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Pfizer -BioNTech COVID -19 Vaccine
C4591008 NON- INTERVENTIONAL STUDY PROTOCOL
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PFIZER CONFIDENTIAL
Page 1of 43NON- INTERVENTIONAL (NI) STUDY PROTOCOL
Study Information
Title HERO- Together :A post-Emergency Use
Authorization observational c ohort s tudy to
evaluate the safet y of the Pfizer -BioNTech
COVID -19 v accine in US h ealthcare
workers , their families, and their
communities
Protocol number C4591008
Protocol version identifier Version 3.0
Date April 20, 2021
EU Post Authorization Study (PAS)
register numberEUPAS38671
Active substance N/A
Medicinal product COVID -19 Vaccine
BNT162b2
Research question and objectives The research questions addressed b y this
study are a) what are the incidence rates of
safet y events of interest and other clinicall y
significant events among persons vaccinated
with the Pfizer -BioNTech COVID -19
vaccine in a cohort of US healthcare
workers , their families, and their
communities b) How do those rates compare
to expected rates of those events?
Primary study objectives:
Estimate the real- world incidence of
safet y events of interest and other
clinically significant events among
US healthcare workers , their
families, and their communities who
arevaccinated with the Pfizer -
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Page 2of 43BioNTech COVID -19 vaccine
following Emergency Use
Authorization.
Seconda ry objective s
Evaluate whether the vaccine
recipients experience increased risk
of safet y events of interest and other
clinically significant events
post-vaccination .
Estimate the incidence rates of safet y
events of interest and other clinicall y
significant events among subcohorts
of interest such as individuals who
are pregnant , individuals who are
immunocompromised, and stratified
by age.
Author Emily O’Brien, PhD
Duke Clinical Research Institute
200 Morris Street
Durham, NC 27701
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Page 3of 431.TABLE OF CONTENTS
1. TABLE OF CONTENTS ................................ ................................ ................................ .......3
2. LIST OF ABBREVIAT IONS ................................ ................................ ................................ 5
3. RESPONSIBLE PARTI ES................................ ................................ ................................ ....6
4. ABSTRACT ................................ ................................ ................................ ........................... 7
5. AMENDMENTS AND UP DATES ................................ ................................ ..................... 13
6. MILESTONES ................................ ................................ ................................ ..................... 13
7. RATIONALE AND BAC KGROUND ................................ ................................ ................ 13
8.BRESEARCH QUESTION AN D OBJECTIVES ................................ ................................ .15
9. RESEARCH METHODS ................................ ................................ ................................ ....15
9.1. Study Design ................................ ................................ ................................ ........... 15
9.2. Setting ................................ ................................ ................................ ...................... 16
9.2.1. I nclusion Cri teria ................................ ................................ ........................ 18
9.2.2. Exclusion Criteria ................................ ................................ ....................... 18
9.2.3. Recruitment ................................ ................................ ................................ .18
9.2.4. Enrollment ................................ ................................ ................................ ..20
9.2.5. Retention ................................ ................................ ................................ .....22
9.2.6. Participant Follow -up and Data Collection ................................ ................ 22
9.3. Variables ................................ ................................ ................................ .................. 23
9.3.1. Safet y events of interest ................................ ................................ .............. 24
9.4. Data Sources ................................ ................................ ................................ ............ 26
9.4.1. Participant Self-report................................ ................................ ................. 26
9.4.2. Call Center Data Collection ................................ ................................ ........ 28
9.4.3. Clinical Events Ascertainment (CEA)................................ ........................ 28
9.4.4. Proxy Completion ................................ ................................ ....................... 30
9.5. Study Size ................................ ................................ ................................ ................ 30
9.6. Data Management ................................ ................................ ................................ ...31
9.6.1. Case Report Forms (CRFs)/Data Collection Tools (DCTs)/Electronic
Data Record ................................ ................................ ................................ .....33
9.6.2. Record Retention ................................ ................................ ........................ 34
9.7. Data Anal ysis................................ ................................ ................................ .......... 34
9.8. Quality Control ................................ ................................ ................................ ........ 35
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Page 4of 439.9. L imitations of the Research Methods................................ ................................ ......35
9.10. Other Aspects ................................ ................................ ................................ ........ 36
10. PROTECTI ON OF HU MAN SUBJECTS ................................ ................................ ........ 36
10.1. Participant Information ................................ ................................ ......................... 36
10.2. Participant Consent ................................ ................................ ............................... 36
10.3. Participant Withdrawal ................................ ................................ .......................... 37
10.4. Institutional Review Board (IRB)/Independent Ethics Committee (I EC)............ 37
10.5. Ethical Conduct of the Study ................................ ................................ ................ 38
11. MANAGEMENT AND R EPORTI NG OF ADVERSE EVENTS/ADVERSE
REACTI ONS ................................ ................................ ................................ ...................... 38
12. PL ANS FOR DI SSEM INATING AND COMMUNI CATING STUDY RESUL TS........ 41
13. REFERENCES ................................ ................................ ................................ .................. 42
14. LIST OF TABLES ................................ ................................ ................................ ............. 43
15. LIST OF FIGURES ................................ ................................ ................................ ........... 43
ANNEX 1. LIST OF STAND ALONE DOCUMENTS .........................................................43
ANNEX 2. ADDITIONAL INFORMATION ................................ ................................ ......... 43
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Page 5of 432. LIST OF ABBREVIATIONS
Abbreviation Definition
AE Adverse Event
AEM Adverse Event Monitoring
AESI Adverse Event of Special Interest
COVID -19 Coronavirus Disease 2019
CRF Case Report Form
DCRI Duke Clinical Research Institute
EUA Emergency Use Authorization
FDA Food and Drug Administration
GPP Guidelines for Good Pharmacoepidemiology Practices
HCW Healthcare Worker
HERO Healthcare Worker Exposure Response and Outcomes
ICF Informed Consent Form
IRB Institutional Review Board
MAAE Medically Attended Adverse Event
NI Non-Interventional
NIS Non-Interventional Study
NISL Non-Interventional Study Lead
PASS Post-Authorization Safety Study
PCORI Patient- Centered Outcomes Research Institute
RCT Randomized Clinical Trial
RMP Risk Management Plan
RNA Ribonucleic Acid
SAE Serious Adverse Event
SAP Statistical Analy sis Plan
WHO World Health Organization
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Page 6of 433.RESPONSIBLE PARTIES
Principal Investigator(s) of the Protocol
Name, degree(s) Job Title Affiliation Address
Emily O’Brien, PhD Epidemiologist Duke Clinical Research
Institute200 Morris Street
Durham, NC 27701
Adrian Hernandez,
MD, MHSExecutive Director Duke Clinical Research
Institute200 Morris Street
Durham, NC 27701
Heather Rubino,
PhD, MSGlobal M edical
Epidemiology ,
DirectorPfizer Inc. 235 E 42ndSt,
New York, NY 10017
Ann Madsen, PhD Global M edical
Epidemiology , Sr.
DirectorPfizer Inc. 235 E 42ndSt,
New York, NY 10017
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Page 7of 434.ABSTRACT
Title: A post-Emergency Use Authorization observational c ohort s tudy to evaluate the safet y
of the Pfizer -BioNTech COVID-19 v accine in US h ealthcare workers , their families, and
their communities
Rationale and background: Pfizer -BioNTech COVID -19 vaccine was approved for
emergency use authorization (EUA) to prevent Coronavirus Disease 2019 (COVID- 19) for
individuals 16 y ears of age and older. Detailed distribution plans for the COVID- 19 vaccine
within the US are determined by local jurisd ictions based on federal recommendations to
prioritize vaccination of healthcare workers and people living in long term care facilities
under an EUA. This study is designed to provide earl y real -world safet y information on a
cohort of vaccinated healthcare workers , their families, and their communities for two years
after vaccination. This non- interventional study is designated as a PASS and is included in
the US pharmacovigilance plan .
Research question and objectives: The research questions addressed by this study are a)
what are the incidence rates of adverse safet y events of interest and other clinically
significant events among persons vaccinated with the Pfizer -BioNTech COVID -19 vaccine
in a cohort of US healthcare workers, their families, and their co mmunities and b) how do
those rates compare to expected rates of those events?
Primary study objectives:
Estimate the real- world incidence of safety events of interest and other clinically
significant events among US healthcare workers , their families, and their
communities who are vaccinated with the Pfizer- BioNTech COVID -19 vaccine
following Emergency Use Authorization.
Secondary objective s
Evaluate whether vaccine recipients experience increased risk of safet y events of
interest and other clinically significant events post -vaccination.
Estimate the incidence rates of safet y events of interest and other clinicall y significant events
among subcohorts of interest such as individuals who are pregnant, individuals who are
immunocompromised, and stratified by age.
Study design: This is a prospective observational cohort study of US healthcare workers ,
their families, and their communities , in which data are collected from participant self-report
at reg ular intervals following vaccination , primarily using a secure web portal, as well as
medical records for confirming the occurrence of safet y events. The stud y period will be 30
months.
Population: The initial inclusion criteria for this study focused on healthcare workers as a
population from whom many vaccin ated persons could be recruited due to national
recommendations for vaccine eligibility given the need to prioritize limited quantities of the
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Page 8of 43vaccine under the EUA. In April 2021, as vaccine supply has grown sufficient to make
vaccine more widel y availab le outside of limited occupational and age groups , the HERO -
Together stud y was expanded to include healthcare worker families and community members
(defined as the group of people that live, work, or interact with healthcare workers in their
households or anyone in the community) to support sufficient sample size for precise
estimation of event rates. I n the context of this expanded population, s tudy participants will
be recruited using a variety of outreach strategies, including digital promotion, referral s from
enrolled participants, and in- person promotion. Eligible participants will be recruited
primarily from three sources:
An existing registry study , the Healthcare Worker Exposure Response and Outcomes
(HERO) Registry , which was launched in April 2020 to characterize COVID-19 risk
factors and outcomes among US healthcare workers, by the Duke Clinical Research
Institute (DCRI) .
The Project Baseline Community Study , an existing communit y of volunteers
interested in contributing to clinical research. This study was launched in April 2019
by Verily Life Sciences and provides an opportunity to acquire, organize, analyze,
and activate phenot ypic data for a group of participants over time.
Major health s ystems distributing Pfizer -BioNTech COVID- 19 vaccine to its
employ ees, their families, and community members as determined b y local
jurisdictional EUA rollout plans. Once receiving systems are identified, study
navigators will be identified for vaccination sites within sy stems and activated to
ensure broad geo graphic diversity in the surveillance study .
In addition to these three strategies, study recruitment will also include outreach through a
variet y of social media channels and promotion from existing members to their families and
community members using technology -enabled sharing capability (see section 9.2.3 for
additional details on recruitment strategies).
To be eligible for enrollment , individuals must meet all of the following criteria:
Participants must be one of the following:
1.A healthcare worker (individual currentl y working in a setting where
individuals receive healthcare in the US including emergency medical
services );
OR
2.Part of a famil yto which health care workers may also belong
OR
3.Anyone in the surrounding communit y
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Page 9of 43Participant s must also be all of the following :
Age ≥18years .
Able to speak and read English or Spanish .
Recei pt of the first dose of a C OVID -19 vaccine for prevention of SARS- CoV -2
infection within the past 60 day s.
Evidence of informed consent indicating that the participant (or a legall y acceptable
representative) has been informed of all pertinent aspects of the study .
Variables: Key variables includ e vaccination exposure characteristics (e.g., number of doses
received, length of interval between doses) and safety events of interest, which are based on
the Priority List of Adverse Events of Special Interest (AESI) from the Brighton
Collaboration’s Saf ety Platform for Emergency vACcines (SPEAC) Project
(https://brightoncollaboration.us/priority -list-aesi-covid /) accessed 12/13/2020 .The safet y
events of interest in this study include:
Neurologic:
Generalized convulsion /seizures
Guilla in-Barre S yndrome
Aseptic meningitis
Encephalitis/encephalomyelitis
Other acute dem yelinating diseases
Transverse m yelitis
Multiple sclerosis
Optic neuritis
Bell’s pals y
Immunologic :
Anaph ylaxis
Vasculitides*
Arthritis /arthralgia
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Page 10of 43Multisy stem inflammatory syndrome (in adults)
Kawasaki disease
Fibrom yalgia
Autoimmune thy roiditis
COVID -19:
Severe COVID -19 disease*
Microangiopath y*
Heart failure and cardiogenic shock*
Stress cardiom yopath y*
Coronary artery disease*
Arry thmia*
Deep vein thrombosis
Pulmonary embolus
Cerebrovascular stroke
Limb ischemia*
Hemorrhagic disease*
Acute kidney injury *
Liver injury
Chillblain -like lesions
Single organ cutaneous vasculitis*
Erythema multiforme*
Cardiac:
Myocarditis
Pericarditis
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Page 11of 43Acute m yocardial infarction
Hematologic:
Thrombocy topenia
Dissem inated intravascular coagulation
Other:
Pregnancy outcomes
Death
Narcoleps y and cataplexy ;
Non-anaph ylactic allergic reactions
*Hospitalized manifestations only
Data sources: Data will be collected via participant self -report and medical record review.
Following enrollment, the participant will enter vaccination and other baseline data into a
secure participant facing web -portal . During follow -up, participants will be prompted to
provide information on hospitalizations and diagnoses of safety events of interest at the
following time points following receipt of the first vaccine dose: 1 week, 2 weeks, 4 weeks, 8
weeks, 12 weeks, and then at 6, 9, 12, 18, and 24 months. Individuals with longer than a 2 -
day interval between vaccination and enrollment will b e administered a retrospective
assessment to capture self -reported safet y information occurring within this interval. The
DCRI Call Center will follow -up on non -responsive participants and request medical records
for participants reporting hospitalization or diagnosis of a safet y event. The DCRI Clinical
Event Ascertainment (CEA) group will adjudicate medical records for event confirmation.
Study size: The study aims to enroll at least 20,000 healthcare workers and members of their
families, or their communities who have received a COVID -19vaccine. As the primary
objective is descriptive, this sample size target is designed to ensure adequate precision for a
plausible range of safet y event rates in the population of vaccinated healthcare wor kers,
family members, and community mem bers.
To address the secondary objective regarding assessment of increased risk, a self -matched
comparative anal ysis will be undertaken for feasible safet y events (e .g., events with a known
risk interval). Statistica l power to detect various effect sizes assuming a range of background
incidence rates in a self- matched comparative analy sis will be described in the statistical
analysis plan.
Data analysis: Vaccination and baseline characteristics will be summarized usin g descriptive
statistics, including measures of central tendency and dispersion (means, medians, standard
deviations) for continuous variables and percentages for categorical variables.
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Page 12of 43The primary anal ysis for each objective will be restricted to partici pants who enrolled within
10days of vaccination to mitigate the risk of selective enrollment and disproportionate
representation of higher risk participants. The number and incidence rate for each safet y
event of interest will be calculated overall, and within subgroups of interest, including
pregnant women, immunocompromised individuals, and within age groups. Rates will also
be stratified by other baseline c haracteristics, such as race/ethnicity , work setting and
geographic region, data permitting.
To evaluate whether vaccinated persons experience increased risk, qualitative and
quantitative comparison approaches will be used . Qualitative comparisons will be made
using hospitalization rates among non -vaccinated participants available from the HERO
Registry and/orexternal sources of background event rates to be defined in the SAP . Aself-
matched comparative analy sis will then be conducted for events that appear to be associated
with vaccination andare amenable to self -matched anal ysis, such as those with an adequate
case count and known risk interval.
Detailed methodology for the statistical anal yses of data collected in this study , including the
analytic methods to be used for self -matched comparative anal yses, will be documented in a
statistical analy sis plan.
Milestones: Data collection start ed17 December 2020, with interim reports to be completed
per the following schedule:
30 June 2021
31 De cember 2021
30 June 2022
31 December 2022
The final study report will be submitted by 31 December 2023.
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Page 13of 435. AMENDMENTS AND UPDATES
Amendment
numberDate Protocol section(s)
changed Summary of
amendment(s)Reason
1 22
January
2021Title page
Abstract
Milestones
Rationale and
BackgroundAdded field for EU PAS
registration number on
title page.
Removed interim report
on 31 March 2021.
Removed designation as
Category 3 post -
authorization safety study
in EU risk management
plan (RMP) and noted
study is included in the
US PVP.EU PAS registration number
was inadvertently left out.
Data from the first quarter of
2021 are limited. US
vaccinations program not
fully deployed until January
Study was not included in
final RMP
2 20
April
2021Title page
Abstract
Research question and
objectives
Research methods
Inclusion criteria
Participant follow -up
Clinical events
ascertainment
Data analysisExpanded population to
include HCW families
and community members
Added Project Baseline
Community Study to
recruitment sources
Updated subgroups
Additional detail about
CEA process and event
confirmation
Additional recruitment
strategies
Removed medical release
requirement for
enrollmentRevisions in response to FDA
protocol review comments
Expanded population
Recruitment pathway through
Project Baseline Community
Study added
Event confirmation step
added
Removal of medical release
requirement from inclusion
criteria only
Editorial changes
6.MILESTONES
Milestone Planned date
Start of data collection 17 December 2020
Registration in the EU PAS register Prior to start of data collection, December
2020
Interim Reports 30 June 2021
31 December 2021
30 June 2022
31 December 2022
End of data collection 30June 2023
Final study report 31 December 202 3
7.RATIONALE AND BACKGR OUND
In December 2019, a viral pneumonia outbreak of unknown origin was identified in Wuhan,
China.1By January 2020 , the outbreak was confirmed to be caused b y a novel coronavirus
named severe acute respiratory syndrome coronavirus 2 (SARS -CoV -2).2The outbreak
quickly reached pandemic levels, spreading to 213 countries and territories worldwide. In
February 2020, the World Health Organization formally named the disease caused by
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Page 14of 43SARS -CoV-2 the coronavirus disease 2019 (COVID -19).3As of October 2, 2020, a total of
34.6 million confirmed cases and over 1 million deaths related to COVI D-19 have been
reported.4Healthcare workers have been disproportionately affected by the pandemic, with
an infection risk 11 times that of the genera l population.5Due to this increased risk, the
National Academies of Science, Engineering, and Medicine has prioritized healthcare
workers for earl y receipt of vaccines to prevent SARS -CoV -2 infection.6
Given the public health emergency caused b y the virus, Pfizer -BioNTech was granted
authorization of emergency use of their COVID -19 vaccine by the Food and Drug
Administration on 11 December 2020, prior to full approval of the biologic license
application (BLA) for the prevention of Coronavirus Disease 2019 (COVID -19) for
individuals 16 y ears of age and older. Detailed distribution plans for the COVID- 19 vaccine
within the US are determined by local jurisdictions based on federal recommendations to
prioritize vaccination of healthcare workers and people living in long term ca re facilities
under an EUA . The init ial inclusion criteria for HERO -Together focused on healthcare
workers as a population from whom many vaccinated persons could be recruited due to
national recommendations for vaccine eligibility given the need to prioritize limited
quantities of the vaccine under the EUA. In April 2021, as vaccine supply has grown
sufficient to make vaccine more widely available outside of limited occupational and age
groups, the HERO -Together study population was expanded from only HCW s to include
members of HCW families and communities, in order to provide a comprehensive
assessment of post -vaccine outcomes in a diverse population. This study is designed to
provide early real-world safet y information on a cohort of vaccinated healthcar eworkers ,
their families, and their communities for two y ears after vaccination.
This non- interventional study is designated as a PASS and is included in the US
pharmacovigilance plan.
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Page 15of 438.RESEARCH QUESTION AN D OBJECTIVES
The research questions addressed b y this study are a) what are the incidence rates of safet y
events of interest and other clinicall y significant events among persons vaccinated with the
Pfizer -BioNTech COVID -19 vaccine in a cohort of US healthcare workers
,their families,
and their communities ;and b) how do those rates compare to expected rates of those events?
Primary study objective:
Estimate the real- world incidence of safety events of interest and other clinically
significant events among US healthcare workers , their families, and their
communities vaccinated with the Pfizer-BioNTech COVID- 19 vaccine following
Emergency Use Authorization.
Secondary objective s
Evaluate whether vaccine recipients experience increased risk of safet y events of
interest and other clinically significant events post -vaccination.
Estimate the incidence rates of safet y events of interest and other clinicall y significant
events among subcohorts of interest such as individuals who are pregnant, individuals
who are immunocompromised , and stratified b y age.
9. RESEARCH METHODS
9.1.Study Design
This study isaprospective observational stud y designed to evaluate the incidence rates of
safet y events of interest and other clinicall y significant events within a cohort ofhealthcare
workers , their families, and their communities who receive the Pfizer -BioNTech COVID -19
vaccine under the EUA program inthe Unite d States. The stud y is a primary data collection
study with review of medical records. Receipt of the vaccine is required for inclusion in the
study , but the decision to be vaccinated is made a t the discretion of the recipient.
This study will aim to enroll and follow 20,000 vaccinated healthcare workers , their families,
and their communities during a 30-month study period. Information on hospitalization and
diagnosis of safet y events of interest will be collected from participant self- report at regular
intervals following vaccination, primarily using a secure web portal. Participant reports of
safet y events of interest and/or hospitalization trigger a request for and review of participant
medical record information for confirmation and adjudication of the event (s ee Figure 2 for
additional details). To address the primary objective, incidence rates of safety events will be
estimated based on cases confirmed b y adjudication. To a ddress the secondary objective
regarding assessment of increased risk, a self- matched comparative an alysis will be
undertaken for feasible safet y events (e .g., events with a known risk interval and sufficient
case counts ). Additional context for the rates observed in vaccinated individuals will be
sought from population background rates and /orunvaccinated person years in the HERO
Registry .
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Page 16of 439.2. Setting
Participants will be recruited from three primary sources. The first is the Healthcare Worker
Exposure Response and Outcomes (HERO) Registry Study , launched in April 2020 to
characterize COVID -19 risk factors and outcomes among healthcare workers (HCWs) in the
United States by the Duke Clinical Research Institute (DCRI). The initial inclusion criteria
for the HERO Registry focused on healthcare workers as a population of high research
interest both due to their elevated infection risk and high priorit y for vaccine distribution
vaccine under the EUA. In April 2021, due to Registry members consistently identify ing the
family unit as an important focus area for research and as vaccine suppl y has grown
sufficient to make vaccine more widely available outside of limited occupational and age
groups, the HERO Registry was expanded to include HCW families and community
members (defined as the group of people that live, work, or interact with healthcare worke rs
in their households, or anyone in the community ). The overall goal of the HERO Registry is
to create and engage a community of healthcare workers, their families, and their
communities, who may be eligible for participation in future research studies, including
studies of COVID -19 prophy laxis and treatment. Participants complete periodic
questionnaire s that capture data on demographics, medical history , employment
characteristics, COVID testing/diagnosis, quality of life, and personal protective equipment
(PPE)availability via an online portal. The registry currentl ycomprises approximately
25,000 participants in all 50 states andis recruiting new participants for inclusion on an
ongoin g basis . Due to the broad population definition and limited inclusion/exclusion
criteria, the registry supports enrollment of a diverse population and greater generalizability
of results.
Table 1provides a current description of registry members, demonstrating the diversity of
participants who self -enrolled into the registry . The current demographic composition (as of
December 2020) of the Registry is shown in Table 2.
Table 1.HERO Registry Participants (Preliminary Data) as of December 2020
HERO Registry Participants
(n=15,629)Frequency Percent Cumulative
FrequencyCumulative
Percent
Physician 3265 20.89 3265 20.89
Nurse (RN/LPN) 5202 33.28 8467 54.17
Param edic/Emergency Medical
Technician463 2.96 8930 57.14
Other (free text) 2442 15.62 11372 72.76
Physician's assistant/Nurse
practitioner (PA/NP)1226 7.84 12598 80.61
Other Health Diagnosing and
Treating Practitioners1321 8.45 13919 89.06
Health technologists,
technicians, and clinical
support staff 343 2.19 14262 91.25
Healthcare support,
administrative, and research
staff 1367 8.75 15629 100.00
Frequency Missing = 220
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Page 17of 43Table 2. Demographic Composition of the Registry (Preliminary Data) as of
December 2020
Gender
Male Fem ale OtheraTotal
Race White 2,973
(18.56%)10,507
(65.59%)41
(0.26%)13,521
(84.41%)
Black or African American 123
(0.77%)487
(3.04%)2
(0.01%)612
(3.82%)
American Indian or Alaska Native 7
(0.04%)33
(0.21%)1
(0.01%)41
(0.26%)
Asian 364
(2.27%)588
(3.67%)2
(0.01%)954
(5.96%)
Native Hawaiian or Other Pacific Islander 4
(0.02%)16
(0.10%)0
(0.00%)20
(0.12%)
Other 81
(0.51%)180
(1.12%)0
(0.00%)261
(1.63%)
Multi -race 72
(0.45%)237
(1.48%)2
(0.01%)311
(1.94%)
Not Available (Prefer not to answer) 94
(0.59%)184
(1.15%)21
(0.13%)299
(1.87%)
Ethnicity Yes, Hispanic (Latino/Latina) 303
(1.89%)961
(6.00%)4
(0.02%)1,268
(7.92%)
No, not of Hispanic, Latino, or Spanish origin 3,347
(20.89%)11,137
(69.52%)46
(0.29%)14,530
(90.70%)
Not Available (Prefer not to answer) 68
(0.42%)134
(0.84%)19
(0.12%)221
(1.38%)
Total 3,718
(23.21%)12,232
(76.36%)69
(0.43%)16,019
(100.00%)
a.Gender = Other include MTF, FTM, gender expansive/variant, gender not listed, and prefer not to answer
Existing HERO Registry members will be sent notifications of the opportunity for healthcare
workers, their families, and community members to participate in a stud y of long -term
outcomes after vaccination as part of the HERO program infrastructure.
The second source will be from the Project Baseline Community Study platform operated b y
Verily. This study was launched in April 2019 by Verily Life Sciences and provides an
opportunity to acquire, organize, anal yze, and activate phenot ypic data for a group of
participants over time.
The third source will be major health s ystems distributing Pfizer -BioNTech COVID -19
vaccine to its employ ees, their families, and community members as determined by local
jurisdictional EUA rollout plans. Healthcare s ystems will be prioritized for involvement
based onthe ordered number of Pfizer COVID -19 vaccine doses, feasibility of recruitment
and geographic diversit y. Once receiving s ystems are identified, study navigators will be
identified for assignment to vaccination sites within these sy stems to facilitate enrollment of
vaccine recipients.
In this stud y,there will not be treating -healthcare providers as investigators overseeing the
recruitment , enrollment, and data collection for study participants .Rather, individuals will
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Page 18of 43self-enroll via a secure participant -facing web portal, either at the vaccination site or
remotely . The web portal is developed and supported by a technology company called
Verily .
9.2.1. Inclusion Criteria
Participant s must be one of the following:
1. A healthcare worker (individual currentl y working in a setting where individuals
receive healthcare in the US including emergency medical services);
OR
2. Part of a famil yto which healthcare workers may also belong
OR
3. Anyone in the surrounding community
Participant s must also be all of the following :
Age ≥18years .
Able to speak and read English or Spanish .
Recei pt of the first dose of a C OVID -19 vaccine for prevention of SARS- CoV -2
infection within the past 60 day s.
Evidence of informed consent indicating that the participant (or a legall y acceptable
representative) has been informed of all pertinent aspects of the study .
9.2.2. Exclusion Criteria
There are no exclusion criteria for this study . All participants meet inginclusion criteria will
be eligible for anal ysis.
9.2.3. Recruitmen t
All methods for recruitment and retention will be detailed in a separate recruitment and
retention plan. Recognizing the limitations of an entirely participant -driven study , there are
several safeguards in place to ensure thatrecruitment goals are met , while minimizing
missing and inaccurate data ,and loss to follow -up.
A potential participant may learn about the opportunity to receive the vaccine through a
variet y of mechanisms that may include their employ eror by email sent to existing HERO
Registry or Project Baseline Community Study members. Recruitment materials may also be
present in the vaccine administration area.
In addition to registry and health sy stem -based recruitment, promotion efforts will leverage
public communication, social media and othe r advertising, and printed enrollment materials
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Page 19of 43with information about the study at vaccination sites. These efforts will include 5 primary
strategies: 1) Digital promotion through online advertising; 2) Partnerships with local health
organizations (for ex ample, NC Department of Health and Human Services) and professional
societies (for example, the American Society for Clinical Oncology and the American
Association for Respiratory Care ) for dissemination of information 3) Grand
rounds/educational presentations to institutional audiences provided by HERO -Together
investigators; 4) Social media influencer partnerships; and 5) Participant -driven outreach
including tag-a- friend campaigns and “Why I joined” videos on the study website. E ach of
these str ategies are anticipated to broaden our reach bey ond major health s ystems and
facilitate connection with healthcare workers , and members of their families and
communities who may have had later access to vaccines . Additionally , given that theprimary
analysis will include recipients of the Pfizer -BioNTech vaccine, digital promotion efforts will
target the geographic regions represented in current Pfizer -BioNTe ch vaccine distribution
plans. P articipant enrollment through these channels will actively be tracke d and recruitment
plans will be revised to reflect the highest -yield strategies.
All recruitment materials will focus on enrollment into a research stud y on vaccine safet y and
will avoid language promoting the Pfizer -BioNTech COVID -19 vaccine itself. E xisting
HERO Registry and Project Baseline Community Study members will receive instructions as
to how they can express interest in joining the study and enroll. If a HER O Registry or
Project Baseline Community Study member expresses interest but, after a notable period of
time, has y et to enroll in the study , additional follow -up will be conducted to remind them of
the opportunity and help them navigate the enrollment process .
In addition to registry and health sy stem -based recruitment, promotion efforts will leverage
public communication, social media and other advertising, and printed enrollment materials
with information about the study at vaccination sites. These efforts will include 5 primary
strategies: 1) Digital promotion through online advertising; 2) Partnerships with local health
organizations (for example, NC Department of Health and Human Services) and professional
societies (for example, the American Society for Clinical Oncology and the American
Association for Respiratory Care ) for dissemina tion of information 3) Grand
rounds/educational presentations to institutional audiences provided b y HERO -Together
investigators; 4) Social media influencer partnerships; and 5) Participant -driven outreach
including tag-a- friend campaigns and “Why I joined ” videos on the stud y website. E ach of
these strategies are anticipated to broaden our reach bey ond major health s ystems and
facilitate connection with healthcare workers , and members of their families and
communities who may have had later access to vaccines . Additionally , given that theprimary
analysis will include recipients of the Pfizer -BioNTech vaccine, digital promotion efforts will
target the geographic regions represented in current Pfizer -BioNTe ch vaccine distribution
plans. Participant enrollment through these channels will actively be tracked and recruitment
plans will be revised to reflect the highest -yield strategies.
Diversity -Focused Recruitment
Adiverse study population is critical to ensuring results from this study are generalizable.
The study team is currently implementing 3 strategies focused on enhancing diversit y in
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Page 20of 43HERO-Together specificall y. These include 1) an extended recruitment plan with broad
strategies to reach healthcare workers , their families and their c ommunities who may not be
connected to major healthcare s ystems, including those who work in long -term care facilities;
2) culturall y sensitive electronic and printed recruitment materials to ensure that imagery
reflects a diverse population with respect to race/ethnicity and professional role; and 3)
customized recruitment materials for specific professional roles (for example, long-term care
facility staff, dental health providers , and first responders ).Thedemographic and
professional role distribution of enrolled participants will be continually monitored and
diversity -focused recruitment strategies will be refined a ccordingl y.
Recruitment of HCW s, and their families and communities not participating in the HERO
Registry will occur via public communication, social media and other advertising, and
printed enrollment materials with information about the study at vaccination sites.
9.2.4. Enrollment
Participants may enroll at the vaccination s ite or may self-enroll remotel y.At select
vaccination sites, study navigators will be available to assist with recruitment and enrollment
after individuals are vaccinated. Virtual study navigators may also assist with enrollment via
phone and/or text. Study navigators may assist with entry of vaccine -related information
(date, manufacturer, lot #) in the online platform to ensure accuracy . Based on conversations
with many institutions affiliated with the HERO Registry , optimal navigator workflow will
be determined depending on institutional plans for vaccinat ion. For example, at some
institutions, the navigator willinteract with the potential participant shortl y before receiving
the vaccine (e .g., at the time of registration, or at check -in to the vaccine administration area),
while others may interact with potential participants in the recovery area where recipients
will spend time after the vaccine.
Existing members of the HERO Registry and the Project Baseline Community Study will be
instructed to complete a screening questionnaire andan informed consent form (I CF),at
which point they will be enrolled in the study . Non -members will be enrolled in the HERO
Registry or in the Project Baseline Community Study Community and then directed to
complete the screening questionnaire andinforme d consent form. In addition, p roxy contact
information will be collected at enrollment to support data capture in the event that the
participant cannot be reached (e .g., participant is hospitalized).
Enrollment metrics will be monitored throughout the enro llment period and will be specified
in the recruitment plan. Potential metrics of interest include time since vaccination and
proportion of total participants receiving each available vaccine, to ensure a sufficient
number of Pfizer -BioNTech vaccine recipients for inclusion in the primary anal ysis.
Additional metrics may be included in the recruitment plan.
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Page 21of 43Figure 1.Overall Study Design
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Page 22of 43Deviations from enrollment projections will be identified rapidl y; efforts to increase
awareness of the stud y will be undertaken accordingl y.
9.2.5. Retention
One strategy for retaining participants in the study relies on engagement through the HERO
Registry within which thisCOVID -19 vaccine study will be conducted. As part of the
HERO R egistry , participant engagement is sought by a series of community building
activities and modules that are informed b y the participant’s “voice .” HERO Registry
members have demonstrated high responsiveness. Approximately 78% of HERO Registry
members filled out an additional survey after enrollment, and nearl y 60% returned to
complete two or more survey s. As described below, “rescue” strategies to prompt survey
completion have resulted in sub stantially improved completion.
Additionally , there is an automated sy stem built into the Verily platform that notifies the
DCRI Call C enter when a participant has not completed a survey . The DCRI Call Center,
with their staff ofbilingual interviewers (Spanish and English), operates 7 day s a week,
offers toll -free lines for participant use, and includes time zone accommodations.
Interviewers undergo extensive orientation, ethics training, and are taught standardized
interviewing techniques. The DCRI Call Center provides follow -up support to participants
who do not complete their digital survey s -this process is known as “rescue” . In addition, the
Call Center is available to answer questions about the study prior to and during enrollment.
The role of the D CRI Call Center will be to rescue survey s that are not completed, or are
missing key components ,by contacting participants, using contact information provided by
the participant at baseline. Participants are offered preferred times to call and a toll -free line
to use at their convenience.
In the HERO -Hydroxy chloroquine randomized controlled trial , which was conducted within
the HERO R egistry and required participant self-report of data, the Call C enter successfully
rescued 81% of survey s administered at 2, 4, and 8 weeks that were not completed on time.
Other recent projects involving DCRI Call Center services have observed similar lyhigh rates
ofrescue. These include the ARTEMI S trial of coronary arter y disease and anticoagulants,
which enrolled 11,000 participants and achieved an 88% rescue rate for surveys administered
at 3 and 12 months; and PROVI DE-HF, a heart failure trial that enrolled 400 participants and
achieved a 79% rescue rate for those who did not return to the online portal at baseline, 2, 4,
8, and 12 weeks.
9.2.6. Participant F ollow -up and Data Collection
Participants will be followed from date of enrollment until the end of the 24 -month period
following first vaccine dose, end of the study period, death, loss- to-follow up (no response
after a notable interval ofattempted Call Center contacts) , or discontinuation from study .
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Page 23of 43Following enrollment, all participants will enter data into a secure participant facing
web-porta l at 1 week, 2 weeks, 4 weeks, 8 weeks, 12 weeks, and 6 -, 9-, 12- 18 -, and 24-
months following receipt of the first dose of the vaccine . Second dose information will be
solicited during follow up. Participants will be queried regarding their general health and
events re quiring medical attention. Participants who do not complete data entry within a
notable period of time of the expected completion date for a given time point will be
contacted b y theCall Center for confirmation of health status. P articipants who report a
clinically important medical event (e.g., non -routine visit to medical provider or
hospitalization) will be prompted to complete a medical record release form in the online
portal, which will be used to collect medical records for review b y the Clinical Event
Ascertainment group for confirmation of the occurrence of a safet y event of interest .For an y
participant who reports a potential safet y event, medical records during the year prior to
vaccination may also be reviewed to support a self-matched comparative analy sis(See
Section 9.3.1 for additional details).
9.3.Variables
Table 3 lists variables of interest for this study ; detailed operational definitions of all
variables will be provided in the statistical analy sis plan.
Table 3.Study Variables
Variable Role Data Source(s)
Date of 1stdose COVID- 19 vaccination Exposure Participant
Site where 1stdose COVID -19 vaccine was
administeredExposure Participant
COVID -19 vaccine lot number (1stdose) Exposure Participant
Date of 2nddose COVID- 19 vaccination Exposure Participant
Site where 2nddose COVID -19 vaccine was
administeredExposure Participant
COVID -19 vaccine lot number (2nddose) Exposure Participant
Pregnancy Information (pregnancy status
and estimated due date)Outcome (utilization
analyses) and covariate
(safety analyses)Participant
Dem ographics Outcome ( utilization
analyses) and covariate
(safety analyses)Participant
Medical History Outcome ( utilization
analyses) and covariate
(safety analyses)Participant
Employment characteristics of the
participantOutcome (utilization
analyses) and covariate
(safety analyses)Participant
Vaccination details Exposure variable Participant
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Page 24of 43Table 3.Study Variables
Variable Role Data Source(s)
Concomitant medications Outcome (utilization
analyses) and covariate
(safety analyses)Participant
Participant -reported outcomes Outcome Participant
Safety events of interest ( Section 9.3.1 ) Outcome Participant, proxy, or medical
record/insurance claims review
COVID -19 Diagnosis Outcome Participant, proxy, or medical
record/insurance claims review
Hospitalizations Outcome Participant, proxy, or medical
record/insurance claims review
Death Outcome Proxy, or medical
record/insurance claims review
9.3.1. Safety events of interest
The safet y events of interest in this study are based on the Priority List of Adverse Events of
Special Interest from the Brighton Collaboration’s Safety Platform for Emergency vACcines
(SPEAC) Project (https://brightoncollaboration.us/priority -list-aesi-covid/ ) accessed
12/13/2020) and CDC enhanced safet y monitoring recommendations
(https://www.cdc.gov/vaccines/acip/meetings/downloads/slides -2020 -09/COVID -03-
Shimabukuro.pdf ;accessed 12/13/2020) . Safet y event definitions will be specified a priori in
the clinical events ascertainment (CEA) charter as appropriate . The safet y events of interest
in this study include:
Neurologic:
Generalized convulsion/seizures
Guilla in-Barre S yndrome
Aseptic meningi tis
Encephalitis/encephalomyelitis
Other acute dem yelinating diseases
Transverse m yelitis
Multiple sclerosis
Optic neuritis
Bell’s pals y
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Page 25of 43Immunologic :
Anaph ylaxis
Vasculitides*
Arthritis/arthralgia
Multisy stem inflammatory syndrome (in adults)
Kawasaki dise ase
Fibrom yalgia
Autoimmune thy roiditis
COVID -19:
Severe COVID -19 disease*
Microangiopath y*
Heart failure and cardiogenic shock*
Stress cardiom yopath y*
Coronary artery disease*
Arry thmia*
Deep vein thrombosis
Pulmonary embolus
Cerebrovascular stroke
Limb ischemia*
Hemorrhagic disease*
Acute kidney injury *
Liver injury
Chillblain -like lesions
Single organ cutaneous vasculitis*
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Page 26of 43Erythema multiforme*
Cardiac:
Myocarditis
Pericarditis
Acute m yocardial infarction
Hematologic:
Thrombocy topenia
Disseminated intrav ascular coagulation
Other:
Pregnancy outcomes
Death
Narcoleps y and cataplexy ;
Non-anaph ylactic allergic reactions
*Hospitalized manifestations only
9.4.Data Sources
Data will be captured through several mechanisms, described below . All data collected in the
context of this study will bestored and evaluated per applicable regulatory requirements and
guidance for electronic records. Data will be stored and evaluated in a manner that protects
participant confidentiality in accordance with the legal stipulations apply ing to
confidentiality of data.
9.4.1. Participant Self-report
Participants will provide information on COVID -19 vaccination, baseline characteristics,
seeking of non- routine medical care (including hospitalization) and potential occurrence of
safet y events of interest . Following enrollment, the part icipant will enter data into a secure
participant facing web -portal (“Digital Platform”). Data entry will occur according to the
schedule of assessments described inTable 4. Participants who miss assessments during
follow -up, and individuals with a longer than a 2 -day interval between vaccination and
enrollment will be administered a retrospective assessment to capture self- reported safet y
information occurring within this interval. If an assessment is incomplete after a notable
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Page 27of 43period of time , the participant will be contacted b y the Call C enter for completion of missed
assessments.
Table 4.Schedule of Assessments
Enrollment
Data
CollectionFollow -up Data Collection
Baseline After 1stdose
1 week 2 weeks 4 weeks 8 weeks 12 weeks 6, 9, 12,
18, 24
months
E-consent X
Eligibility criteria confirmed X
Vaccine Dose 1 information
Date
Lot number
SiteX
Vaccine Dose 2 information
Date
Lot number
SiteX
(and
subsequent
visits if
second dose
not reported
as received )
Medical record release X** X** X** X** X** X** X**
Demographics
Demographics formX
Medical history
Medical history formX
Employment Information
Employment information formX
Concomitant medications
All current medications
reported at baseline
Changes to medications
reported at follow -up X X*
PROs
Fatigue severity scale
PROMIS Global 10
CDC Impact ScaleX X X X X X X*
COVID -19 Information
Positive COVID -19 test with
date
COVID -19 diagnosis
(presumptive)X X X X X
Health questionnaire
Potential safety events of
interest or clinically significant
events
Pregnancy statusX X X X X X X*
*Follow -up pregnancy, PROs and medication information collected only at 6, 12, 18, and 24month intervals .
** Medical record release collected at the time of reporting a health event of interest.
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Page 28of 439.4.2. C all Center Data Collection
The DCRI Call C enter will serve two main functions in this study :
1. To serve as a “rescue” mechanism to minimize incomplete data from non-response
and loss to follow -up, and
2.To request medical records for c onfirmation of the occurrence of safet y events of
interest .
If a participant does not complete an assessment after a notable period of time , the DCRI Call
Center will be alerted to co ntact the participant using p articipant contact information
transferred from the web portal into the communications sy stem used b y the Call C enter.
This communications system manages call queues, scheduling, and call processing
information. The study data obtained b y the Call Center will be entered directly into the
study portal. For a given survey assessment, i f the participant is not reached after a notable
interval of call attempts, the participant data will be considered missing.
9.4.3. Clinical Events Ascert ainment (CEA)
The Call C enter will request medical records for all participants reporting a hospitalization or
potential safet y event of interest at an y point during follow -up. The following components of
medical records will be sought as appropriate :
Emergency room notes
Discharge summary /death summary
Admission history and p hysical exam
Progress/ clinic/ urgent c are notes
Diagnostic tests
Lab reports
Medication r ecords
Event assessment will proceed through two phases: confirmation and adjudication. As shown
inFigure 2the DCRI Call Center will provide a listing of events reported and status of
source documents obtained to the DCRI CEA Confirmation Team for review and
confirmation of the event. During the confirmation phase, the DCRI CEA Clinical Tria l
Coordinator or CEA Project Leader will review the available source do cuments for discharge
diagnosis/ diagnostic code consistent with the reported even t. During the confirmation stage,
each event will be classified as suspected event (unknown), suspected event (not confirmed),
or probable event (diagnosis code consistent with reported AESI is present in source
document) . DCRI CEA will provide the listing with these categories to the DCRI Statistical
Group for interim reporting anal ysis. Probable events will then proceed to clinical event
adjudication, where e ach event will be classified into one of the following categories:
oNegativel y adjudicated event
oPositively adjudicated event
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Page 29of 43The “probable event” category isdefined for interim reporting purposes and do esnot
constitute a final classification. Table 5 provides the definitions for final event classifications.
Table 5.Defini tions of Final Event Classification Categories
# Category Description
1 Suspected event
(unknown)Participant reports an AESI on the portal, but requests
for medical records are not successful
2 Suspected event (not
confirmed)Medical records are received, but the diagnosis code
list does not indicate an event consistent with the
participant report
3 Negativel y
adjudicated eventMedical records are reviewed b y the CEA Committee,
but the event does not meet the event definition in the
CEA Charter or there is insufficient information
4 Positively adjudicated
eventMedical records are reviewed b y the CEA Committee,
and the event does meet the event definition in the
CEA Charter
Upon completion of the CEA Charter and CEA adjudication platform sy stem, these events
will be adjudicated b y CEA phy sician reviewers trained on the HERO- Together study
protocol and CEA charter.
All events classified as “Probable” during the confirmation process will proceed to CEA
adjudication. Following confirmation, f or each probable event, t he DCRI Clinical Ev ent
Ascertainment (CEA) group will review the medical records andconfirm the occurrence of
an event as part of an adjudication process. Safet y event definitions will be specified a priori
in the clinical events ascertainment (CEA) charter as appropriate . Refer to Figure 2for a
summary of this process.
The CEA group is responsible for ongoing anal ysis of potential safet y events of interest or
other clinicall y significant diagnoses and of their adjudication as study endpoints.
The CEA group includes specialists relevant to the safet y events of interest, including
cardiologist s, immunologists, neurologists, and other specialists. Additional details about
review procedures will be provided in an adjudication charter.
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Page 30of 43Figure 2.Confirmation of Safety Events of Interest During Follow -up
9.4.4. Proxy Completion
At enrollment, participants will provide contact information for a prox y to complete
assessments in the situation where the participant is non -responsive to survey prompts. If a
proxy cannot be reached, the call center will continue to contact the partici pant for a defined
period of time , after which the data for that assessment will be marked as “missing”. Future
assessments will be targeted for completion according to the planned schedule.
9.5.Study Size
This study will aim to enroll at least 2 0,000
HCWs and members of their families and
communities who have received a COVID- 19 vaccine for prevention of COVID- 19. This
study size will help ensure a diverse population of participants with respect to geograph y,
primary work setting, and demographics , and stratification by important subgroups of
professional role, age, and region. It is anticipated that there will be at least
15,000 participants who received the Pfizer -BioNTech COVID- 19 vaccine with complete
assessments throughout the follow -up period .
As the primary objective is descriptive, this sample size target is designed to ensure adequate
precision for a plausible range of AE and SAE rates in the population of vaccinated HCWs
and members of their families and communities .Table 6. display santicipated precision (95%
confidence interval widths )generated using the Clopper -Pearson exact method for a range of
safet yevent rates in a sample of 20,000 participants (overall) and samples of 5,000 and
10,000 participants (potential subgroups and allowing for some exclusions due to attrition).
As shown below, precision is high for observed event rates ranging from 0.1% to 20.0%.
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Page 31of 43Table 6. Estimated Precision of Observed Event Rat es
Observed Rate Exact 95% Confidence
Interval
(n=5,000)Exact 95% Confidence
Interval
(n=10,000)Exact 95% Confidence
Interval
(n=20,000)
0.1% 0.0, 0.23 0.0, 0.18 0.0, 0.15
0.5% 0.32, 0.74 0.37, 0.66 0.41, 0.61
1% 0.74, 1.32 0.81, 1.21 0.87, 1.15
2% 1.63, 2.43 1.73, 2.29 1.81, 2.20
5% 4.41, 5.64 4.58, 5.45 4.70, 5.31
10% 9.18, 10.87 9.42, 10.6 0 9.59, 10.42
20% 18.90, 21.14 19.22, 20.80 19.45, 20.56
The following forecasts for this study are b ased on experience to date with the HERO
registry :a 2% withdrawal rate, a 75% survey completion rate and enrollment of n=200
participants (1%) who would be excluded from primary anal yses due to receipt of non-
Pfizer -BioNTech vaccine. This would result in withdrawal of n=400 people, exclusion of
n=200 par ticipants due to receiving a non -Pfizer -BioNTech vaccine and no or partial
questionnaire data for ~4,900 participants. Therefore, it isanticipate dthat enrollment of
approximately 20,000 participants will result in comprehensive questionnaire data for
approximately 14,500 participants.
To address the second objective re garding assessment of increased risk of safet y events in
vaccinated individuals, informal comparisons will made with hospitalization rates among
non-vaccinated participants available from the HERO Registry . To formally evaluate
whether vaccinated persons experience increased risk, a self-matched comparative analysis
will be conducted for feasible events, such as those with an adequate case count and known
risk interval. Statistical power to detect various effect sizes assuming a range of background
incidence rates in a self- matched comparative analy sis will be described in the statistical
analysis plan.
9.6.Data Management
The DCRI utilizes a “Fit for Purpose” approach to selecting and utilizing information
systems, particularl yas it pertains to EDC, CTMS, anal ysis and reporting.
All solutions utilized by the DCRI are fully vetted by IT personnel, and representatives from
core teamssuch as Clinical Data Management and Safety Surveillance to ensure solutions
support primary business requirements and meet all applicable regulatory requirements (e .g.,
21 CFR Part 11). Externally hosted solutions are audited to ensure compliance with
appropriate securit y and data privacy requirements, and that robust data backup/recovery and
business continuity solutions are in place.
The data management platform for this study is primarily focused on a single web- based
portal that will support all dat a collection and interactions with particip ants and the D CRI
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Page 32of 43Call Center . Related operational sy stems supporting the Call Center activities will be
embedded within each of those organizations and interfaced via a routine set of data transfers
or application interfaces. The figure b elow (Figure 3 ) illustrates thesystems and interactions
required to enable a well- coordinated stud y delivery plan. Stud y participant s accessing the
system directly and the emphasis on self -reported data does require primary identifiers to be
maintained within a limited number of s ystems. These data will be secured such that it is
only maintained in the minimum required sy stems and acce ssible to the minimum number of
people to perform the study procedures described in this protocol. The primary method of
identify ing a participant will be with a unique participant identification number.
Participants will use a study portal developed b y Verily for the informed consent form ,
medical release form and data reporting. The Verily system leverages the Google
infrastructure, including hosting, security , user account management and t he study -specific
data sy stem. Leveraging this infrastructure ensures very high levels of s ystem securit y and
support are embedded in the portal. Although leveraging Google infrastructure this is a stand -
alone portal and no data are shared from other sources with the study , and no study data will
be shared with an y othe r Google s ystems.
The Call Center staff will contact study participants directly , as described in the study
consent form, to obtain follow -up information should a participant not respond directly
within the portal. The participant contact information will be transferred from the portal into
the communications sy stem used by the Call Center for these contacts. This sy stem manages
call queues, scheduling, and call processing information. The study data obtained by the call
center will be entered d irectly into the study portal. The study data is managed using a set of
tools including Oracle (relational database management sy stem), Informatica (data
exchange/extract- transform -load procedures), Cognos (operational reporting), MS SQL,
SAS, and SAS Visual Analy tics (statistics).
Data qualit y is managed at each stage of its lifecycle. Data collected in the portal conforms at
inception to highl y structured data elements and protocol- specific rules, subsequent data
transfers are checked to conform to format and semant ic specifications and all data is
assessed for referential integrit y across sources through a set of reconciliation practices upon
integration then followed by a variety of logical checks within a participant and in aggregate.
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Page 33of 43Figure 3. Data Flow Diagram
NOTE: Pfizer will not receive individual level data only aggregate reports
9.6.1. Case Report Forms (CRFs)/Data C ollection Tools (DCTs)/Electronic Data Record
As used in this protocol, the term eCRF should be understood to refer to either a paper form
or an electronic data record or both, depending on the data collection method used in this
study .
A completed eCRF is required for each included participant . The completed original eCRF
are the sole propert y of Pfizer and should not be made available in an y form to third parties,
except for authorized representatives of Pfizer or appropriate regulatory authorities, without
written permission from Pfizer . Verily shall ensure that the eCRF are securely stored at the
Verily in electronic form and will be password protected to prevent access by unauthorized
third parties.
Verily has ultimate responsibility for the collection and reporting of all data entered on the
eCRF as required and ensuring that they are accurate, authentic/original, attr ibutable,
complete, consistent, legible, timely (contemporaneous), enduring, and available when
required. The eCRF serves as the source document. Any corrections to entries made in the
eCRF must be dated, initialed, and explained (if necessary ) and should not obscure the
original entry .
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Page 34of 439.6.2. Record Retention
To enable evaluations and/or inspections/audits from regulatory authorities or Pfizer, Veril y
agrees to keep all study -related records. The records should be retained b y Verily according
to local regulations or as specified in the Verily contract ,whichever is longer. Verily must
ensure that the records continue to be stored securely for so long as they are retained.
IfVerily becomes unable for any reason to continue to retain s tudy records for the required
period, Pfizer should be prospectivel y notified. The study records must be transferred to a
designee acceptable to Pfizer.
Study records must be kept for a minimum of 15 years after completion or discontinuation of
the study ,unless Verily and Pfizer have expressly agreed to a different period of retention via
a separate written agreement. Record must be retained for longer than 15 y ears if required by
applicable local regulations.
Verily must obtain Pfizer's written permiss ion before disposing of an y records, even if
retention requirements have been met.
9.7.Data Analysis
Vaccin ation and baseline characteristics will be summarized using descriptive statistics,
including measures of central tendency and dispersion (means, medians, standard deviations)
for continuous variables and percentages for categorical variables.
Only those safet y events that were adjudicated as confirmed cases will be included in the
primary analysis. The primary anal ysis for each objective will be restricted to participants
who enrolled within 10days of vaccination to mitigate the risk of selective enrollment and
disproportionate representation of higher risk participants. The number and incidence rate for
each safet y event of interest will be calculated for participants enrolled within 10 day s of
vaccination and for participants enrolled at a ny time relative to vaccination. Event rates will
also be calculated overall, and within subgroups of intere st, including pregnant women,
immunocompromised individuals, dosing number ( received one dose, received both doses
per the Pfizer/BioNT ech recommended schedule, and received both doses not according to
the Pfizer/BioNTech recommended schedule ) and within age groups. Rates will also be
stratified by other baseline characteristics, such as work setting and geographic region, data
permitting . Multiple imputation methods will be used for missing data as appropriate and will
be described in the statistical ana lysis plan.
To evaluate whether vaccinated persons experience increased risk, qualitative and
quantitative comparison approaches will be used . Qualitative comparisons will be made
using hospitalization rates among non -vaccinated participants available fr om the HERO
Registry and/orexternal sources of background event rates to be defined in the SAP . A self -
matched comparative analy sis will then be conducted for events that appear to be associated
with vaccination are amenable to self -matched analysis, such as those with an adequate case
count and known risk interval.
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Page 35of 43Detailed methodology for summary and statistical anal yses of data collected in this study ,
including the anal ytic methods to be used for self -matched comparative analy ses, will be
documented i n a statistical anal ysis plan(SAP) , which will be dated, filed and maintained by
the sponsor. The SAP may modify the plans outlined in the protocol; any major
modifications of primary endpoint definitions or their anal yses would be reflected in a
protocol amendment.
9.8.Quality Control
Data will be transferred from the Veril y platform to the DCRI data manage ment team
nightly . Data will be reviewed for completeness and to identify any needed queries of the
Verily platform or to transfer to the DCRI Call Center for follow -up with the participant .
Data captured b y the DCRI Call Center will be input directly into the Verily platform for
quality control.
Data reconciliation consists of reconciling the primary participant identifiers and all queries
generated b y the EDC s ystem are resolved online. Both automatic and manual queries can be
generated in the EDC s ystem. Auto queries generate immediately upon data submission and
manual queries are generated as a result of data review. Data quality strategies and data
surveillance may also include data status reports and other data status reports as defined by
the needs of the stud y.
9.9.Limitations of the R esearch M ethods
This study is intended to provide comprehensive real -world safet y information about the
Pfizer -BioNTech COVID-19 vaccine in US HCWs , their families, and their communities . A
key strength of this study is the capture of data on vaccination during a pandemic when
vaccines will be administered outside of usual settings of doctor’s offices and pharmacies.
Additional strengths include the utilization of an existing cohort of healthcare workers, the
HERO Registry , and participants in the Project Baseline Community Study who are alread y
engaged in COVID -related research and the minimal burden on participants for safet y data
collection via a web portal.
To help maximize enrollment of vaccinated HCWs , their families, and their communities ,
there is flexibility in participant enrollment location (on -site or remote) and timing (up to 6 0
days following the first vaccination dose). However, f or individuals enrolling several day s or
weeks following vaccination, there is the potential for preferential self -enrollment of
individuals experiencing a safet y event (or earl y symptoms of a safet y event). To help
mitigate this, individuals with a more than a 2 -day interval between vaccination and
enrollment will be administered an assessment to capture self -reported safety information
occurring within this interval, and the primary analy sis will be restricted to individuals
enrolling within 10 day s of f irst vaccination dose .
Because participants enroll voluntarily , the generalizability of study results will depend on
the diversity of the enrolled sample. Sample diversity will be enhanced through several key
design features, including the large study size, the broad definition of healthcare workers,
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Page 36of 43enrollment of family members and community members, and placement of study navigators
in geographicall y diverse vaccination sites. Additionally , the study team will regularl y
review aggregate participant charac teristics for representativeness and will tailor engagement
strategies address an y areas of underrepresentation. The observational nature of this study
also has the potential to introduce bias due to measured and unmeasured confounders. Bias
reduction stra tegies include capture of clinical covariates/ employ ment characteristics , robust
follow -up data ascertainment through a central call center to reduce missing data , and self -
matched comparative analy ses.
9.10. Other A spects
Not appli cable.
10.PROTECTION OF HUMAN SUBJECTS
10.1. Participant Information
All parties will comply with all applicable laws, including laws regarding the implementation
of organizational and technical measures to ensure protection of participant personal data.
Such measures will include omitting participant names or other directl y identifiable data in
any reports, publications, or other disclosures, except where required by applicable laws.
Participant personal data will be stored at Veril yin encry pted electronic form and will be
password protec ted through a multi -authenticated sy stem to ensure that only authorized study
staff have access. Verily will implement appropriate technical and organizational measures to
ensure that the personal data can be recovered in the event of disaster. In the even t of a
potential personal data breach, Veril y shall be responsible for determining whether a personal
data breach has in fact occurred and, if so, providing breach notifications as required b y law.
To protect the rights and freedoms of natural persons with regard to the processing of
personal data, when study data are compiled for transfer to Pfizer and other authorized
parties, an y participant names will be removed and will be replaced by a single, specific,
numerical code .All other identifiable data tran sferred to Pfizer or other authorized parties
will be identified by this single, participant -specific code. Veril ywill maintain a confidential
list of participants who participated in the stud y, linking each participant’s numerical code to
his or her actual identity . In case of data transfer, Pfizer will maintain high standards of
confidentiality and protection of participant s’ personal data consistent with the research
agreement a nd applicable privacy laws.
10.2. Participant Co nsent
At enrollment, participants who are existing members of the Healthcare Worker Exposure
Response and Outcomes (HERO) Registry or the Project Baseline Community Study will be
instructed to log in to their existing profile, complete an informed consent form (I CF) and
enroll. Eligible individuals not y et enrolled in HERO Registry or in the Project Baseline
Community Study but wanting to participate in this vaccine study will be enrolled in either
the HERO Registry or the Project Baseline Community Study and then directed to complete
the study -specific ICF form, and enroll. Electronic consent will be obtained by Veril y’s
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Page 37of 43Baseline Platform, which currentl y supports both the HERO R egistry and the Project
Baseline Community Study .
The Baseline Platform is co mpliant with all applicable regulatory standards, as follows:
a.FDA 21 CFR Part 11: The Baseline Platform supports electronic records and
electronic signatures, maintaining rigorous access controls, audit trail, and identity
verification. Password management. Veril y leverages Google’s password policy
designed to enhance s ystem securit y by encouraging users to employ strong
passwords and use them properl y.
Authentication Verily uses a user ID management s ystem (Gaia) to authenticate
users via Single Sign On (SSO).
Access Management Verily restricts access to the Baseline Platform and its data to
only authorized users or processes, based on the principle of strict
need -to-know and least privilege.
Password
ManagementVerily leverages Google’s pa ssword policy designed to enhance
system security by encouraging users to employ strong passwords
and use them properly .
b.HIPAA: The Baseline platform’s ISO 27001 controls map to the HI PAA Securit y
Rule (for more, please see HIPAA Security Rule Crosswalk toNISTCybersecurit y
Framework ).
10.3. Participant W ithdrawal
Participants will be followed until participant closeout, withdrawal of consent, or death. A
participant may withdraw from the study at an y time at his/her own request, ormay be
withdrawn at an y time at the discretion of the principal investigator for safety, behavioral,
compliance, or administrative reasons. This is expected to be uncommon.
Those who withdraw from thestudy will be asked to continue on study follow -up with
limited participation through stud y closeout. Limited participation may include a call at
12months and 24 months or collection of medical records to ascertain possible safet y events .
If the participant withdraws consent for disclosure of future informat ion, the sponsor may
retain and continue to use an y data collected before such a withdrawal of consent.
10.4. Institutional R eview Board (IRB)/Independen t Ethics Committee (IEC)
It is the responsibility of the DCRI to have prospective approval of the study proto col,
protocol amendments, materials describing the consent process, and other relevant
documents, (e.g., recruitment advertisements), if applicable, from the IRB/IEC. All
correspondence with the IRB/IEC should be retained by the DCRI. Copies of I RB/IEC
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Page 38of 43approvals should be forwarded to Pfizer. All study procedures and materials will be reviewed
and approved by a central I RB ( WCG IRB).
10.5. 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 generall y accepted research practices
described in Guidelines for Good Pharmacoepidemiology Practices (GPP) issued by the
International Societ y for Pharmacoepidemiology , and Good Epidemiological Practice (GE P)
guidelines issued b y the International Epidemiological Association (IEA).
11.MANAGEMENT AND REPOR TING OF ADVERSE EVEN TS/ADVERSE
REACTIONS
To address the safet y surveillance objectives of this study, the management and reporting of
adverse events/adverse reactions are separated into two components. The first component
entails primary data collection, in which Pfizer -BioNTech COVID-19 vaccine recipients in
the HERO R egistry or in the Project Baseline Commu nity Study opt to participate in HERO -
Together and complete a web -based data collection tool. The data collection tool completed
by the HERO -Together participants is designed to provide preliminary information on the
occurrence of a potential safet y event of interest or other clinicall y significant diagnosis.
The second component entails secondary data collection, in which the HERO -Together
participant self -report ed events are examined vi a review of the participant’s medical record.
The DCRI Call Center will request m edical record s for an y participants who reported in the
data collection tool a potential safet y event of interest or other clinically significant
diagnosis. The CEA group will review the medical records as part of the adjudication
process de signed to confirm events for inclusion in the statistical analy ses(Section 9.7).
The requirements to report to Pfizer Safety anyproduct safet y information volunteered b y a
participant during an interaction with the DCRI Call C enter or discovered during medical
record r eview are described in two separate sections below.
Product safety information volunteered by participants
This study does not involve data collection on individual patients by their treating healthcare
professionals. The web-based questionnaires for this study will be completed online via a
secure website, and do not provide a free text field where stud y participants could specify
information that may constitute product safet y information. However, it is possible that a
study participant may volunteer pro duct safet y information to DCRI Call C enter staff during
completion of a survey assessment by phone (a “rescue” assessment when the participant is
non-responsive to online prompts), or for an y other reason (e.g., seeking information about
the purpose of the stud y); this information must be reported as described below.
The following safet y events must be reported on the non -interventional study (NIS) adverse
event monitoring (AEM) Rep ort Form: serious and non -serious AEs when associated with
the use of the Pfizer product, and scenarios involving exposure during pregnancy , exposure
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Page 39of 43during breast feeding, medication error, overdose, misuse, extravasation, lack of efficacy and
occupationa l exposure (all reportable, regardless of whether associated with an AE) ,
when associated with the use of a Pfizer product.
In the event that a stud y participant volunteers product safet y information, DCRI Call Center
staff must complete the NI S AEM Report Form and submit to Pfizer within 24 hours of
becoming aware of the safety event. Included in the completion of the NIS AEM Report
Form *is the study participant’s contact information; complete contact information should be
obtained so that, once the NI S AEM Report Form is sent to Pfizer, the NI S AEM Report
Form can be assessed and processed according to Pfizer’s standard operating procedures,
including requests for follow- up to the study participant. DCRI Call Center staff who will
serve to address an y query from a study participant must complete the following Pfizer
training requirements:
“YRR Training for Vendors W orking on Pfizer Studies (excluding interventional
clinical studies and non- interventional primary data collection studies with
sites/investi gators) ”.
*Non-Interventional Study Adverse Event Report Form for Protocols without Stipulated Active Collection of
Adverse Events ;this type of report ismanaged as spontaneous by Pfizer Safety.
These trainings must be completed by DCRI Call Center staff prior to the start of data
collection. All trainings include a “Confirmation of Training Certificate” (for signature b y
the trainee) as a record of completion of the training, which must be kept in a retrievable
format. DCRI Call Center will also p rovide copies of all signed training certificates to Pfizer.
Re-training must be completed on an annual basis using the most current Your Reporting
Responsibilities training materials.
Medical record review abstraction
In this study protocol , the DCRI Clinical Event Ascertainment (CEA) group will perform
human review of patient- level unstructured data; unstructured data refer to verbatim medical
data, including text -based descriptions and visual depictions of medical information, such as
medical record s, images of phy sician notes, neurological scans, X- rays, or narrative fields in
a database . The reviewer is obligated to report adverse events (AEs) with explicit attribution
to any Pfizer drug that appear in the reviewed information (defined per the patient population
and study period specified in the protocol). Explicit attribution is not inferred b y a temporal
relationship between drug administration and an AE, but must be based on a definite
statement of causality by a healthcare provider linking dru g administration to the AE.
The requirements for reporting safet y events on the NIS AEM Report Form **to Pfizer
Safety are as follows:
All serious and non- serious AEs with explicit attribution to any Pfizer drug that
appear in the reviewed information must be recorded on the chart abstraction form
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Page 40of 43and reported, within 24 hours of awareness, to Pfizer Safet y using the NIS AEM
Report Form.
Scenarios involving drug exposure, including exposure during pregnancy , exposure
during breast feeding, medication error , overdose, misuse, extravasation, lack of
efficacy , and occupational exposure associated with the use of a Pfizer product must
be reported, within 24 hours of awareness, to Pfizer Safet y using the NI S AEM
Report Form.
For these AEs with an explicit attrib ution or scenarios involving exposure to a Pfizer product,
the safet y information identified in the unstructured data reviewed is captured in the Event
Narrative section of the report form, and constitutes all clinical information known regarding
these AEs . No follow- up on related AEs will be conducted.
**Non- Interventional Study Adverse Event Report Form For Protocols with Stipulated Active Collection of
Adverse Events ; this type of report is managed as solicited by Pfizer Safety .
All the demographic fields on the NI S AEM Report Form may not necessarily be completed,
as the form designates, since not all elements will be available due to privacy concerns with
the use of secondary data sources. While not all demographic fields will be completed, at the
very least, at least one patient identifier (e.g., gender, age as captured in the narrative field of
the form) will be reported on the NI S AEM Report Form, thus allowing the report to be
considered a valid one in accordance with pharma covigilance legislation. All identifiers will
be limited to generalities, such as the statement “A 35- year-old female...” or “An elderl y
male...” Other identifiers will have been removed.
Additionally , the onset/start dates and stop dates for “Illn ess”, “Study Drug”, and “Drug
Name” may be documented in month/y ear (MM/ YYYY ) format rather than identify ing the
actual date of occurrence within the month /y ear of occurrence in the day /month/y ear
(DD/MMM/YYYY ) format.
All research staff members must c omplete the following Pfizer training requirements:
“YRR Training for Vendors W orking on Pfizer Studies (excluding interventional
clinical studies and non- interventional primary data collection studies with
sites/investigators) ”.
These trainings must be completed by DCRI CEA staff members prior to the start of data
collection. All trainings include a “Confirmation of Training Certificate” (for signature b y
the trainee) as a record of completion of the training, which must be kept in a retrievable
format. Copies of all signed training certificates must be provided to Pfizer.
Re-training must be completed on an annual basis using the most current Your Reporting
Responsibilities training materials.
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Page 41of 4312.PLANS FOR DISSEMINAT ING AND COMMUNICATING STUDY R ESULTS
Interim study reports will be completed according to the milestone schedule in Section 4.The
final study results will be posted in the European Union (EU) Post- Authorization Study
(PAS) Register. Results will be further disseminated through a variety of mechanisms,
including pre sentation at national meetings and publication in peer -reviewed journals.
In the event of an y prohibition or restriction imposed (e .g., clinical hold) by an applicable
competent a uthorit y in any area of the world, or if the investigator at DCRI or Verily 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 immediately .
In addition, the investigator will inform Pfizer immediately of any urgent safet y measures
taken b y the DCRI or Verily to protect the study participant s against an y immediate hazard,
and of an y serious breaches of this NI (observational) study protocol that the DCRI or Verily
becomes aware of.
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Page 42of 4313.REFERENCES
1. WHO Novel coronavirus –China. Jan 12, 2020.
http://www.who.int/csr/don/12 -january -2020- novel- coronavirus -china/en/ .
2. Jiang S, Xia S, Ying T, Lu L . A novel coronavirus (2019 -nCoV) causing pneumonia -
associated respiratory syndrome. Cell Mol Immunol. 2020;17(5):554 .
3. World Health Organization. Naming the coronavirus disease (COVID -19) and the virus
that causes it. Accessed October 2, 2020. Available:
https://www.who.int/emergencies/diseases/novel- coronavirus- 2019/technical-
guidance/naming -the-coronavirus- disease -(covid -2019)- and-the-virus -that-causes -it.
4. COVID -19 Dashboard by the Center for S ystems Science and Engineering (CSSE) at
Johns Hopkins University (JHU). https://coronavirus.jhu.edu/map.html .
5. Nguyen LH, Drew DA, Graham MS, et al. Risk of COVID- 19 among front -line health-
care workers and the general community : a prospective cohort study . Lancet Public
Health. 2020;5(9):e475- e483.
6. National Academies of Sciences, Engineering, and Medicine. Framework for Equitable
Allocation of COVID -19 Vaccine. 2020. Available:
https://www.nap.edu/catalog/25917/framework -for-equitable -allocation -of-covid -19-
vaccine#resources.
7. Public Policy Committee I SoP. Guidelines for good pharmacoepidemiology practice
(GPP). Pharmacoepidemiol Drug Saf. 2016;25(1):2 -10.
8. Anderson S. CBER Plans for M onitoring COVID- 19 Vaccine Safet y and Effectiveness.
Presentation at the CDC Adivsory Committee on Immunization Practices. October 28,
2020. Available: https://www.cdc.gov/vaccines/acip/meetings/downloads/slides -2020 -
10/COVI D-Anderson.pdf .
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Pfizer -BioNTech COVID -19 Vaccine
C4591008 NON- INTERVENTIONAL STUDY PROTOCOL
V3.0, 20 April 2021
PFIZER CONFIDENTIAL
Page 43of 4314.LIST OF TABLES
Table 1. HERO Registry Participants (Preliminary Data) as of December
2020 ................................ ................................ ................................ .......... 16
Table 2. Demographic Composition of the Registry (Preliminary Data) as of
December 2020 ................................ ................................ ......................... 17
Table 3. Study Variables ................................ ................................ ......................... 23
Table 4. Schedule of Assessments ................................ ................................ .......... 27
Table 5. Definitions of Final Event Classification Categories ............................... 29
15.LIST OF FIGURES
Figure 1. Overall Study Design ................................ ................................ ................ 21
Figure 2. Confirmation of Sa fety Events of Interest During Follow -up.................. 30
Figure 3. Data Flow Diagram ................................ ................................ ................... 33
ANNEX 1. LIST OF STAND ALONE DOCUMENTS
None
ANNEX 2 . ADDITIONAL INFORMATION
N/A.
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