to and including
end of pregnancy
Pfizer -BioNTech
COVID -19 vaccine
doseCovariate Maternal report
Medical recordMaternal report of the specific doses (1st, 2nd,
3rd, booster) of the Pfizer -BioNTech COVID -
19 vaccine any time from one month prior to
the first day of LMP up to and including the
end of pregnancy
COVID -19 vaccine
prior to pregnancyConfounder Maternal report
Medical recordMaternal report of exposure to at least one
dose of any COVID -19 vaccine any time prior
to one month before the first day of LMP
COVID -19 infection
symptoms and/or
positive test during
pregnancyConfounder Maternal report
Medical recordSymptom inventory from maternal interviews;
test results from maternal report and medical
record
COVID -19 infection
positive test prior to
pregnancyConfounder Maternal report
Medical recordTest results from maternal report and medical
record
Abbreviations: BMI, body mass index; CDC, Centers for Disease Control and Prevention;
cm, centimeters; kg, kilograms; HCP, health care provider; LMP, last menstrual period; OTIS, Organization
of Teratology Information Specialists.
9.4.Data Source
The OTIS Pregnancy Registry was established in 1999 for addressing questions regarding
drug and vaccine safet y in pregnancy among other research objectives. It is conducted by the
OTIS Research Group, a network of university and health department -based telephone
information centers serving pregnant women and healthcare providers throughout the US and
090177e19a3ab0c5\Approved\Approved On: 17-May-2022 21:36 (GMT)
FDA-CBER-2022-5812-0236210
Pfizer -BioNTech COVID -19 Vaccine
C4591022 NON -INTERVENTIONAL STUDY PROTOCOL
Version 4.0, 09 May 2022
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 3 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
20-May-2021
Page 27of 50Canada ( Leen -Mitchell et al, 2000 ). These services receive over 70,000 spontaneous
inquiries per year from women and healthcare providers abo ut the safet y or risk associated
with environmental exposures in pregnancy , including medications and vaccines. Trained
Teratogen Information Specialists at each site provide appropriate risk assessment and
referral for all patient and healthcare provider callers free of charge.
These services also provide a basis for collaborative research. Pregnant women who call are
recruited for the OTI S Pregnancy Registry , and the healthcare providers are requested to
contact the OTI S Pregnancy Registry to provide pati ent referrals. Active recruitment
strategies are also used, e.g., direct mailings to healthcare providers, website, and
professional meetings. Enrollment in the OTI S Pregnancy Registry is voluntary and requires
informed consent b y the pregnant woman. The O TIS Research Center is responsible for
verify ing the participant selection criteria, enrolling each participant and securing informed
consent, oral and written (when available or applicable), providing all pregnancy
(intake/enrollment and interim I and II) and post -partum follow -up interviews and medical
record review, recording and storage of all data, and subsequent data anal ysis and
interpretation.
As part of the OTI S Pregnancy Registry protocol, data are collected using maternal
interview(s), medical record review (obstetric, delivery hospital, pediatric, vaccine provider,
and/or other specialty provider if applicable), and the pregnancy exposure diary (see
Table 3).
Table 3. Timing of Cohort Enrollment, Interviews, Examinat ions, 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 participant is enrolled and Intake Intervie w is conducted after 18 w eeks’ gestation, only one interim
interview is conducted during pregnancy at 32 -34 w eeks gestation.
090177e19a3ab0c5\Approved\Approved On: 17-May-2022 21:36 (GMT)
FDA-CBER-2022-5812-0236211
Pfizer -BioNTech COVID -19 Vaccine
C4591022 NON -INTERVENTIONAL STUDY PROTOCOL
Version 4.0, 09 May 2022
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 3 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
20-May-2021
Page 28of 50Table 3. Timing of Cohort Enrollment, Interviews, Examinat ions, and Medical
Records
Any Time
In
Pregnancy20-22
Weeks’
Gestationb32-34
Weeks’
Gestationc0-6
Weeks
Post-
Delivery0-12
Months
Post-
Delivery1 Year
Post-
Delivery
c.If participant is enrolled and Intake Intervie w is conducted at 30 w eeks’ gestation or after, no Interim
Interview is collected.
Medication or vaccine exposures entered into the database are coded using the Slone Drug
Dictionary . Major congenital malformations are coded using the MACDP coding list. Data
are recorded on hard copies of forms and these records are retained b y OTIS at the OTI S
Research Center. These forms are con sidered the primary data sources for studies and can be
adapted to add new data elements. Data from these forms are extracted and entered into a
customized OTI S study database located in the Research Center.
9.4.1. Modalities of Recruitment
All exposed and compar ison individuals will be recruited through spontaneous callers to
participating OTIS member services in locations throughout North America and through
active recruitment strategies, e.g., direct mailings to healthcare providers, website, and
professional m eetings, in alignment with the OTI S Pregnancy Registry Protocol. Each OTI S
service will provide exposure counseling in the routine manner for all exposed and
unexposed women who initially make contact with the service with questions regarding a
current pre gnancy . Subsequently , each OTI S service will request permission to refer the
participant to the Research Center at the University of California, San Diego. Potential
participants who agree to be referred will contact the Research Center or be contacted if they
prefer. W omen can self -refer via the OTIS Pregnancy Registry website, telephone, email,
text, or chat. Healthcare providers can also contact the OTI S Pregnancy Registry and refer
patients; however, in all cases the participant is the individual who pr ovides informed
consent for participation and completes the interview- based data collection.
To reach a broad population and raise awareness about the study , OTIS Pregnancy Registry
studies use direct to consumer social media . OTIS also has partnerships wi th healthcare
provider s ystems such as Kaiser Permanente, agencies such as CDC, and professional
societies including the Society for Maternal Fetal Medicine, the American Academ y of
Pediatrics, and the American Academ y of Allergy Asthma and Immunology. Par tners
promote the OTIS Pregnancy Registry network and studies on their websites and through
presentations and exhibits at professional meetings. These strategies haveresulted in cohort
recruitment of a diverse sample including representation of women from each of the major
race/ethnicity groups as well as across the range of socioeconomic status.
Once the target sample size is met for th isPfizer -BioNTech COVID -19 vaccine study (see
Section 9.5Study Size), recruitment efforts for the study will cease, and study enrollment
will be closed. However, the OTI S Pregnancy Registry will remain open for enrollment for
its other ongoing studies unrelated to the Pfizer -BioNTech COVID- 19 vaccine study .
090177e19a3ab0c5\Approved\Approved On: 17-May-2022 21:36 (GMT)
FDA-CBER-2022-5812-0236212
Pfizer -BioNTech COVID -19 Vaccine
C4591022 NON -INTERVENTIONAL STUDY PROTOCOL
Version 4.0, 09 May 2022
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 3 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
20-May-2021
Page 29of 50Retention of participants in the OTI S Pregnancy Registry is supported b y frequent contact
with the enrolled participant, building and maintaining a relationship between the study
interviewer and the mother herself, and by ensuring the multiple alternative contact
numbers/addresses are obtained and updated. Retention rates in OTIS Pregnancy Registry
studies are typicall y extremely high at 95% or better.
9.4.2. Maternal Interviews
Below is a detailed descr iption of each interview as conducted under the OTI S Pregnancy
Registry protocol:
Intake/Enrollment Interview : A structured maternal intake telephone interview is
conducted at enrollment by a trained Research Associate from the OTI S Research
Center. This interview includes questions on the following: pregnancy history ,
including major congenital malformations, genetic disorders, number of live births,
and multiple gestations; current health history ; pre-pregnancy weight and height;
socioeconomic and demogr aphic information including maternal and paternal
occupation, education and ethnicity ; income category ;current medication use, both
prescription and over the counter; other environmental or occupational exposures,
alcohol, tobacco, caffeine and illicit dr ug use, vaccine exposure prior to and during
pregnancy ; current pregnancy complications including illnesses; famil y history of
adverse pregnancy outcomes, including major congenital malformations and genetic
disorders ; names and addresses of health care pr oviders; and vaccine use from one
month prior to L MP and throughout pregnancy . To supplement future interviews and
improve recall, participants are given a pregnancy exposure diary to record any
additional exposures (medications, vaccinations, vitamins, et c.) or events as the
pregnancy progresses. Each woman is also sent the informed consent document and
the US Health Insurance Portability and Accountability Act (HIPAA) Authorization
Addendum (when applicable) via electronic signature or paper, and a resear ch
HIPAA compliant obstetric medical record release form.
Interim Interviews I and II : Telephone interviews are conducted at 20 -22 and 32 -34
weeks’ gestation (if enrolled at those times) by a trained Research Associate from the
OTIS Research Center. Women who have enrolled prior to 18 weeks post -LMP will
be interviewed b y telephone at 20 -22 weeks post -LMP, 32 -34 weeks post -LMP and
within 2 to 6 weeks after the expected due date. Women who have enrolled between
19 and 20 weeks post -LMP will be interviewed at 32 -34 weeks post -LMP (See
Table 2Schedule of Follow -up). These interviews are intended to update records of
pregnancy exposures (medications, vaccinations, vitamins, etc.), results of prenatal
tests, events of interest since last interview (including if the pregnancy has ended
prior to the expected due date), and contact info.
Pregnancy Outcome Interview : A structured telephone interview are conducted b y a
trained Research Associate from the OTIS Research Center at 0 to 6 weeks after the
expected due date, or at an interim interview point or earliest convenient time for the
090177e19a3ab0c5\Approved\Approved On: 17-May-2022 21:36 (GMT)
FDA-CBER-2022-5812-0236213
Pfizer -BioNTech COVID -19 Vaccine
C4591022 NON -INTERVENTIONAL STUDY PROTOCOL
Version 4.0, 09 May 2022
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 3 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
20-May-2021
Page 30of 50participant if pregnancy has ended. This interview elicits information based on type
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; ty pe and leng th of hospital stay for pregnant women and their
infant s; delivering ph ysician’s and infant phy sician’s names and addresses;
method of infant feeding; pregnancy weight gain; and additional exposures
and results of prenatal tests occurring since the previou s 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 above for women with
spontaneous abortions, plus sex, delivery or birth complications including
malformations, birth size and autops y results if available.
9.4.3. Medical Records and General Pediatric Evaluation
Upon completion of the outcome interview, each woman is sent a packet electronicall y or by
hard cop y mail containing research HI PAA compliant medical records release forms for the
delivery hospital, obstetrician, pediatrician, vaccine provider, and specialist i f applicable. For
women whose pregnancies have ended in spontaneous abortion, elective
termination/abortion, or stillbirth, records release forms are mailed for the specialist’s
evaluation, if applicable, and if prenatal diagnosis, pathology or autopsy reports are available.
Each eligible woman is asked to sign (electronically or wet signature) the medical records
release forms, as well as UCSD HI PAA Authorization Addendum (if they or their infant
receives medical care at UCSD/Rady Children’s hospital) and to return them along with the
pregnancy exposure diary form.
Upon receipt of the signed medical records release forms, a standard ph ysical evaluation
form is mailed to each pediatrician or other ph ysician responsible for the care of each live
born infant. This form includes information on infant size at the time of the latest
examination and an open -ended question about postnatal complications and congenital
anomalies.
At one y ear of age, another research HIPAA compliant medical records release form for the
pediatrician, or health care provider caring for the child, is sent to the mother of the infant for
signature electronicall yor by hard cop y mail. The signed form with a standard phy sical
evaluation form is sent to the health care provider to request upda ted information on growth,
and major congenital malformations.
090177e19a3ab0c5\Approved\Approved On: 17-May-2022 21:36 (GMT)
FDA-CBER-2022-5812-0236214
Pfizer -BioNTech COVID -19 Vaccine
C4591022 NON -INTERVENTIONAL STUDY PROTOCOL
Version 4.0, 09 May 2022
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 3 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
20-May-2021
Page 31of 50Medical records for pregnant women and their infants are also captured at birth and again for
the infant at one year of age. Medical records are reviewed b y trained abstractors to
supplement information self -reported b y the participant related to vaccine exposure,
outcomes, prenatal tests, and medical history .
9.4.4. Scientific Advisory Board
An existing external Scientific Advisory Board under the Vaccines and Medication in
Pregnancy Surveillance Sy stem (VAMPSS) provides oversight for the study and reviews
study summary data on an annual basis. Members of the Board provide advice to the Registry
investigators on interpretation of the data and provide advice on strategies for the
dissemination of infor mation regarding the stud y.
The VAMPSS Scientific Advisory Board is managed by the American Academy of Allergy
Asthma and Immunology. The Scientific Advisory Board is comprised of membership
representing specialization in maternal fetal medicine, biostatis tics, vaccine epidemiology ,
and representation from the Centers for Disease Control, National Institutes of Health/Child
Health Institute, the American Academ y of Pediatrics, and a consumer representative. The
Board is chaired b y a designated member, and e ach member has one vote. A dedicated
charter describes roles and responsibilities of the Board members, and members complete
conflict of interest disclosures on an annual basis.
9.5.Study Size
Recruitment goals are set at 1100 participants in the Pfizer -BioNTe ch COVID -19 vaccine
expos urecohort and 900 participants in the comparator cohort, for a total of 2000
participants enrolled in the study .The target sample size for the Pfizer -BioNTech COVID-
19 vaccine exposure cohort was increased from an initial sample size of 900 to 1100 to allow
for increased capture of women receiving a booster dose during pregnancy. The rationale for
the target sampl e size of 1100 pregnant women in the exposed cohort and 900 pregnant
women in the comparator cohort was based on several considerations for feasibility of
enrollment. These considerations included early trends in referrals of COVID -19 vaccinated
pregnant w omen to the OTI S Pregnancy Registry , inclusion of women exposed to a booster
dose as well as a reasonable time period for recruitment of pregnant women and the
necessary time to collect outcome data to one y ear postpartum. An additional consideration
was r easonable statistical power to detect differences for each outcome of interest . Balance in
the cohort numbers b y trimester of exposure in the vaccine -exposed cohort and by trimester
of enrollment in both cohorts will be monitored on a monthly basis, and ov erall balance
addressed b y adjusting recruitment activities as needed. It is not possible to predict if the
recruitment rates will be equal in all y ears, and therefore, sample size is based on estimates
that may require revision as the study progresses.
Aswomen will be eligible to enroll at an y time in pregnancy, the gestational age at
enrollment is expected to vary from 2 weeks to 41 weeks. Based on the gestational week at
enrollment, only the portion of the overall sample enrolled prior to 20 weeks’ gest ation will
be eligible for the anal ysis of spontaneous abortion. We estimate based on prior experience
that half the overall sample will enroll prior to 20 weeks. Similarly , only the subset of the
090177e19a3ab0c5\Approved\Approved On: 17-May-2022 21:36 (GMT)
FDA-CBER-2022-5812-0236215
Pfizer -BioNTech COVID -19 Vaccine
C4591022 NON -INTERVENTIONAL STUDY PROTOCOL
Version 4.0, 09 May 2022
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 3 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
20-May-2021
Page 32of 50sample enrolled prior to 37 weeks’ gestation will be eligib le for the anal ysis of preterm birth.
It is estimated that 95% of the overall sample will enroll before 37 weeks. For the outcome of
major birth defects, the main subset eligible for this assessment will be restricted in the
exposed cohort to women who rec eived at least one dose of the Pfizer -BioNTech COVID-19
vaccine from one month prior to L MP to the end of the first trimester. Pregnant women who
received the Pfizer -BioNTech COVID -19 vaccine only during the ir second or third trimester
will be excluded fro m the anal ysis. Based on previous experience in OTIS studies, the
estimated lost to follow -up rate is 5% ( Chambers et al, 2016 ).
Based on these assumptions, for the outcome of major birth defects, it is estimated that 85%
will result in live birth after exclusion of pregnancy losses (10%) in women enrolled in the
first half of pregnancy , and lost- to-follow -up (5%). For spontaneous abortion, it is estimated
that half of the overall sample will enroll prior to 20 weeks’ gestat ion. For preterm delivery ,
it is estimated that 80% of the overall sample will enroll prior to 37 weeks’ gestation and will
end in a singleton live birth. For the outcome of small for gestational age, it is estimated that
85% of the overall sample will en d in a singleton live birth.
Baseline birth prevalence, incidence rates, and incidence proportions of major congenital
malformations, preterm delivery , and small for gestational age, respectivel y, are based on
previous OTIS Pregnancy Registry studies and o n general population data. Table 4 gives the
power for various detectable relative risks (RRs) /hazard ratios (HRs) for two-sided alpha
level of 0.05 in the comparisons of the exposed cohort to the comparator cohort for the range
of background risks of the outcomes of interest.
Table 4.Sample Size and Power for a Specified Effect Size
Outcom e N in Exposed
CohortN in Compar ator
CohortBirth Prevalence/
Incidence in
Comparator
CohortDetectable
Relative Risk /
Hazard RatioPower1
Major congenital
malformations2311 765 3%32.1 65.8%
2.5 86.7%
2.7 92.6%
Spontaneous
abortion550 450 10%41.5 66.6%
1.7 90.1%
1.8 95.6%
Preterm delivery 880 720 10%51.4 69.1%
1.5 85.6%
1.6 94.7%
Small for
gestational age935 765 10%61.4 71.7%
1.5 87.6%
1.6 95.8%
Small for age
postnatal growth
at one year of age935 765 10%61.4 71.7%
1.5 87.6%
1.6 95.8%
090177e19a3ab0c5\Approved\Approved On: 17-May-2022 21:36 (GMT)
FDA-CBER-2022-5812-0236216
Pfizer -BioNTech COVID -19 Vaccine
C4591022 NON -INTERVENTIONAL STUDY PROTOCOL
Version 4.0, 09 May 2022
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 3 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
20-May-2021
Page 33of 50Table 4.Sample Size and Power for a Specified Effect Size
Outcom e N in Exposed
CohortN in Compar ator
CohortBirth Prevalence/
Incidence in
Comparator
CohortDetectable
Relative Risk /
Hazard RatioPower1
1.Arcsine transformation using pw r.2p.test() in R package ‘pwr’ to obtain effect size h, where ℎ=2∗
sin −2∗sin and p1= event rate in the exposed cohort, p 2= event rate in the comparison
cohort, assuming 2 sided alpha = 0.05.
2.Among livebirths.
3.CDC, 2017.
4.Avalos et al., 2012.
5.Ferré et al., 2016.
6.CDC, 2017; Nellhaus, 1968; Olsen et al., 2010.
NOTES
i.Major Congenital Malformations
N in exposed cohort for Major congenital malformations based on assumptions that 366 exposed
to at least one dose from 1 month prior to LMP through the first trimester, and of these 10% will
be lost to spontaneous abortion or stillbirth, and 5% lost to follow -up; 85% of the 366 enrolled w ill
thus yield 311 eligible for the analysis.
N in comparator cohort = 900 enrolled x 85% resulting in at least one live birth = 765.
ii.Spontaneous Abortion
N in exposed cohort for spontaneous abortion based on estimate that ½ will be exposed and enroll
in the first 20 w eeks of gestation and thus be at risk of spontaneous abortion until 20 completed
weeks; N of 1100 enrolled and exposed x 50% enrolled and exposed prior to 20 weeks = 550.
N in comparator cohort = 900 of which 50% will be enrolled prior to 20 w eeks = 450.
iii.Preterm Delivery
N in exposed cohort based on 95% of the 1100 enrolled and exposed to at least one dose prior to
37 w eeks, 10% pregnancy loss, and 5% lost to follow -up for an overall estimated 80% eligible for
the analysis; 1100 enrolled x 80% = 880.
N in comparator cohort based on same assumptions; 900 enrolled x 80% = 720.
iv.Small for Gestational Age
N in exposed cohort based on 1100 enrolled and exposed to at least one dose from 1 month prior
to LMP up through the end of pregnancy, 10% pregnancy loss, and 5% lost -to-follow -up; 1100 x
85% = 935.
N in comparator cohort based on same assumptions; 900 x 85% = 765.
v.Small for Age Postnatal Growth at One Year of Age
N in exposed cohort based on 1100 enrolled and exposed to at least one dose from 1 month prior
to LMP up through the end of pregnancy; 10% pregnancy loss and 5% lost -to-follow -up; 1100 x
85% = 935.
N in comparator cohort based on same assumptions; 900 x 85% = 765.
090177e19a3ab0c5\Approved\Approved On: 17-May-2022 21:36 (GMT)
FDA-CBER-2022-5812-0236217
Pfizer -BioNTech COVID -19 Vaccine
C4591022 NON -INTERVENTIONAL STUDY PROTOCOL
Version 4.0, 09 May 2022
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 3 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
20-May-2021
Page 34of 509.6.Data Management
As per the OT IS Pregnancy Registry protocol, data are collected using maternal interview,
medical record, and the pregnancy diary . Maternal interview data are recorded on hard copies
of forms, and these forms will be retained by OTIS. These forms are considered the primary
data sources for the registry . Medical records and medical record abstraction forms are hard
copies or electronic copies and are retained on a secure server or in locked files . Data from
maternal interview an d medical record abstraction forms are extracted and entered into a
customized OTI S registry database located in the Research Center and developed specificall y
for the OTIS Pregnancy Research Studies.
The database itself has built in range limits for key v ariables that prevent certain data entry
errors. In addition, all data entry forms are reviewed for logical errors b y the registry data
manager on a bi -monthly basis, and 100% of key variables are double -checked for data entry
accuracy . The registry statis tician also conducts reviews of the cumulative data in the
database for distributions and values that are illogical. The registry manager is responsible
for working with the data manager and the supervisory staff to oversee the data validation
procedures.
Access to the database is controlled by password, with different access privileges assigned to
the managers, interviewers and data entry staff, and administrative staff; these privileges are
outlined in detail in the OTI S Data Management Guide, Data Entry Standard Operating
Procedure (SOP), and supplements to these guides. An audit log is built into the database to
archive all such entry edits.
Hard copies of participant files and participant signed consent forms are kept in locked
cabinets in locked file rooms, or electronically secured files, under the supervision of the
study investigators.
9.7.Data Analysis
9.7.1. Statistical Methods
The distributions of demographic and baseline characteristics will be summarized within
each exposure cohort. The following measur es will be calculated for the pregnancy and
infant outcomes: birth prevalence of major congenital malformations ; incidence rates of
spontaneous abortion, elective termination/abortion, stillbirth, and preterm delivery ;and
incidence proportions of small fo r gestational age andsmall for age postnatal growth at one
year of age . For each outcome, risk estimates will be described separatel y for the Pfizer -
BioNTech COVID -19 vaccine exposure cohort and each of the comparator cohorts. The
outcomes will be compared between the Pfizer -BioNTech COVID -19 vaccine -exposed
cohort and the comparator cohort. Where feasible, comparisons will also be made using
methods to control potential confounding. Detailed methodology for summary and statistical
analyses of data collected in this study will be documented in the SAP, which will be dated,
filed and maintained b y the sponsor. The SAP may modify the plans outlined in the protocol;
any major modifications of endpoint definitions or their anal yses would be reflected in a
protocol amendment.
090177e19a3ab0c5\Approved\Approved On: 17-May-2022 21:36 (GMT)
FDA-CBER-2022-5812-0236218
Pfizer -BioNTech COVID -19 Vaccine
C4591022 NON -INTERVENTIONAL STUDY PROTOCOL
Version 4.0, 09 May 2022
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 3 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
20-May-2021
Page 35of 509.7.2. Primary Analyses
The eligible populations and time periods for analy ses may differ by pregnancy outcome
depending on a participant’s timing of vaccine exposure/study enrollment as it relates to the
at-risk period for an outcome, in addition to ty pe of birth ( Table 5). For example, the
analyses for major congenital malformations will be restricted to women exposed to at least
one dose of the Pfizer -BioNTech COVID- 19 vacci ne during their first trimester (or enrolled
in the study for COVID-19 unvaccinated comparator) whose pregnancies resulted in at least
one live born infant. For preterm delivery , only those women exposed to at least one dose of
the Pfizer -BioNTech COVID-19 vaccine (or enrolled in the study for unvaccinated
comparator) prior to 37 weeks’ gestation and whose pregnancies resulted in a live- born
singleton are eligible for the anal ysis. The denominators for each exposure/comparator cohort
and outcome analy sis wi ll include participants as follows:
Table 5.Denominators for Outcomes by Exposure/Comparator Cohort
Outcome Pfizer -BioNTech COVID -19
Vaccine -Exposed
(Exposure)COVID -19 Vaccine -
Unexposed
(Comparator)
Major congenital
malformationsParticipants who received the
Pfizer- BioNTech COVID -19
vaccine (1st, 2nd, 3rd, or booster
dose) any time from one month
before the first day of LMP
through their first trimester and
whose pregnancy resulted in >1
live birthParticipants who did not receive
any COVID -19 vaccines any
time from one month before the
first day of LMP up to and
including end of pregnancy and
whose pregnancy resulted in >1
live birth
Spontaneous abortion Participants who received the
Pfizer- BioNTec h COVID -19
vaccine (1st, 2nd, 3rd,or booster
dose) any time from one month
before the first day of LMP up to
20 weeks’ gestation andwere
enrolled in the study prior to 20
weeks’ gestationParticipants who did not receive
any COVID -19 vaccines any
time from one month before the
first day of LMP up to and
including end of pregnancy and
were enrolled in the study prior
to 20 weeks’ gestation
Elective
termination/abortionParticipants who received the
Pfizer- BioNTech COVID -19
vaccine (1st, 2nd, 3rd, or boo ster
dose) any time from one month
before the first day of LMP up to
and including end of pregnancyParticipants who did not receive
any COVID -19 any time from
one month before the first day
of LMP up to and including end
of pregnancy
Stillbirth Particip ants who received the
Pfizer- BioNTech COVID -19
vaccine (1st, 2nd, 3rd, or booster Participants who did n ot receive
any COVID -19 vaccines any
090177e19a3ab0c5\Approved\Approved On: 17-May-2022 21:36 (GMT)
FDA-CBER-2022-5812-0236219
Pfizer -BioNTech COVID -19 Vaccine
C4591022 NON -INTERVENTIONAL STUDY PROTOCOL
Version 4.0, 09 May 2022
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 3 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
20-May-2021
Page 36of 50Table 5.Denominators for Outcomes by Exposure/Comparator Cohort
Outcome Pfizer -BioNTech COVID -19
Vaccine -Exposed
(Exposure)COVID -19 Vaccine -
Unexposed
(Comparator)
dose) any time from one month
before the first day of LMP up to
and including end of pregnancy,
but must have follow -up at or after
20 weeks’ gestationtime from one month before the
first day of LMP up to and
including end of pregnancy ,but
must have follow -up at or after
20 weeks’ gestation
Preterm delivery Participants who received the
Pfizer- BioNTech COVID -19
vaccine (1st, 2nd, 3rd, or booster
dose) any time from one month
before the first day of LMP up to
37 weeks’ gestation, were enrolled
in the study prior to 37 weeks’
gestation, and whose pregnancy
resulted in a live -born singletonParticipants who did not receive
any COVID -19 vaccines any
time from one month before the
first day of LMP up to and
including end of pregnancy ,
were enrolled in the study prior
to 37 weeks’ gestation, and
whose pregnancy resulted in a
live-born singleton
Small for gestational
ageParticipants who received the
Pfizer- BioNTech COVID -19
vaccine (1st, 2nd, 3rd, or booster
dose) any time from one month
before the first day of LMP up to
and including end of pregnancy
andwhose preg nancy resulted in a
live-born singletonParticipants who did not receive
any COVID -19 vaccines any
time from one month before the
first day of LMP up to and
including end of pregnancy and
whose pregnancy resulted in a
live-born singleton
Small for age postnatal
growth at one year of
ageParticipants who received the
Pfizer- BioNTech COVID -19
vaccine (1st, 2nd, 3rd, or booster
dose) any time from one month
before the first day of LMP up to
and including end of pregnancy
and whose pregnancy resulted in a
live-born singletonParticipants who did not receive
any COVID -19 vaccines any
time from one month before the
first day of LMP up to and
including end of pregnancy and
whose pregnancy resulted in a
live-born singleton
For the endpoint of major congenital malformations, the birth prevalence among pregnancies
resulting in at least one live born infant will be compared between the Pfizer -BioNTech
COVID -19 vaccine expos ure cohort and the comparator cohort. A point estimate of the crude
(i.e.unadjusted) risk r atio (RR) of the exposed cohort versus the comparison cohort, as well
as its 95% confidence interval (CI), will be computed using normal approximation method.
090177e19a3ab0c5\Approved\Approved On: 17-May-2022 21:36 (GMT)
FDA-CBER-2022-5812-0236220
Pfizer -BioNTech COVID -19 Vaccine
C4591022 NON -INTERVENTIONAL STUDY PROTOCOL
Version 4.0, 09 May 2022
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 3 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
20-May-2021
Page 37of 50When the expected frequency of an y of the cells of the contingency table is less than five, the
CI will be obtained b y an exact method using the software StatXact.
Due to the observational nature of the stud y, the above crude estimate of RR will be adjusted
for potential confounders (Rosenbaum, 2002 ),provided that there are sufficient number of
events. A list of potential confounders will be provided in a separate table in the SAP for
each outcome prior to the final anal ysis, based on scientific knowledge including literature
review. In addition, all of the following three criteria will be applied in accordance with the
definition of confounders (Greenland et al., 1999 ;Xu et al., 2018 ):1) by assessing each
considered variable in a logistic regression mod el containing the exposure variable and the
outcome variable to determine if inclusion of that single covariate changes the estimate of the
odds ratio for exposure by 10% or more; 2) standardized mean differences greater than 0.1;
3) association with the o utcome with p -value < 0.2 in the unexposed cohort. Care will be
taken not to include those variables that are strongl y associated with the exposure variable
but only weakly associated with the outcome variable (Brookhart e t al., 2006 ).
The confounders identified above will be used to build the propensity score for exposure
(Rosenbaum, 2002 ).R package ‘twang’ or similar R package available at the time of anal ysis
will be used for this purp ose, following which standardized mean differences will be used to
check the balance of the covariates between the cohorts.
The primary anal ysis will be performed with inverse probability of treatment weighting
(IPTW) using the propensity score to estimate the causal risk ratio . In the IP TW approach,
we will use stabilized weights that are further trimmed to be between 0.1 and 10 if necessary
(Austin and Stuart, 2015 ). The bootstrap variance estimator will be used following the IPT W
approach.
Anadditional analysisof major congenital malformations will be conducted using outcome
regression ,i.e., a logistic regression model will be fitted with major congenital malformation
(Y) as the outcome, and exposure (A) and propensity score ( L) as regressors. Outcomes
regression tends to be more stable and efficient than I PTW especially given the expected rare
number of events (Xu et al., 2018), and has known robust properties against model
misspecification (Vansteelandt and Daniel, 2014 ).Standardization will be performed to
obtain the estimated causal risk ratio ( Hernán and Robins, 2019 ). The variance estimator will
be obtained using bootstrap .
The analysis of spontaneous abortion and stillbirth is complicated by left truncation in the
data, i.e., women enter the study at arbitrary times in gestation (Xu et al., 2012 ). Only those
women who are enrolled prior to 20.0 weeks of gestation are eligible for the anal ysis of
spontaneous abortion. Since they are not followed from gestational age zero, survival
analysis methods will be used to handle left truncation, as well as right -censoring when a
participant is lost- to-follow -up prior to 20 weeks’ gestation. The Cox proportional hazards
marginal structural model incorporating time-dependent vaccine exposure will be used for
the causal hazard ratio (HR) of different cohorts, a s well as to obtain the 95% CI s. To
090177e19a3ab0c5\Approved\Approved On: 17-May-2022 21:36 (GMT)
FDA-CBER-2022-5812-0236221
Pfizer -BioNTech COVID -19 Vaccine
C4591022 NON -INTERVENTIONAL STUDY PROTOCOL
Version 4.0, 09 May 2022
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 3 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
20-May-2021
Page 38of 50account for potential confounding, propensity score methods with the I PTW approach will be
applied. Stillbirth will be anal yzed in a similar fashion.
The anal ysis of preterm delivery can also be complicated by left truncation in the data, i.e.,
women enter the stud y at arbitrary times in gestation. Only those women who are enrolled
prior to 37.0 weeks of gestation are eligible for the anal ysis of preterm delivery . These data
will be a nalyzed similarly to spontaneous abortion, as described above, using survival
analysis methods, to handle possible left truncation and right -censoring.
The anal ysis of elective termination/abortion will be descriptive as the number of events is
expected to be low.
The following are binary endpoints: small for gestational age at birth in weight, length, and
head circumference; and small for age postnatal growth at one year of age ≤10thcentile in
weight, length, and head circumference. The anal ysis of the proportion of infants with each
of these outcomes will be similar to the analy sis of the outcome major congenital
malformations and will be restricted to pregnancies ending in a live born singleton. For these
outcomes, exposure to the Pfizer -BioNTech COVID -19 vaccine in an y trimester will be
compared to the unexposed cohort .
9.7.3. Secondary Analyses
9.7.3.1. Stratified/Subgroup Analyses
For the endpoint of major congenital malformations, the comparison will also be carried out
within each of two strata, according to whether the participant had prenatal diagnostic
testing, such as level 2 ultrasound, amniocentesis or chorionic villus sampling, prior to
enrollment in the study or not.
In stratified analy ses, the separate effects of vaccine exposure during the first, second, and
third trimester of pregnancy will be studied as applicable to the following pregnancy
outcomes: preterm delivery , small for gestational age, and small for age postna tal growth at
one y ear of age.
A variable for prior COVID -19infection will be used in the propensity score generation for
the adjusted anal yses, and, if numbers permit, a stratified analy sis for prior COVID -19
infection will be conducted as well .
9.7.3.2. Individu al Dose Effects
Secondary analyses will also address the potentially different effects of the 1st, 2nd, 3rd,and
booster dose sduring relevant pregnancy windows (e.g., 1sttrimester exposure for the
outcome of major congenital anomalies, and prior to 20 we eks’ gestation for the outcome of
spontaneous abortion) . More specificall y these will be considered four separate exposures.
An additive effects marginal structural model will be used for each pregnancy outcome.
090177e19a3ab0c5\Approved\Approved On: 17-May-2022 21:36 (GMT)
FDA-CBER-2022-5812-0236222
Pfizer -BioNTech COVID -19 Vaccine
C4591022 NON -INTERVENTIONAL STUDY PROTOCOL
Version 4.0, 09 May 2022
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 3 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
20-May-2021
Page 39of 509.7.3.3. Evaluation for a Pattern of Major Congenit al Malformations
The following steps will be taken to evaluate an y pattern of major congenital malformations:
A review of major congenital malformations will be made by category . A review of specific
major congenital malformations will be conducted taking into consideration timing and
biological plausibility . In addition, specific defects that are plausibl y related to second or
third trimester exposure will also be evaluated.
9.7.3.4. Lost to Follow -Up
Pregnancies enrolled in the cohort stud y for which outcome information is unobtainable
within 1 y ear after the estimated date of delivery are considered lost to follow -up. It is
possible that outcomes among pregnancies lost to -follow -up could differ from t hose with
documented outcomes. Because of differences in follow -up and reporting patterns, it is
currentl y not possible to assess with an y certainty what impact with regard to potential biases
the lost to follow -up may have on an y analysis of the cohort st udy. Should lost to follow -up
numbers be substantial, however, efforts at comparing some of the characteristics of each
cohort will be made in an attempt to address this potential source of bias. However, the OTIS
Research Center prior experience has been that the lost to follow -up rate is extremely low,
typicall y 5%.
9.7.4. Sensitivity A nalyses
The following sensitivity anal yses will be performed for the outcome of major congenital
malformations.
A sensitivity anal ysis will be performed for the outcome of major c ongenital
malformations among all pregnancies excluding those that are lost -to-follow -up. The
analysis population will be those with exposure to the Pfizer -BioNTech COVID-19
vaccine at an y time from one month prior to the first day of LMP to the end of the
first trimester excluding those that are lost -to-follow -up. The anal ysis population for
the comparison cohort will be all pregnancies excluding those that are lost -to-follow -
up. The purpose of this analysis is to account for major congenital malformations that
may occur in pregnancies that are terminated or spontaneously lost and are therefore
excluded from the primary anal ysis of major congenital malformations among live
births.
A second sensitivity analy sis will be performed for the outcome of major cong enital
malformation s stratified on any abnormal finding (y es/no) among those with prenatal
testing prior to enrollment.
In a third sensitivity analy sis, both the exposure and comparator cohorts will be
restricted to women who enrolled in the study during t heir first trimester.
090177e19a3ab0c5\Approved\Approved On: 17-May-2022 21:36 (GMT)
FDA-CBER-2022-5812-0236223
Pfizer -BioNTech COVID -19 Vaccine
C4591022 NON -INTERVENTIONAL STUDY PROTOCOL
Version 4.0, 09 May 2022
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 3 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
20-May-2021
Page 40of 50A fourth sensitivity analysis will be conducted to expand the comparator cohort to
include women who received any dose of the Pfizer -BioNTech COVID -19 vaccine
only in their second or third trimester .
Sub-analyses using graphical presentation based on gestational timing of exposure to
the Pfizer -BioNTech COVID-19 vaccine will also be performed.
An additional sensitivity anal ysis will be performed for the outcome of preterm delivery
stratified on elective cesarian section or labor i nduction leading to delivery prior to 37 weeks’
gestation vs. delivery prior to 37 weeks’ gestation following spontaneous labor.
9.7.5. Missing Data
Multiple imputation (MI) will be conducted to handle the missing data. Missing values
typicall y occur in less than 5% of the cases for any single covariate based on prior
experience. They are assumed to be missing at random. When there are missing values in an y
of the selected confounders, multiple imputation (MI) will be conducted, using the R package
MICE (multivari ate imputation by chained equations). Demographic information, pregnancy
history , information about current pregnancy , and concurrent diseases will be used as
possible ‘predictors’ in MI CE. The generalized R2will be used as a measure of correlations
betwe en each ‘target’ (i.e. ,the variable to be imputed) and a predictor. If the value of R (i.e.,
square root of R2) is over 0.1, the variable will be retained as a predictor. Predictors with
strong collinearity might be excluded (for example, one of race and ethnicity , and one of
gravidity and parit y). Although each outcome within each cohort comparison has its unique
set of participants, MI is conducted for missing data using the entire dataset, i.e., on all
cohorts combined.
For the outcome of spontaneous abortion, for some cases the exact date of the event might be
unknown, and instead a window for possible spontaneous abortion time is available. This is
known as interval censored data, and can also be handled using M I. An ex act spontaneous
abortion time will be imputed by sampling uniformly from the corresponding time window.
The number of above imputations will be 10, i.e., 10 datasets with imputed data will be
created. Each imputed data set gives a point estimate of the re gression coefficients as well as
its standard deviation, which will be combined across the 10 datasets to obtain the final
estimate of the causal RR /HR and their 95% CI’s. Further details will be provided in the
SAP.
9.7.6. Analysis Software
All summaries and sta tistical anal yses will be performed using the current version of open -
source statistical programming language R and StatXact.
9.8.Quality Control
Data used in this study are secondary use of data collected as part of the existing OTIS
Pregnancy Registry protoc ol, which includes established quality control practices. Interview
090177e19a3ab0c5\Approved\Approved On: 17-May-2022 21:36 (GMT)
FDA-CBER-2022-5812-0236224
Pfizer -BioNTech COVID -19 Vaccine
C4591022 NON -INTERVENTIONAL STUDY PROTOCOL
Version 4.0, 09 May 2022
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 3 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
20-May-2021
Page 41of 50and examination data will be recorded on hard copies of forms, and medical records and
medical record abstraction forms will be electronic or hard copies of forms. These records
and forms will be retained at the Research Center. Data from these forms will be extracted
and entered into a customized database located at the Research Center. The data will be
extracted and entered b y trained study personnel with extensive experience with this ty pe of
information. Entries will be periodicall y reviewed for logical errors, and a random subset of
intake and outcome forms will be double -checked for data entry accuracy . The method and
duration of storage of data is addressed in the informed consent, th at each participant will
agree to in order to receive medical record information. All records are maintained for a
minimum of 15 years following stud y completion.
Access to the database will be controlled by password. Hard copies of participant files and
signed consent forms will be kept in a locked cabinet under the supervision of the study
investigators.
The data will be entered by trained study personnel with extensive experience with this ty pe
of information. Data will be collected and entered into the database according to the SOPs for
data collection and data entry established for this study .
The data manager will calculate monthly error rates for each data entry staff person and for
the study overall and will recommend and initiate training/retraini ng where quality standards
are not being met. The study manager will oversee this process and verify that training
standards are achieved.
For the stud y endpoint of major congenital malformations, verification of the outcome
identified , and classification is performed on a monthly basis is provided by blinded review
by co-investigator, Kenneth Ly ons Jones, MD.
9.9.Limitations of the Research Methods
This study will use data from the well -established OTI S Pregnancy Registry which collects
detailed data on prena tal/birth exposures (including timing of exposures during pregnancy )
and outcomes. The primary limitation of this cohort study utilizing volunteer participants is
potential selection bias in that women who agree to enroll in the study may represent
particularl y high -or low -risk pregnancies ( Johnson et al., 2001). For example, women who
receive the vaccine and have a history of spontaneous abortion (high baseline risk) may be
more likely to preferentially enroll than women who did not receive the vaccine and who did
not have a history of prior spontaneous abortion because of concerns about their pregnancy .
In addition, the study results will be strictly generalizable to women fitting the profile of the
sample of women who enro ll. The use of inverse probability weighting to account for
differences between the exposure and comparator cohorts will address these concerns to
some extent. The data analy sis stratify ing on use of prenatal testing and on gestational timing
of enrollment will also help control for confounding introduced by potential selection bias.
Another limitation of the study design relates to the evaluation of the incidence of
spontaneous abortion. Incidence rates of early spontaneous abortion, i.e., at 7 -9 weeks pos t-
090177e19a3ab0c5\Approved\Approved On: 17-May-2022 21:36 (GMT)
FDA-CBER-2022-5812-0236225
Pfizer -BioNTech COVID -19 Vaccine
C4591022 NON -INTERVENTIONAL STUDY PROTOCOL
Version 4.0, 09 May 2022
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 3 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
20-May-2021
Page 42of 50LMP or less, will not be measured in a stud y that enrolls women after recognition of
pregnancy . Therefore, spontaneous abortion will be defined as late first-trimester and earl y
second -trimester pregnancy loss. Analy sis of spontaneous abortion will be re stricted to those
who enroll prior to 20 weeks’ gestation. In addition, if a high proportion of women enroll
later in pregnancy , other survival biases may be introduced. A sensitivity analy sis by
gestational age at enrollment will be performed in order to address these questions. Analy ses
will be stratified by gestational age at enrollment to help address the potential selection bias.
As early prenatal testing is so prevalent in the US and Canada, it may be difficult to achieve
adequate numbers of particip ants if all pregnancies with prenatal testing prior to enrollment
are excluded from the analy sis. Therefore, the study will include pregnant women enrolled
prior to outcome but after a prenatal test has been performed as long as the test does not
indicate the presence of a major congenital malformation. 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 numb ers.
However, this practice could potentially bias the results by lowering the overall estimate of
the birth prevalence of major congenital malformations ( Honein et al., 1999 ).
The calculation of frequency of major congenital malformations excludes fetal losses
(spontaneous abortions, elective terminations/abortions, or fetal deaths) for which no major
congenital malformations have been detected as they may introduce a classification bias. I t is
unknown what percentage of thes e pregnancies consists of potentially normal outcomes or
pregnancies with major congenital malformations. The study attempts to obtain information
on major congenital malformations detected at the time of the outcome. However, the
malformation status of th e aborted fetus may not be known. For this reason, the primary
comparison for the endpoint of the study will be conducted among pregnancies ending in at
least one live birth; a separate sensitivity anal ysis of the endpoint will be conducted including
all pregnancies with known outcome.
It is expected that exposure to the Pfizer -BioNTech COVID- 19 vaccine will occur in
unintended pregnancies as more than half of all pregnancies in the US are unintended
(Henshaw, 1998 ). Therefor e, the possibility of confounding b y age, race, and other
demographic variables will be considered. For example, the rate of unintended pregnancies is
higher among low -income women/families than among the other socioeconomic cohorts. I t is
possible that de mographic variables will be associated with vaccination as well ( MMWR,
2021 ). As such, in reviewing annual reports, if clear differences in demographic factors (i.e.,
age, race/ethnicit y, socioeconomic status , education )are no ted, enhancement of recruitment
efforts to increase diversity will be taken into consideration .
Although all possible efforts will be made to retain participants in the registry or follow up
with their healthcare providers, some participants will be lost d uring follow up. I t could be
possible that participants lost during follow up and with missing data on outcomes may be
different compared to those with complete follow up data. In previous OTIS studies, lost -to-
follow -up rates have been low, ty picall y <5% (Chambers et al., 2016 ).However, the
characteristics of women lost to follow up will be compared to those who are retained in
order to understand the direction and magnitude of the bias due to loss to follow up.
090177e19a3ab0c5\Approved\Approved On: 17-May-2022 21:36 (GMT)
FDA-CBER-2022-5812-0236226
Pfizer -BioNTech COVID -19 Vaccine
C4591022 NON -INTERVENTIONAL STUDY PROTOCOL
Version 4.0, 09 May 2022
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 3 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
20-May-2021
Page 43of 50The study design has relative strengths with respect to the control of a large number of
potential confounders. Information will be collected repeatedl y throughout pregnancy on a
variet y of factors which may be related to exposure and to pregnancy outcome, and the u se of
a vaccine comparison cohort can aid in addressing confounding. Misclassification bias due to
poor recall is thought to be reduced in prospective study designs such as this, as each
participant is interviewed at several predetermined intervals during pregnancy . Another
strength of the study design is the anticipated minimal lost- to-follow -up rate. Based on
previous experience of the investigators in the OTIS Pregnancy Studies and other similar
studies, and the frequent participant contact, lost- to-follow-up is expected to be less than 5%,
and therefore not expected to pose a threat to the validity of study results.
Finally , the sample size that is projected to be achievable for this study has limitations in
statistical power for the outcome of major con genital malformations. The investigators and
the Scientific Advisory Board’s expert review and comment on the data and the inclusion of
evaluation of a pattern of major anomalies are strengths.
9.10. Other Aspects
Not applicable.
090177e19a3ab0c5\Approved\Approved On: 17-May-2022 21:36 (GMT)
FDA-CBER-2022-5812-0236227
Pfizer -BioNTech COVID -19 Vaccine
C4591022 NON -INTERVENTIONAL STUDY PROTOCOL
Version 4.0, 09 May 2022
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 3 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
20-May-2021
Page 44of 5010. PROTECTION OF HUMAN SUBJECTS
10.1. Patient Information
This study involves data that exist in anony mized structured format and contain no patient
personal information. If automated/algorithmic methods, such as natural language
processing, will be used to convert unstructured data to structu red data during the
implementation of the protocol, no patient personal data will be accessed.
10.2. Participant Consent
As this study involves anony mized structured data, which according to applicable legal
requirements do not contain data subject to privacy laws, obtaining informed consent from
patients by Pfizer is not required.
10.3. Institutional Review Board (IRB)/Independent Ethics Committee (IEC)
There must be prospective approval of the study protocol, protocol amendments, and other
relevant documents (e.g., i nformed consent forms if applicable) from the relevant I RBs/IECs.
All correspondence with the I RB/IEC must be retained. Copies of I RB/IEC approvals must
be forwarded to Pfizer.
This protocol and informed consent documents are approved b y the Institutional Review
Board (IRB) at the University of California, San Diego. The chairperson or the recording
secretary of the IRB sign a form indicating approval. Notification of the Board’s approval of
the study is provided to the Sponsor prior to initiation of the st udy.
10.4. Ethical Conduct of the Study
The study will be conducted in accordance with legal and regulatory requirements, as well as
with scientific purpose, value and rigor ,and follow generally accepted research practices
described in Guidelines for Good Pharm acoepidemiology Practice ( ISPE, 2016 ), in
accordance with the ethical principles of the Declaration of Helsinki (World Medical
Association, 2013 )and HIPAA (Health Insurance Portability and Accountab ility Act)
(National Institutes of Health, 2002 ; Andrews et al., 1996 ).
11.MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE
REACTIONS
This study involves data that exist as structured data by the time of study start. In this
structured pregnancy database, individual patient data are not retrieved or validated, and it is
not possible to link (i.e., identify a potential association between) a particular product and
medical event for an y individua l. Thus, the minimum criteria for reporting an adverse event
(AE) (i.e., identifiable patient, identifiable reporter, a suspect product, and event) cannot be
met.
090177e19a3ab0c5\Approved\Approved On: 17-May-2022 21:36 (GMT)
FDA-CBER-2022-5812-0236228
Pfizer -BioNTech COVID -19 Vaccine
C4591022 NON -INTERVENTIONAL STUDY PROTOCOL
Version 4.0, 09 May 2022
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 3 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
20-May-2021
Page 45of 5012.PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS
A final report describing the study endpoints will be prepared b y the OTIS Research Center
and provided to the Pfizer team. Pfizer will communicate the results to FDA and other
regulatory authorities as appropriate .Conference abstracts and manuscripts based on specific
endpoints of interest may be developed for publication purposes and will be reviewed b y
Pfizer for comment. Thefinal report will be disclosed on the EU PAS Register.
In addition, the OTIS Research Center will develop annual interim reports and any additional
ad hoc reports w ith the advice of the VAMPSS Scientific Advisory Board members. Each
report will be a composite of the cumulative data to date and will supersede any previous
reports. Descriptive analyses may be presented, but no formal interim statistical anal ysis is
planned. The rationale for this is that given sample size limitations, an interim analy sis will
likely be statisticall y underpowered to provide informative results. However, at each interim
Scientific Advisory Board review, consideration will be given to any findings that might
indicate that a formal interim anal ysis should be performed. The final anal ysis will be
conducted when the cohort study has been completed.
In the event of an y prohibition or restriction imposed (e.g., clinical hold) by an applicable
competent authorit y in any area of the world, or if the party responsible for collecting data
from the participant is aware of an y new information which might influence the evaluation of
the benefits and risks of a Pfizer product, Pfizer should be informed i mmediately .
090177e19a3ab0c5\Approved\Approved On: 17-May-2022 21:36 (GMT)
FDA-CBER-2022-5812-0236229
Pfizer -BioNTech COVID -19 Vaccine
C4591022 NON -INTERVENTIONAL STUDY PROTOCOL
Version 4.0, 09 May 2022
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 3 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
20-May-2021
Page 46of 5013.REFERENCES
1. ACOG Practice Bulletin 700 (2017). Available at https://www.acog.org/clinical/clinical-
guidance/committee -opinion/articles/2017/05/methods -for-estimating -the-due- date.
Accessed November 18, 2021.
2. Andrews EA, Avorn J, Bortnichak EA, Chen R, Dai WS, Dieck GS, et al (1996).
Guidelines for Good Epidemiology Practices for drug, device, and vaccine research in
the United States. Pharmacoepidemiol Drug Saf; 5:333-8.
3. Austin PCand Stuart E (2015) . Moving towards best practice when using inve rse
probability of treatment weighting (I PTW) using the propensity score to estimate causal
treatment effects in observational studies. Stat Med; 34:3661-79.
4. Avalos LA, Galindo C, Li D -K(2012). A systematic review to calculate background
miscarriage rates using life table anal ysis. Birth Defects Res A Clin Mol Teratol
94:417 –23.
5. Brookhart MA, Schneeweiss S, Rothman KJ, Gly nn RJ, Avorn J, and Sturmer T (2006).
Variable selection for propensity score models. Am J Epidemiol;163:1149 -56.
6. CDC (2000) . National Center for Health Statistics I ndividual Growth Charts.
https://www.cdc.gov/growthcharts/charts.htm. Accessed November 23, 2021.
7. CDC (2017) . Metropolitan Atlanta Congenital Defects Program (MACDP) .
https://www.cdc.gov/ncbddd/birthdefects/macdp.html. Accessed November 23, 2021.
8. CDC (2021a) . V-Safe COVID -19 Vaccine Pregnancy Registry . Available at:
https://www.cdc.gov/coronavirus/2019 -
ncov/vaccines/safet y/vsafepregnancy registry .html . Accessed October 30, 2021.
9. CDC (2021b). What is Stillbirth? Available at:
https://www.cdc.gov/ncbddd/stillbirth/facts.html . Accessed November 18, 2021.
10. CDC (2021c). Premature Birth. Available at:
https://www.cdc.gov/reproductivehealth/features/premature -birth/index.html . Accessed
November 18, 2021.
11. Chambers CD, Johnson DL , Xu R, L uo YJ, L ouik C, Mitchell AA, et al. (2016). Safet y
of the 2010-11, 2011- 12, 2012 -13, and 2013- 14 seasonal influenza vaccines in
pregnancy : Birth defects, spontaneous abortion, preterm delivery , and small for
gestational age infants, a study from the cohort arm of VAMPSS. Vaccine;34:4443-9.
12. Chambers CD, Braddock SR, Briggs GG, Einarson A, Johnson YR, Miller RK, et al.
(2001). Postmarketing surveillance for human teratogenicit y: a model approach.
Teratology ;64:252 -61.
090177e19a3ab0c5\Approved\Approved On: 17-May-2022 21:36 (GMT)
FDA-CBER-2022-5812-0236230
Pfizer -BioNTech COVID -19 Vaccine
C4591022 NON -INTERVENTIONAL STUDY PROTOCOL
Version 4.0, 09 May 2022
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 3 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
20-May-2021
Page 47of 5013. FDA (2019). Draft Postapproval Pregnancy Safety Studies; Guidance for Industry .
Mary land, May 2019.
14. FDA (2021a) . Pfizer COVID -19 Vaccine EUA Letter of Authorization reissued 02 -25-
21. Available at: https://www.fda.gov/media/144412/downlo ad. Accessed March 3,
2021.
15. FDA (2021b). Comirnaty Approval Letter –August 23, 2021. Available at:
https://www.fda.gov/media/151710/download. Accessed October 30, 2021.
16. FDA (2021c) .Vaccine information fact sheet for recipients and caregivers about
Comirnaty (COVID -19 vaccine, mRNA) and the Pfizer -BioNTech COVID- 19 vaccine
to prevent coronavirus disease 2019 (COVID- 19) for use in individuals 12 y ears of age
and older. Available at: https://www.fda.gov/media/153716/download . Accessed
November 14, 2021.
17. FDA (2021d) .Vaccine information fact sheet for recipients and caregivers about the
Pfizer -BioNTech COVID-19 vaccine to prevent coronavirus disease 2019 (COVID- 19)
for use in individuals 5 to 11 y ears of age. Available at:
https://www.fda.gov/media/1537 17/download. Accessed November 14, 2021.
18. FDA (2021e ). Comirnat y and Pfizer -BioNTech COVID- 19 Vaccine. Available at:
https://www.fda.gov/emergency -preparedness- and-response/coronavirus- disease -2019-
covid- 19/comirnat y-and-pfizer -biontech -covid-19- vaccine . Accessed October 30, 2021.
19. Ferré C, Callaghan W, Olson C, Sharma A, and Barfield W (2016). Effects of maternal
age and age -specific preterm birth rates on overall preterm birth rates —United States,
2007 and 2014. MMWR Morb Mortal Wkly Rep;65:1181–4.
20. Greenl and S, Robins JM, and Pearl JS (1999). Confounding and collapsibility in causal
inference Stat. SCI ;14:29 -46.
21. Henshaw SK (1998). Unintended pregnancy in the United States. Fam Plann Perspect;
30:24 -9, 46.
22. Hernán MA and Robins JM (2019). Casual Inference, B oca Raton, FL, Chapman &
Hall/CRC.
23. Hollingshead, A (1975). Four factor index of social status. Unpublished Working Paper.
Department of Sociology, Yale Universit y, New Haven, CT. Available at:
https://sociology .yale.edu/sites/default/files/files/y js_fall_2011.pdf#page=21 . Accessed
October 30, 2021.
24. Honein MA, Paulozzi L J, Cragan JD, and Correa A (1999). Evaluation of selected
characteristics of pregnancy drug registries. Teratology ;60:356 -64.
090177e19a3ab0c5\Approved\Approved On: 17-May-2022 21:36 (GMT)
FDA-CBER-2022-5812-0236231
Pfizer -BioNTech COVID -19 Vaccine
C4591022 NON -INTERVENTIONAL STUDY PROTOCOL
Version 4.0, 09 May 2022
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 3 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
20-May-2021
Page 48of 5025. International Societ y for Pharmacoepidemiology (2016) Guidelines for good
pharmacoepidemiology practice (GPP). Pharmacoepidemiol Drug Saf;25:2-10.
26. Johnson KA, Weber PA, Jones KL , Chambers CD (2001). Selection bias in Teratology
Information Service pregnancy outcome studies. Teratology ;64:79 -82.
27. Jones KL , Jones MC, and del Campo M (2021). Smith’s Recognizable Patterns of
Malformation, 8th Edition. Elsevier.
28. Leen -Mitchell M, Martinez L , Gallegos S, Robertson J, Carey JC (2000). Mini -review:
history of organized teratology information services in North America.
Teratology ;61:314 -7.
29. MMWR Morb Mortal Wkly Rep (2008). Update on overall prevalence of major birth
defects --Atlanta, Georgia, 1978 -2005;57:1 -5.
30. MMWR Morb Mortal Wkly Rep (2020). Birth and infant outcomes following
laboratory -confirmed SARS -CoV -2 infection in pregnancy —SET-NET, 16
Jurisdictions, March 29–October 14; 69:1635 -40.
31. MMWR Morb Mortal Wkly Rep (2021). COVID -19 vaccination coverage among
pregnant women durin g pregnancy —eight integrated health care organizations, United
States, December 14, 2020–May 8, 2021; June 18, 2021 / 70(24);895 –899.
32. National Institutes of Health (2002). Standards for Privacy of Individuall y Identifiable
Health Information (45 CFR Part s 160 and 164) (Online) Available at:
https://www.hhs.gov/sites/default/files/introduction.pdf . Accessed March, 2020.
33. Nellhaus G (1968). Head circumference from birth to eighteen years. Pediatrics;41:106 -
14.
34. Olsen IE, Groveman SA, L awson ML, Clark RH, and Zemel BS (2010) New
intrauterine growth curves based on United States data. Pediatrics; 125 (2):e214 -e224.
35. Prager S, Micks E, Dalton VK (2021) Pregnancy loss (miscarriage): terminology , risk
factors and etiology . Available at: https://www.uptodate.com/ contents/pregnancy -loss-
miscarriage -clinical -presentations- diagnosis -and-initial -evaluationPregnancy loss
(miscarriage): Terminology , risk factors, and etiology . Accessed November 18, 2021.
36. Rosenbaum PR (2002). Observational Studies (Second Edition), New York , Springer -
Verlag.
37. Schlaudecker EP, Munoz FM, Bardaji A, Boghossian NS, Khalil A, Mousa H, Nesin M,
Nisar MI, Pool V, Spiegel HML , Tapie MD, Kochhar S, Black S and the Brighton
Collaboration Small for Gestational Age Working Group (2017). Small for gestati onal
090177e19a3ab0c5\Approved\Approved On: 17-May-2022 21:36 (GMT)
FDA-CBER-2022-5812-0236232
Pfizer -BioNTech COVID -19 Vaccine
C4591022 NON -INTERVENTIONAL STUDY PROTOCOL
Version 4.0, 09 May 2022
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 3 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
20-May-2021
Page 49of 50age: case definition & guidelines for data collection, anal ysis, and presentation of
maternal immunization safet y data. Vaccine;3:6518 -6528.
38. The Center for Sy stems Science and Engineering at Johns Hopkins University .
Coronavirus COVID -19 Global Cases. 2021. Available at:
https://gisanddata.maps.arcgis.com/apps/opsdashboard/index.html#/bda7594740fd40299
423467b48e9ecf6 . Accessed 17 May 2021.
39. Vansteelandt S and Daniel RM (2014). On regression adjustment for the propensity
score. Stat Med; 33:4053-72.
40. World Medical Association (2013). World Medical Association Declaration of Helsinki
Ethical Principles for Medical Research Involving Human Subjects.
JAMA ;310(20):2191-2194.
41. Xu R, L uo Y, Chambers CD (2012). Assessing the effect of vaccine on spontaneous
abort ion using time -dependent covariates Cox models. Pharmacopeidemiol Drug
Saf;21:844-850.
42. Xu R, Hou J, Chambers CD (2018) .The impact of confounder selection in propensity
scores when applied to prospective cohort studies in pregnancy . Reprod Toxicol;78:75 -
80.
090177e19a3ab0c5\Approved\Approved On: 17-May-2022 21:36 (GMT)
FDA-CBER-2022-5812-0236233
Pfizer -BioNTech COVID -19 Vaccine
C4591022 NON -INTERVENTIONAL STUDY PROTOCOL
Version 4.0, 09 May 2022
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 3 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
20-May-2021
Page 50of 5014.LIST OF TABLES
Table 1. Exposure, Comparator, Exclusion, and Outcome Variables .................... 21
Table 2. Demographic and Clinical Variables ................................ ........................ 24
Table 3. Timing of Cohort Enrollment, I nterviews, Examinations, and
Medical Records ................................ ................................ ....................... 27
Table 4. Sample Size and P ower for a Specified Effect Size ................................ .32
Table 5. Denominators for Outcomes by Exposure/Comparator Cohort ............... 35
15.LIST OF FIGURES
Not applicable
ANNEX 1. LIST OF STAND ALONE DOCUMENTS
None
ANNEX 2. ADDITIONAL INFORMATION
Not applicable
090177e19a3ab0c5\Approved\Approved On: 17-May-2022 21:36 (GMT)
FDA-CBER-2022-5812-0236234
Document Approval Record
Document Name:
Document Title:
Signed By: Date(GMT) Signing Capacity
!"#$!% &'"('
) ) & " "*!%++% ,"-
!.!% "%/ ."%"%" &'"('
)0) 12
++% ,"-
090177e19a3ab0c5\Approved\Approved On: 17-May-2022 21:36 (GMT)
FDA-CBER-2022-5812-0236235