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Pfizer -BioNTech COVID- 19 Vaccine
C4591008 NON- INTERVENTIONAL STUDY PROTOCOL
V2.0, 27 January 2021
PFIZER CONFIDENTIAL
Page 1 of 42
NON- INTERVENTIONAL (NI) STUDY PROTOCOL
Study Information
Title HERO Together : A post-Emergency Use
Authorization observational cohort study to
evaluate the safety of the Pfizer -BioNTech
COVID-19 vaccine in US h ealthcare
workers
Protocol number C4591008
Protocol version identifier Version 2.0
Date 27 January 2021
EU Post Authorization Study (PAS)
register number EUPAS38671
Active substance N/A
Medicinal product COVID -19 Vaccine
BNT162b2
Research question and objectives The research questions addressed by this
study are a) what are the incidence rates of safety events of interest and other clinically
significant events among persons vaccinated with the Pfizer -BioNTech COVID-19
vaccine in a cohort of US healthca re workers
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 vaccinated
with the Pfizer -BioNTech COVID-
19 vaccine following Emergency Use
Authorization.
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Secondary objectives
• Evaluate whether the vaccine
recipients experience increased risk of safety events of interest and other clinically significant events post- vaccination .
• Estimate the incidence rates of safety
events of interest and other clinically
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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PFIZER CONFIDENTIAL
Page 3 of 42 1. TABLE OF CONTENTS
1. TABLE OF CONTENTS .......................................................................................................3
2. LIST OF ABBREVIATIONS ................................................................................................5
3. RESPONSIBLE PARTIES ....................................................................................................6
4. ABSTRACT ...........................................................................................................................7
5. AMENDMENTS AND UPDATES .....................................................................................13
6. MILESTONES .....................................................................................................................13
7. RATIONALE AND BACKGROUND ................................................................................13
8. RESEARCH QUESTION AND OBJECTIVES .................................................................15
9. RESEARCH METHODS ....................................................................................................15
9.1. Study Design ...........................................................................................................15
9.2. Setting ......................................................................................................................16
9.2.1. Inclusion Criteria ........................................................................................18
9.2.2. E xclusion Criteria .......................................................................................18
9.2.3. Recruitment .................................................................................................18
9.2.4. Enrollment ..................................................................................................19
9.2.5. Retention .....................................................................................................21
9.2.6. Participant Follow-up and Data Collection ................................................22
9.3. Variables ..................................................................................................................22
9.3.1. Safety events of interest ..............................................................................23
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 .......................................................................................29
9.5. Study Size ................................................................................................................29
9.6. Data Management ...................................................................................................30
9.6.1. Case Report Forms (CRFs)/Data Collection Tools (DCTs)/Electronic
Data Record .....................................................................................................32
9.6.2. Record Retention ........................................................................................33
9.7. Data Analysis ..........................................................................................................33
9.8. Quality Control ........................................................................................................34
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Page 4 of 42 9.9. Limitations of the Research Methods ......................................................................34
9.10. Other Aspects ........................................................................................................35
10. PROTECTION OF HUMAN SUBJECTS ........................................................................35
10.1. Participant Information .........................................................................................35
10.2. Participant Consent ...............................................................................................35
10.3. Participant Withdrawal ..........................................................................................36
10.4. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ............36
10.5. Ethical Conduct of the Study ................................................................................36
11. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE
REACTIONS ......................................................................................................................37
12. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS ........39
13. REFERENCES ..................................................................................................................41
14. LIST OF TABLES .............................................................................................................42
15. LIST OF FIGURES ...........................................................................................................42
ANNEX 1. LIST OF STAND ALONE DOCUMENTS .........................................................42
ANNEX 2. ADDITIONAL INFORMATION .........................................................................42
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Page 5 of 42 2. LIST OF ABBREVIATIONS
To be updated when protocol finalized .
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 Analysis Plan
WHO World Health Organization
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Page 6 of 42 3. RESPONSIBLE PARTIES
Principal Investigator(s) of the Protocol
Name, degree(s) Job Title Affiliation Address
Emily O’Brien, PhD Epidemiologist Duke Clinical Research
Institute 200 Morris Street
Durham, NC 27701
Adrian Hernandez,
MD, MHS Executive Director Duke Clinical Research
Institute 200 Morris Street
Durham, NC 27701
Heather Rubino,
PhD, MS Global Medical
Epidemiology,
Director Pfizer Inc. 235 E 42nd St,
New York, NY 10017
Ann Madsen, PhD Global Medical
Epidemiology, Sr.
Director Pfizer Inc. 235 E 42nd St,
New York, NY 10017
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Page 7 of 42 4. ABSTRACT
Title: A post-Emergency Use Authorization observational cohort study to evaluate the safety
of the Pfizer -BioNTech COVID-19 vaccine in US h ealthcare workers
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 years 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 care facilities
under an EUA. This study is designed to provide early real- world safety informa tion on a
cohort of vaccinated health workers 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 thi s study are a)
what are the incidence rates of adverse safety 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, 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 vaccinated with the Pfizer -
BioNTech COVID -19 vaccine fol lowing Emergency Use Authorization.
Secondary objectives
• Evaluate whether the vaccine recipients experience increased risk of safety events of interest and other clinically significant events post- vaccination.
• Estimate the incidence rates of safety events of interest and other clinically 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 healt hcare workers , 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 safety events. The study period will be 30 months. Population:
Study participants will be recruited from two sources:
• An existing registry study, the Healthcare Worker Exposure Response and Outcomes
(HERO) Registry Study, which was launched in April 2020 to characterize
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PFIZER CONFIDENTIAL
Page 8 of 42 COVID-19 risk factors and outcomes among US healthcare workers by the Duke
Clinical Research Institute (DCRI)
• Major health systems distributing Pfizer -BioNTech COVID-19 vaccine to its
employees , as determined by local jurisdictional EUA rollout plans. Once receiving
systems are identified, study navigators will be identified for vaccination sites within
systems and activated to ensure broad geographic diversity in the surveillance study.
To be eligible for enrollment, individuals must meet all of the following criteria:
• Individua l currently works in a setting where individuals receive healthcare in the US
(“healthcare worker”; including emergency medical services) .
• Age ≥ 18 years .
• Able to speak and read English or Spanish.
• Recei pt of C OVID -19 vaccine for prevention of SARS-CoV-2 infection within the
past 60 days.
• Evidence of informed consent indicating that the participant (or a legally acceptable
representative) has been informed of all pertinent aspects of the study.
• Medical release providing for r elease of all pertinent medical information for
assessment of vaccine safety during the one-year period prior to vaccination and during the follow-up period.
Variables :
Key variables include vaccination exposure characteristics (e g, number of disease
recei ved, 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 Safety Platform for Emergency vACcines (SPEAC) Project (https://brightoncollaboration.us/priority- list-aesi-covid/
) accessed 12/13/2020 The safety
events of interest in this study include:
Neurologic:
• Generalized convulsion/seizures
• Guilla in-Barre Syndrome
• Aseptic meningitis
• Encephalitis/encephalomyelitis
• Other acute demyelinating diseases
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Page 9 of 42 • Transverse myelitis
• Multiple sclerosis
• Optic neuritis
• Bell’s palsy
Immunologic:
• Anaphylaxis
• Vasculitides *
• Arthritis/arthralgia
• Multisystem inflammatory syndrome (in adults)
• Kawasaki disease
• Fibromyalgia
• Autoimmune thyroiditis
COVID-19:
• Severe COVID -19 disease*
• Microangiopathy*
• Heart failure and cardiogenic shock*
• Stress cardiomyopathy*
• Coronary artery disease*
• Arrythmia*
• Deep vein thrombosis
• Pulmonary embolus
• Cerebrovascular stroke
• Limb ischemia*
• Hemorrhagic disease*
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Page 10 of 42 • Acute kidney injury*
• Liver injury
• Chillblain -like lesions
• Single organ cutaneous vasculitis*
• Erythema multiforme*
Cardiac:
• Myocarditis
• Pericarditis
• Acute myocardial infarction
Hematologic:
• Thrombocytopenia
• Disseminated intravascular coagulation
Other:
• Pregnancy outcomes
• Death
• Narcolepsy and cataplexy ;
• Non-anaphylactic 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 w ith longer than a 2 -
day interval between vaccination and enrollment will be administered a retrospective
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Page 11 of 42 assessment to capture self -reported safety 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 safety event. The DCRI Clinical
Event Ascertainment (CEA) group will adjudicate medical records for event confirmation.
Study size: The study aims to enroll at le ast 20,000 healthcare workers who have received a
COVID-19 va ccine. As the primary objective is descriptive, this sample size target is
designed to ensure adequate precision for a plausible range of safety event rates in the
population of vaccinated healthcare workers.
To address the secondary objective regarding assessment of increased risk, a self- matched
comparative analysis will be undertaken for feasible safety events (eg, events with a known
risk interval). Statistical power to detect various effect sizes assuming a range of background
incidence rates in a self -matched comparative analysis will be described in the statistical
analysis plan.
Data analysis: Vaccination and baseline characteristics will be sum marized using descriptive
statistics, including measures of central tendency and dispersion (means, medians, standard
deviations) for continuous variables and percentages for categorical variables.
The primary analysis for each objective will be restricte d to participants who enrolled within
10 days of vaccination to mitigate the risk of selective enrollment and disproportionate representation of higher risk participants. The number and incidence rate for each safety event of interest will be calculated ov erall, and within subgroups of interest, including
pregnant women, immunocompromised individuals, and within age groups. Rates will also be stratified by other baseline characteristics, such as work setting and geographic region, data permitting. To eva luate whether vaccinated persons experience increased risk, we will use qualitative
and quantitative comparison approaches. Qualitative comparisons will be made using
hospitalization rates among non- vaccinated healthcare workers available from the parent
HERO registry and external sources of background event rates. A self -matched comparative
analysis will then be conducted for events that appear to be associated with vaccination and
are amenable to self -matched analysis , such as those with an adequa te case count and known
risk interval.
Detailed methodology for the statistical analyses of data collected in this study, including the
analytic methods to be used for self- matched comparative analyses, will be documented in a
statistical analysis p lan.
Milestones:
Data collection is anticipated to start 17 December 2020, with interim reports
completed per the following schedule:
• 30 June 2021
• 31 December 2021
• 30 June 2022
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Page 12 of 42 • 31 December 2022
The final study report will be submitted by 31 December 2023.
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Page 13 of 42 5. AMENDMENTS AND UPDATES
Amendment
number Date Protocol
section(s)
changed Summary of amendment(s) Reason
1 22
January
2021 • Title page
• Abstract
• Milestones
• Rationale and
Background • Added 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 quar ter of 2021
are limited . US vaccinations program
not fully deployed until January
• Study was not included in final RMP
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 30 June 2023
Final study report 31 December 202 3
7. RATIONALE AND BACKGROUND
In December 2019, a viral pneumonia outbreak of unknown origin was identified in Wuhan,
China .1 By January 2020, the outbreak was confirmed to be caused by a novel coronavirus
named severe acute respiratory syndrome coronavirus 2 (SARS-CoV- 2).2 The 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 SARS -CoV-2 the coronavirus disease 2019 (COVID-19).
3 As of October 2, 2020, a total of
34.6 million confirmed cases and over 1 million deaths related to COVID-19 have been reported.
4 Healthcare workers have been disproportionately affected by the pandemic, with
an infection risk 11 times that of the general population.5 Due to this increased risk, the
National Academies of Science, Engineering, and Medicine has prioritized healthcare workers for early receipt of vaccines to prevent SARS -CoV-2 infection.
6
Given the public health emergency caused by 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 years of age and older. Detailed distribution plans for the COVID-19 v accine
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Page 14 of 42 within the US are determined by local jurisdictions 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 early real- world safe ty information on a
cohort of vaccinated health workers for two years after vaccination.
This non-interventional study is designated as a PASS and is included in the US pharmacovigilance plan.
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Page 15 of 42 8. RESEARCH QUESTION AND OBJECTIVES
The research questions addres sed by this study are a) what are the incidence rates of safety
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 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 vaccinated with the Pfizer -
BioNTech CO VID-19 vaccine following Emergency Use Authorization.
Secondary objectives
• Evaluate whether the vaccine recipients experience increased risk of safety events of
interest and other clinically significant events post- vaccination.
• Estimate the incidence rates of safety events of interest and other clinically significant
events among subcohorts of interest such as individuals who are pregnant, individuals
who are immunocompromised, and stratified by age.
9. RESEARCH METHODS
9.1. Study D esign
This study is a prospective observational study designed to evaluate the incidence rates of safety events of interest and other clinically significant events within a cohort of healthcare workers who receive the Pfizer -BioNTech COVID -19 vaccine under the EUA program in the
Unite d States. The study 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 at the discretion o f the recipient.
This study will aim to enroll and follow 20,000 vaccinated healthcare workers during a 30-
month study period. Information on hospitalization and diagnosis of safety events of interest will be collected from participant self -report at reg ular intervals following vaccination,
primarily using a secure web portal. Participant reports of safety events of interest and/or hospitalization trigger a request for and review of participant medical record information for
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 by
adjudication . To a ddress the secondary objective regarding assessment of increased risk, a
self-matched comparative analysis will be undertaken for feasible safety events (eg, events
with a known risk interval and sufficient case counts ). Additional context f or the rates
observed in vaccinated individuals will be sought from population background rates and unvaccinated person years in the HERO registry.
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Page 16 of 42
9.2. Setting
Healthcare worker participants , including individuals with and without medical training, will
be recruited from two 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 overall goal of the HERO Registry is to create and
engage a community of HCWs, who may be eligible for participation in future research studies, including studies of COVID -19 prophylaxis and treatment. Participants complete
periodic questionnaires 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 currently comprises approximately
17,000 participants in all 50 states and is recruiting new HCWs for inclusion in the registry
on an ongoing basis. Due to the broad definition of healthcare worker and limited inclusion/exclusion criteria, the registry supports enrollment of a diverse population and greater generalizability of results.
Table 1 provides a current description of registry members, demonstrating the diversity of
healthcare workers who self -enrolled into the registry. The current demographic composition
of the Registry is shown in Table 2.
Table 1. HERO Registry Participants (Preliminary Data)
HERO Registry Participants
(n=15,629) Frequency Percent Cumulative
Frequency Cumulative
Percent
Physician 3265 20.89 3265 20.89
Nurse (RN/LPN) 5202 33.28 8467 54.17
Paramedic/Emergency Medical
Technician 463 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 Practitioners 1321 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 17 of 42 Table 2. Current Demographic Composition of the Registry (Preliminary Data)
Gender
Male Female Othe ra Total
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 members will be sent notifications of the opportunity to participate in a study
of long- term outcomes after vaccination as part of the HERO study infrastructure.
The second source will be major health systems distributing Pfizer -BioNTech COV ID-19
vaccine to its employees , as determined by local jurisdictional EUA rollout plans. H ealthcare
systems will be prioritized for involvement based on the ordered number of Pfizer COVID-19 vaccine doses, feasibility of recruitment and geographic diversity. Once receiving systems are identified, study navigators will be identified for assignment to vaccination sites within these systems to facilitate enrollment of vaccine recipients .
In this study, there will not be treating -healthcare providers as investigators overs eeing the
recruitment , enrollment, and data collection for study participants. Rather, individuals will
self-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.
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Page 18 of 42 9.2.1. Inclusion C riteria
Participant s must meet all of the following inclusion criteria to be eligible for inclusion in the
study:
• Individual currently works in a setting where individuals receive healthcare in the US
(“healthcare worker”; including emergency medical services) .
• Age ≥ 18 years .
• Able to speak and read English or Spanish.
• Recei pt of C OVID -19 vaccine for prevention of SARS-CoV-2 infection within the
past 60 days.
• Evidence of informed consent indicating that the participant (or a legally acceptable
representative) has been informed of all pertinent aspects of the study.
• Medical release providing for release of all pertinent medical information for
assessment of vaccine safety during the one-year period prior to vaccination and during the follow-up period.
9.2.2. Exclusion C riteria
There are no exclusion criteria for this study. A ll participants meeting inclusion criteria will
be eligible for analysis .
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 that recruitment goals are met , while minimizing
missing and inaccurate data, and loss to follow-up.
A healthcare worker may learn about the opportunity to receive the vaccine either through
his/her empl oyer or by email sent to existing HERO Registry members . Recruitment
materials may also be present in the vaccine administration area.
All recruitment materials will focus on enrollment into a research study on vaccine safety and will avoid language promoting the Pfizer -BioNTech COVID -19 vaccine itself. Existing
HERO members will receive instructions as to how they can express interest in joining the study and enroll. If a HER O member expresses interest but, after a notable period of time,
has yet to enroll in the study, additional follow-up will be conducted to remind them of the opportunity and help them navigate the enrollment process.
Recruitment of HCW s not participating in the HERO registry will occur via public
communication, social media and other advertising, printed enrollment materials with
information about the study at vaccination sites.
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Healthcare workers may enroll at the vaccination s ite or may self -enroll remotely. At select
vaccination sites, study navigators wi ll 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 will 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 parent HERO Registry study, optimal navigator
workflow will be determined depending on institutional plans for vaccination. For exa mple,
at some institutions , the navigator will interact with the potential participant shortly before
receiving the vaccine (eg, 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 healthcare workers will spend time after the vaccine.
Existing members of the HERO R egistry will be instructed to complete a screening
questionnaire, an informed consent form (ICF), and a medical release form, at which point they will be enrolled in the study. Non-members will be enrolled in the HERO Registry and then directed to complete the screening questionnaire, informed consent and medical release form. In addition, proxy contact information will be collected at enrollment to support data
capture in the event that the participant cannot be reached (eg, participant is hospitalized).
Enrollment metrics will be monitored throughout the enrollment period and will be specified in the recrui tment 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 analysis.
Additional metrics may be included in the recruitment plan.
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Figure 1. Overall Study Design
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The HERO Registry is ‘siteless’ and enrollment has primarily been driven through word of
mouth, coupled with some promotional materials provided to 40 healthcare institutions affiliated with PCORnet and the HERO -Hydroxychloroquine trial. From April to October
2020, only 164 Registry participants (<1%) have withdrawn from the Registry.
Deviations from enrollment projections will be identified rapidly; efforts to increase
awareness of the study will be undertaken accordingly.
9.2.5. Retention
One strategy for retaining participants in the study relies on engagement through the HERO
Registry parent study within which this COVID -19 vaccine stu dy will be conducted. As part
of the HERO registry, participant engagement is sought by a series of community building
activities and modules that are informed by 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 nearly 60% returned to complete two or more surveys. As described below, “rescue” strategies to prompt survey completion have resulted in substantially improved completion.
Additionally, there is an automated system built into the Verily platform that notifies the
DCRI C all C enter when a participant has not completed a survey. The DCRI Call Center,
with their staff of bilingual interviewers (Spanish and English), operates 7 days 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 follo w-up support to participants
who do not complete their digital surveys - 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 DCRI Call Center will be to rescue surveys 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 li ne
to use at their convenience.
In the HERO-Hydroxychloroquine randomized controlled trial, which was conducted within
the HERO registry and required participant self -report of data, the C all C enter successfully
rescued 81% of surveys administered at 2, 4, and 8 weeks that were not completed on time.
Other recent projects involving DCRI Call Center services have observed similar ly high rates
of rescue. These include the ARTEMIS trial of coronary artery disease and anticoagulants, which enrolled 11,000 participants and achieved an 88% rescue rate for surveys administered at 3 and 12 months; and PROVIDE-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.
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9.2.6. Participant Follow- up and Data C ollection
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 of attempted Call Center contacts) , or discontinuation from study.
Following 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 requiring medical attention. Participants who do not com plete data entry within a
notable period of time of the expected completion date for a given time point will be contacted by the Call Center for confirmation of health status. For participants who report clinically important medical event (eg, non-routine visit to medical provider or
hospitalization) medical records will be obtained for review by the Clinical Event
Ascertainment group for confirmation of the occurrence of a safety event of interest. For any participant who reports a potential safety event, medical records during the year prior to vaccination may also be reviewed to support a self -matched comparative analysis (See
Section 9.3.1 f or additional details).
9.3. Variables
Table 3 lists variables of interest for this study; d etailed operational definitions of all
variables will be provided in the statistical analysis plan.
Table 3. Study Variables
Variable Role Data Source(s)
Date of 1st dose COVID -19 vaccination Exposure Participant
Site where 1st dose COVID -19 vaccine
was administered Exposure Participant
COVID -19 vaccine lot number
(1st dose) Exposure Participant
Date of 2nd dose COVID -19
vaccination Exposure Participant
Site where 2nd dose COVID -19 vaccine
was administered Exposure Participant
COVID -19 vaccine lot number
(2nd dose) Exposure Participant
Pregnancy Information (pregnancy
status and estimated due date) Outcome (utilization
analyses) and
covariate (safety analyses) Participant
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Table 3. Study Variables
Variable Role Data Source(s)
Demographics Outcome ( utilization
analyses) and
covariate (safety
analyses) Participant
Medical History Outcome ( utilization
analyses) and covariate (safety analyses) Participant
Employment characteristics Outcome (utilization
analyses) and
covariate (safety
analyses) Participant
Vaccination details Exposure variable Participant
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 safety 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 safety monitoring recommendations (https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2020- 09/COVID-03-
Shimabukuro.pdf, accessed 12/13/2020). Safety event definitions will be specified a priori in
the clinical events ascertainment (CEA) charter as appropriate. The safety events of interest
in this study include:
Neurologic:
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• Generalized convulsion/seizures
• Guilla in-Barre Syndrome
• Aseptic meningitis
• Encephalitis/encephalomyelitis
• Other acute demyelinating diseases
• Transverse myelitis
• Multiple sclerosis
• Optic neuritis
• Bell’s palsy
Immunologic:
• Anaphylaxis
• Vasculitides*
• Arthritis/arthralgia
• Multisystem inflammatory syndrome (in adults)
• Kawasaki disease
• Fibromyalgia
• Autoimmune thyroiditis
COVID-19:
• Severe COVID -19 disease*
• Microangiopathy*
• Heart failure and cardiogenic shock*
• Stress cardiomyopathy*
• Coronary artery disease*
• Arrythmia*
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• 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
• Acute myocardial infarction
Hematologic:
• Thrombocytopenia
• Disseminated intra vascular coagulation
Other:
• Pregnancy outcomes
• Death
• Narcolepsy and cataplexy ;
• Non-anaphylactic allergic reactions
*Hospitalized manifestations only
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9.4. Data S ources
Data will be captured through several mechanisms, described below . All data collected in the
context of this study will be stored 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 applying to
confidentiality of data.
9.4.1. Participant S elf-report
Participants will provide information on COVID- 19 vaccination, baseline characteristics,
seeking of non-routine medical care (including hospitalization) and potential occurrence of
safety 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 in Table 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 safety
information occurring within this interval. If an assessment is incomplete after a notable period of time, the participant will be contacted by the C all C enter for completion of missed
assessments.
Table 4. Schedule of Assessments
Enrollment
Data
Collection Follow -up Data Collection
Baseline After 1st dose
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
• Site X
Vaccine Dose 2 information
• Date
• Lot number
• Site X
(and
subsequent
visits if
second
dose not
reported as
received )
Medical release X
Demographics
• Demographics form X
Medical history
• Medical history form X
Employment Information
• Employment information form X
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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 Scale X X X X X X X*
COVID -19 Information
• Positive COVID-19 test with date
• COVID-19 diagnosis (presumptive)
• X X X X X X X
Health questionnaire
• Potential safety events of
interest or clinically
significant events
• Pregnancy status X X X X X X X
* PROs and medication information collected only at 6, 12, 18, and 24 month intervals .
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9.4.2. Call C enter D ata C ollection
The DCRI C all 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 confirmation of the occurrence of safety events of
interest .
If a participant does not complete an assessment after a notable period of time, the DCRI C all
Center will be alerted to contact the participant using participant contact information
transferred from the web portal into the communications system used by the C all C enter.
This communications system manages call queues, scheduling, and call processing information. The study data obtained by the C all 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 Ascertainment (CEA)
The C all C enter will request medical records for all participants reporting a hospitalization or
potential safety event of interest at any point during follow-up. The following components of medical records will be sought as appr opriate:
Emergency room notes
Discharge summary/death summary
Admission history and physical exam
Progress/ clinic/urgent c are notes
Diagnostic t ests
Lab reports
Medication records
For each participant-reported event, t he DCRI Clinical Event Ascertainment (CEA) group
will review the medical records and confirm the occurrence of an event as part of an
adjudication process. Safety event definitions will be specified a priori in the clinical events
ascertainment (CEA) charter as appropriate. Refer to Figure 2 for a summary of this process.
The CEA group is responsible for ongoing analysis of potential safety events of interest or
other clinically significant diagnos es and of their adjudication as study endpoints.
The CEA group includes specialists relevant to the safety events of interest, including
cardiologists, immunologists, neurologists, and other specialists. Additional details about review procedures will be provided in an adjudication charter.
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Figure 2. Confirmation of Safety Events of Interest During Follow- up
9.4.4. Proxy Completion
At enrollment, participants will provide contact information for a proxy 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 participant 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. If more than 2 consecutive assessments are missed and no proxy can be reached, medical records will be requested for further investigation about the reason for loss to follow-up (for example, the participant has died).
9.5. Study S ize
This study will aim to enroll at least 20,000 healthcare workers who have received the
Pfizer -BioNTech COVID -19 vaccine for prevention of COVID-19. This study size will help
ensure a diverse population of healthcare workers with respect to geography, 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 ensur e adequate
precision for a plausible range of AE and SAE rates in the population of vaccinated
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healthcare workers. Table 5 displays anticipated precision (95% confidence interval widths)
generated using the Clopper- Pearson exact method for a range of safety event rates in a
sample of 20,000 participants (overall) and samples of 5,000 and 10,000 participants
(potential subgroups and al lowing for some exclusions due to attrition ). As shown below,
precision is high for observed event rates ranging from 0.1% to 20.0%.
Table 5. Estimated Precision of Observed Event Rates
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
Based on experience to date with the HERO registry, in this study we forecast a 2%
withdrawal rate, a 75% survey completion rate and enrollment of n=200 participants (1%) who would be excluded from primary analyses due to receipt of non- Pfizer -BioNTech
vaccine. This would result in withdrawal of n=400 people, exclusion of n=200 participants due to receiving a non- Pfizer -BioNTech vaccine and no or partial questionnaire data for
~4,900 participants. Therefore, we anticipate that enrollment of approximately 20,000 participants will result in comprehensive questionnaire data for approximately 14,500 participants.
To address the second objective regarding assessment of increased risk of safety events in
vaccinated individuals, informal comparisons will made with hospitalization rates among non-vaccinated healthcare workers available from the parent 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 analysis 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, particularly as it pertai ns to EDC, CTMS, analysis and reporting.
All solutions utilized by the DCRI are fully vetted by IT personnel, and representatives from
core teams such as Clinical Data Management and Safety Surveillance to ensure solutions
support primary business requirements and meet all applicable regulatory requirements (eg,
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21 CFR Part 11). Externally hosted solutions are audited to ensure compliance with
appropriate security 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 data collection and interactions with particip ants and the D CRI
Call Center . Related operational systems supporting t he 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 the systems and interactions
required to enable a well -coordinated study delivery plan. Study participants accessing the
system directly and the emphasis on self-reported data does require primary identifiers to be maintained within a limited number of systems. These data will be secured such that it is only maintained in the minimum required systems and accessible to the minimum number of people to perform the study procedures described in this protocol. The primary method of identifying a participant will be with a unique participant identification number.
Participants will use a study portal developed by 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 the study- specific
data system. Leveraging this infrastructure ensures very high levels of system security and support are embedded in the portal. Although leveraging Google infrastructure this is a stand-alone portal an d no data are shared from other sources with the study, and no study data will
be shared with any other Google systems.
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 system used by the Call Center for these contacts. This system 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 system), Informatica (data exchange/extract -transform -load procedures), Cognos (operational reporting), MS SQL,
SAS, and SAS Visual Analytics (statistics).
Data quality is managed at each stage of its lifecycle. Data collected in the portal conforms at inception to highly structured data elements and protocol- specific rules, subsequent data
transfers are checked to conform to format and semantic specifications and all data is assessed for referential integrity across sources through a set of reconciliation practices upon integration then follow ed by a variety of logical checks within a participant and in aggregate.
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Figure 3. Data Flow Diagram
NO
NOTE: Pfizer will not receive individual level data only aggregate reports
9.6.1. Case R eport Forms (CRFs)/Data C ollection T ools (DCT s)/Electronic Data R ecord
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 property of Pfizer and should not be made available in any 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 collectio n and reporting of all data entered on the
eCRF as required and ensuring that they are accurate, authentic/original, attributable, 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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9.6.2. Record Retention
To enable evaluations and/or inspections/audits from regulatory authorities or Pfizer, Verily
agrees to keep all study -related records. The records should be retained by 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.
If Verily becomes unable for any reason to continue to retain study records for the required
period, Pfizer should be prospectively 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 years if required by applicable local regulations.
Verily must obtain Pfizer's written permission before disposing of any 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 analysis for each objective will be restricted to participants
who enrolled within 10 days of vaccination to mitigate the risk of selective enrollment and disproportionate representation of higher risk participants. The number and incidence rate for each safety 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 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 a nalysis plan.
To evaluate whether vaccinated persons experience increased risk, we will use qualitative and quantitative comparison approaches. Qualitative comparisons will be made using
hospitalization rates among non- vaccinated healthcare workers available from the parent
HERO registry and external sources of background event rates. A self -matched comparative
analysis 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.
Detailed methodology for summary and statistical analyses of data collected in this study,
including the analytic methods to be used for self- matched comparative analyses, will be
documented in a statis tical analysis p lan (SAP) , which will be dated, filed and maintained by
the sponsor. The SAP may modify the plans outlined in the protocol; any major
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modifications of primary endpoint definitions or their analyses would be reflected in a
protocol amendment.
9.8. Quality Control
Data will be transferred from the Verily platform to the DCRI data management 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 follo w-up with the participant.
Data captured by the DCRI Call Center and CEA group will be input directly into the Verily
platform for quality control.
Data reconciliation consists of reconciling the primary participant identifiers and all queries
generated by the EDC system are resolved online. Both automatic and manual queries can be generated in the EDC system. Auto queries generate immediately upon data submission and manual queries are generated as a result of data review. Data quality strategies and da ta
surveillance may also include data status reports and other data status reports as defined by the needs of the study.
9.9. Limitations of the R esearch M ethods
This study is intended to provide comprehensive real -world safety information about the
Pfizer -BioNTech COVID-19 vaccine in US healthcare worker s, who will be among the first
individuals to be vaccinated as part of an EUA. 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, who are already engaged in COVID- related research and the minimal burden on participants for safety data collection via
a web portal.
To help maximize enrollment of vaccinated healthcare workers , there is flexibility in
participant enrollment location (on -site or remote) and timing (up to 60 days following the
first vaccination dose). However, for individuals enrolling several days or weeks following
vaccination, there is the potential for preferential self -enrollment of individuals experiencing
a safety event (or early symptoms of a safety event). To help mitigate this, individuals with a
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 analysis will be restricted to individuals enrolling within 10 days of first 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 se veral key
design features, including the large study size, the broad definition of healthcare workers, and placement of study navigators in geographically diverse vaccination sites. Additionally, the study team will regularly review aggregate participant characteristics for representativeness and will tailor engagement strategies address any areas of underrepresentation. The observational nature of this study also has the potential to introduce bias due to measured and
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unmeasured confounders. Bias reduction strategies include capture of clinical covariates /
employment characteristics , robust follow- up data ascertainment through a central call center
to reduce missing data, and self- matched comparative analyses .
9.10. Other A spects
Not applic able.
10. PROTECTION OF HU MAN 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 Verily in encrypted electronic form and will be
password protected through a multi- authenticated system 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 event of a potential personal data bre ach, Verily shall be responsible for determining whether a personal
data breach has in fact occurred and, if so, providing breach notifications as required by law.
To protect the rights and freedoms of natural persons with regard to the processing of
perso nal data, when study data are compiled for transfer to Pfizer and other authorized
parties, any participant names will be removed and will be replaced by a single, specific, numerical code. All other identifiable data transferred to Pfizer or other authori zed parties
will be identified by this single, participant -specific code. Verily will maintain a confidential
list of participants who participated in the study, linking each participant’s numerical code to
his or her actual identity. ” In case of data tran sfer, Pfizer will maintain high standards of
confidentiality and protection of participant s’ personal data consistent with the research
agreement and applicable privacy laws.
10.2. Participant Consent
At enrollment, HCWs who are existing members of the Healthcare Worker Exposure
Response and Outcomes (HERO) Registry will be instructed to log in to their existing
profile, complete an informed consent form (ICF) and medical release form, and enroll.
Eligible individuals not yet enrolled in HERO but wanting to participate in this vaccine study
will be enrolled in the HERO Registry and then directed to complete the study- specific ICF
and medical release form, and enroll. Electronic consent will be obtained by Verily’s
Baseline Platform, which currently supports the HERO registry.
The Baseline Platform is compliant 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
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verification. Password management. Verily leverages Google’s password policy
designed to enhance system security by encouraging users to employ strong
passwords and use them properly.
Authentication Verily uses a user ID management system (Gaia) to
authenticate users via Single Sign On (SSO).
Access Management Verily restricts access to the Basel ine Platform and its data to
only authorized users or processes, based on the principle of
strict need -to-know and least privilege.
Password
Management Verily leverages Google’s password policy designed to
enhance system security by encouraging users t o employ
strong passwords and use them properly .
b. HIPAA: The Baseline platform’s ISO 27001 controls map to the HIPAA Security Rule (for more, please see
HIPAA Security Rule Crosswalk to NIST Cybersecurity
Framework ).
10.3. Participant Withdrawal
Participants will be followed until participant closeout, withdrawal of consent, or death. A participant may withdraw from the study at any time at his/her own request, or may be
withdrawn at any time at the discretion of the principal investigator for saf ety, behavioral,
compliance, or administrative reasons. This is expected to be uncommon.
Those who withdraw from the study will be asked to continue on study follow-up with
limited participation through study closeout. Limited participation may include a c all at
12 months and 24 months or collection of medical records to ascertain possible safety events .
If the participant withdraws consent for disclosure of future information, the sponsor may
retain and continue to use any data collected before such a with drawal of consent.
10.4. Institutional R eview B oard (IRB)/Independent Ethics C ommittee (IEC)
It is the responsibility of the DCRI to have prospective approval of the study protocol, protocol amendments, materials describing the consent process, and other relevan t
documents, (eg, recruitment advertisements ), if applicable, from the IRB/IEC. All
correspondence with the IRB/IEC should be retained by the DCRI. Copies of IRB/IEC approvals should be forwarded to Pfizer. All study procedures and materials will be reviewed and approved by a central IRB (Western IRB).
10.5. Ethical C onduct of the S tudy
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 Pharmacoepidemiology Practices (GPP) issued by the
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International Society for Pharmacoepidemiology, and Good Epidemiological Practice (GEP)
guidelines issued by the International Epidemiological Association (IEA).
11. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE
REACTIONS
To address the safety 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 Registry opt to participate and complete a web -based data collection tool. T he
data collection tool completed by the HERO R egistry participants is designed to provide
preliminary
information on the occurrence of a potential safety event of interest or other
clinically significant diagnos is.
The second component entails secondary data collection, in which the HERO Registry participant self -report ed events are examined via review of the participant’s medical record.
The DCRI Call Center will request medical record s for any participants who reported in the
data collection tool a potential safety event of interest or other clinically significant
diagnosis. The CEA group will review the medical records as part of the adjudication process designed to confirm events for inclusion in the statistical analyses (Section 9.7).
The requirements to report to Pfizer Safety any product safety information volunteered by a
participant during an interaction with the DCRI Call Center or discovered during medical
record review 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 study participants could specify information that may constitute product safety information. However, it is possible that a study participant may volunteer product safety information to DCRI Call C enter staff during
completion of a survey assessment by phone (a “res cue” assessment when the participant is
non-responsive to online prompts), or for any other reason (e.g., seeking information about the purpose of the study); this information must be reported as described below.
The following safety events must be reported on the non-interventional study (NIS) adverse
event monitoring (AEM) Report Form: serious and non-serious AEs when associated with
the use of the Pfizer product, and scenarios involving exposure during pregnancy, exposure during breast feeding, medication error, overdose, misuse, extravasation, lack of efficacy and occupational exposure (all reportable, regardless of whether associated with an AE) ,
when associated with the use of a Pfizer product.
In the event that a study participant volunteers product safety information, DCRI Call Center
staff must complete the NIS 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
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Form * is the study participant’s contact information; complete contact information should be
obtained so that, once the NIS AEM Report Form is sent to Pfizer, the NIS 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 any query from a study participant must complete the following Pfizer training requirements:
• “YRR Training for Vendors Working on Pfizer Studies (excluding interventional clinical studie s and non-interventional primary data collection studies with
sites/investigators)
”.
*Non-Interventional Study Adverse Event Report Form for Protocols without Stipulated Active Collection of
Adverse Events ; this type of report is managed 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 by the trainee) as a record of comp letion of the training, which must be kept in a retrievable
format. DCRI Call Center will also provide copies of all signed training certificates to Pfizer.
Re-training must be completed on an annual basis using the most current Your Reporting
Responsibili ties 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 records, images of physician 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 by a temporal relationship between drug administration and an A E, but must be based on a definite
statement of causality by a healthcare provider linking drug administration to the AE.
The requirements for reporting safety events on the NIS AEM Report Form** to Pfizer
Safety are as follows:
• All serious and non- seriou s AEs with explicit attribution to any Pfizer drug
that
appear in the reviewed information must be recorded on the chart abstraction form and reported, within 24 hours of awareness, to Pfizer Safety 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 Safety using the NIS AEM Report Form.
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For these AEs with an explicit attribution or scenarios involving exposure to a Pfizer product,
the safety 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 NIS AEM Report Form may not necessarily be completed, as the form designates, since not all elements will be av ailable 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 NIS AEM Report Form, thus allowing the report to be considered a valid one in accordance with pharmacovigilance legislation. All identifiers will be limited to generalities, such as the statement “A 35 -year-old female...” or “An elderly
male...” Other identifiers will have been removed.
Additionally, the onset/start dates and stop dates for “Illness”, “Study Drug”, and “Drug
Name” may be documented in month/year ( MMM/ YYYYyy) format rather than identifying
the actual date of occurrence wi thin the month /year of occurrence in the day/month/year
(DD/MMM/YYYY ) format.
All research staff members must complete the following Pfizer training requirements:
• “YRR Training for Vendors Working on Pfizer Studies (excluding interventional clinica l 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 by 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.
12. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS
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 presentation at national meetings and publication in peer-reviewed journals.
In the event of any prohibition or restriction imposed (eg, clinical hold) by an applicable
competent authority in any area of the world, or if the investigator at DCRI or Verily i s aware
of any new information which might influence the evaluation of the benefits and risks of a Pfizer product , Pfizer sh ould be informed immediately.
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In addition, the investigator will inform Pfizer immediately of any urgent safety measures
taken by the DCRI or Verily to protect the study participants against any immediate hazard, and of any serious breaches of this NI (observational) study protocol that the DCRI or Verily becomes aware of.
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13. 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/emergen cies/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 Systems 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 ISoP. Guidelines for good pharmacoepidemiol ogy practice
(GPP). Pharmacoepidemiol Drug Saf. 2016;25(1):2-10.
8. Anderson S. CBER Plans for Monitoring COVID- 19 Vaccine Safety 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/COVID -Anderson.pdf.
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14. LIST OF TABLES
Table 1. HERO Registry Participants (Preliminary Data)
Table 2. Current Demographic Composition of the Registry (Preliminary Data)
Table 3. Study Variables
Table 4. Schedule of Assessments
Table 5. Estimated Precision of Observed Event Rates
15. LIST OF FIGURES
Figure 1. Overall Study Design
Figure 2. Confirmation of Safety Events of Interest During Follow-up
Figure 3. Data Flow Diagram
ANNEX 1. LIST OF STAND ALONE DOCUMENTS
To be added when protocol finalized. ANNEX 2. ADDITIONAL INFORMATION
N/A.
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