Document text
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON -INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
NON- INTERVENTIONAL ( NI)STUDY INTERIM REPORT
PASS Information
Title Post-Emergency Use Authorization Active
Safety Surveillance Study among Individuals
in the Veteran’s Affairs Health Sy stem
Receiving Pfizer -BioNTech Coronavirus
Disease 2019 (COVID -19) Vaccine
Protocol number C4591012
Version identifier for the interim study
report1.0
Date 22June 2021
EU Post Authorization Study (PAS)
register numberEUPAS39779
Active substance COVID -19 mRNA Vaccine is single -stranded,
5’-capped messenger RNA (mRNA) produced
using a cell -free in vitro transcription from the
corresponding DNA templates, encoding the
viral spike (S) protein of SARS -CoV -2.
Medicinal product Pfizer -BioNT ech COVID -19 Vaccine
Joint PASS No
Research question and objectives Research question: what are the incidence
rates of safet y events of interest (based on
adverse events of special interest [AESI ])
among individuals vaccinated with Pfizer -
BioNTech COVID -19 vaccine within the US
Veterans Health Administration (VHA)
system overall and in sub -cohorts of interest,
as compared to expected rates of those events?
Primary study objectives:
To assess whether individuals in the
VHA s ystem experience increased risk
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 1
FDA-CBER-2021-5683-1076042
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON -INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
of safet y events of interest following
receipt of Pfizer -BioNTech COVID-19
vaccine; and
To assess whether sub- cohorts of
interest (i.e., immunocompromised,
elderl y, individuals with specific
comorbidities, individuals receiving
only one dose of Pfizer -BioN Tech
COVID -19 vaccine, and individuals
with prior SARS -CoV -2 infection) in
the VHA s ystem experience increased
risk of safet y events of interest
following receipt of Pfizer -BioNTech
COVID -19 vaccine.
Secondary study objective:
To characterize utilization patterns of
Pfizer -BioNTech COVID- 19 vaccine
among individuals within the VHA,
including estimating the proportion of
individuals receiving vaccine, two-
dose vaccine completion rate, and
distribution of time gaps between the
first and second dose, demographics
and health histories of recipients,
overall and among the sub -cohorts of
interest.
Country of study United States
Authors Yinong Young- Xu, ScD, MA, MS
Director, Clinical Epidemiology Program
Veteran s Affairs Medical Center
White River Junction, VT
Cynthia de Luise, PhD, MPH
Senior Epidemiologist/ Safet y Surveillance
Research Scientist; Risk Management and
Safety Surveillance Research
Pfizer, I nc.
New York, NY
Mei Sheng Duh, ScD, MPH
Managing Principal and Chief Epidemiologist
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 2
FDA-CBER-2021-5683-1076043
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON -INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
Analy sis Group, Inc.
Boston, MA
This document contains confidential information belonging to Pfizer. Except as otherw ise agreed to in
writing, by accepting or reviewing this document, you agree to hold this in formation in confidence and not
copy or disclose it to others (except where required by applicable law ) or use it for unauthorized purposes. In
the event of any actual or suspected breach of this obligation, Pfizer must be promptly notified.
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 3
FDA-CBER-2021-5683-1076044
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON -INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
TABLE OF CONTENTS
LIST OF TABLES ..................................................................................................................... 7
LIST OF FIGURES ................................................................................................................... 7
1. ABSTRACT (STAND -ALONE DOCUMENT) ...................................................................9
2. LIST OF ABBREVIAT IONS .............................................................................................. 10
3. INVESTIGATORS .............................................................................................................. 12
4. OTHER RESPONSI BLE PARTIES .................................................................................... 13
5. MILESTONES ..................................................................................................................... 13
6. RATIONALE AND BAC KGROUND ................................................................................ 14
7. RES EARCH QUESTION AND O BJECTI VES ................................................................ .15
8. AMENDMENTS AND UP DATES ..................................................................................... 16
9. RESEARCH METHODS ....................................................................................................16
9.1. Study Design ........................................................................................................... 16
9.2. Setting ...................................................................................................................... 17
9.3. Subjects ................................................................................................................... 18
Inclusion Criteria ............................................................................................. 18
9.3.1.1. Pfizer -BioNTech COVID -19 Vaccine Sample ..................................18
9.3.1.2. Seasonal Influenza Vaccine Sample .................................................. 18
Exclusion Criteria ............................................................................................ 19
9.3.2.1. Pfizer -BioNTech COVID -19 Vaccine Sample ..................................19
9.3.2.2. Seasonal Influenza Vaccine Sample .................................................. 19
Subgroups ........................................................................................................19
9.4. Variables .................................................................................................................. 19
Outcomes ......................................................................................................... 19
Exposures of I nterest ....................................................................................... 20
9.4.2.1. Pfizer -BioNTech COVID -19 Vaccine Groups of Interest ................. 20
Baseline Characteristics ................................................................................... 20
9.5. Data Sources and Measurement .............................................................................. 21
VHA EMR Database ....................................................................................... 22
Measurement ...................................................................................................23
9.5.2.1. Outcomes ........................................................................................... 23
9.5.2.2. Exposures of I nterest .........................................................................23
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 4
FDA-CBER-2021-5683-1076045
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON -INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
9.5.2.3. Baseline Characteristics .....................................................................24
9.6. Bias .......................................................................................................................... 25
9.7. Study Size ................................................................................................................ 26
Power............................................................................................................... 26
9.8. Data Transformation ............................................................................................... 27
9.9. Sta tistical Methods ..................................................................................................27
Main Summary Measures ................................................................................ 27
9.9.1.1. Baseline Characteristics .....................................................................27
9.9.1.2. Pfizer -BioNTech COVID -19 Vaccine Utilization Patterns ............... 27
9.9.1.3. Safet y Signal Analysis .......................................................................28
Main Statistical Methods ................................................................................. 29
9.9.2.1. Subgroup Analy ses............................................................................ 30
Missing Values ................................................................................................ 30
Sensi tivity Analy ses........................................................................................ 31
Amendments to the Statistical Analy sis Plan .................................................. 31
9.10. Quality Control ......................................................................................................31
9.11. Protection of Human Subjects ............................................................................... 31
10. RESUL TS.......................................................................................................................... 33
10.1. Descriptive Data ....................................................................................................38
Baseline Characteristics................................................................................. 38
10.1.1.1. Pfizer -BioNTech COVID -19 Vaccine Sample ................................ 38
10.1.1.2. Seasonal Influenza Vaccine Sample ................................................ 38
10.2. Vaccination utilization patterns ............................................................................. 47
10.3. Safet y signal anal yses............................................................................................ 51
10.4. Main results ........................................................................................................... 51
10.5. Other an alyses.......................................................................................................51
10.6. Adverse events / adverse reactions ........................................................................51
11. DI SCUSSION .................................................................................................................... 51
11.1. Summary of key results ......................................................................................... 51
11.2. L imitations ............................................................................................................ 52
11.3. Generalizability .....................................................................................................54
11.4. I nterpretation ......................................................................................................... 54
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 5
FDA-CBER-2021-5683-1076046
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON -INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
12. OTHER INFORMATIO N ................................ ................................ ................................ .55
13. CONCL USIONS ................................ ................................ ................................ ................ 55
14. REFERENCES ................................ ................................ ................................ .................. 56
15. LIST OF SOURCE T ABLES AND FIGURES ................................ ................................ .63
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 6
FDA-CBER-2021-5683-1076047
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON -INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
LIST OF TABLES
Table 1. Calendar Time Distribution for the Receipt of Pfizer- BioNTech
COVID -19 Vaccine (from December 11, 2020 to March 12, 2021)
or Seasonal Influenza Vaccine (from 2014/2015 to 2018/ 2019
influenza seasons) in the VHA Database ................................ .................. 35
Table 2. Basel ine Demographic Characteristics of Individuals who Received
Pfizer -BioNTech COVID- 19 Vaccine or Seasonal I nfluenza
Vaccine[1]................................ ................................ ................................ ..39
Table 3. Baseline Clinical Characteristics of Individuals who Received
Pfizer -BioNTech COVID- 19 Vaccine or Seasonal I nfluenza
Vaccine[1]................................ ................................ ................................ ..43
Table 4. Vaccine Utilization Patterns among Individuals who Received
Pfizer -BioNTech COVID- 19 Vaccine ................................ ...................... 48
Table 5. Vaccine Dos es among Individuals who Received Pfizer -BioNTech
COVID -19 Vaccine ................................ ................................ .................. 49
LIST OF FIGURES
Figure 1. Sample Selection of Individuals who Received Pfizer -BioNTech
COVID -19 Vaccine (from December 11, 2020 to March 12, 2021)
or Seasonal Influenza Vaccine (from October 1, 2014 to May 31,
2019) in the VHA Database................................ ................................ ......34
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 7
FDA-CBER-2021-5683-1076048
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON -INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
Annex 1. List of stand -alone documents
Appendix 1. SIGNATURES
Appendix 2.PROTOCOL
Appendix 3. I NVESTIGATORS AND CORRESPONDI NG IND EPENDENT
ETHI CS COMMITTEES (I ECs) OR INSTITUTIONAL REVIEW BOARDS (I RBs)
Not applicable
Appendix 4.STATI STICAL ANALYSI S PL AN
Not applicable
Appendix 5.SAMPLE CASE REPORT FORM (CRF) / DATA COLLECTION TOOL
(DCT))
Not applicable
Appendix 6.SAMPLE STANDAR D SUBJECT INFORMATION SHEET AND
INFORMED CONSENT DOCUMENT (I CD)
Not applicable
Appendix 7.LIST OF SUBJECT DATA LI STINGS
Not applicable
Appendix 8. ADDI TIONAL DOCUMENTS
Not applicable
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 8
FDA-CBER-2021-5683-1076049
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON -INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
1.ABSTRACT (STAND -ALONE DOCUMEN T)
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 9
FDA-CBER-2021-5683-1076050
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON -INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
2.LIST OF ABBREVIATIONS
Abbreviation Definition
ACOS Associate Chief of Staff
ACIP Advisory Committee on Immunization Practices
AESI Adverse event of special interest
BMI Body mass index
CAD Coronary artery disease
CI Confidence interval
CCI Charlson comorbidity index
CDC Centers for Disease Control and Prevention
CDW Corporate Data Warehouse
CEP Clinical Epidemiology Program
CHAMPVA Civilian Health and Medical Program of the Department of Veterans
Affairs
CIOMS Council for International Organizations of Medical Sciences
COPD Chronic obstructive pulmonary disease
COVID -19 Coronavirus disease 2019
CPT Current Procedural Terminology
CRADA Cooperative Research and Data Agreement
CRF Case report form
Tdap Diphtheria, tetanus and (acellular) pertussis
Td Diphtheria and tetanus
ED Emergency department
EMA European Medicines Agency
EMR Electronic medical record
ENCePP European Network of Centres for Pharmacoepidemiology and
Pharmacovigilance
EUA Emergency Use Authorization
EU PAS European Union Post -Authorization Safety
FDA Food and Drug Administration
GEP Good Epidemiological Practice
GPP Good Pharmacoepidemiology Practices
HBV Hepatitis B virus
HCPCS Healthcare Common Procedure Coding S ystem
HCV Hepatitis C virus
HIV Human immunodeficiency virus
HPV Human papillomavirus
HRU Healthcare resource utilization
ICD-9-CM International Classification of Diseases, Ninth Revision, Clinical
Modification
ICD-10-CM International Classification of Diseases, Tenth Revision, Clini cal
Modification
ICD-10-PCS International Classification of Diseases , Tenth Revision, Procedure
Coding Sy stem
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 10
FDA-CBER-2021-5683-1076051
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON -INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
Abbreviation Definition
IEA International Epidemiological Association
IEC Independent Ethics Committee
IQR Interquartile range
IRB Institutional Review Board
IRR Incidence rate ratio
MaxSPRT Maximized sequential probability ratio test
MenACWY Meningococcal conjugate
MenB Serogroup B meningococcal
mRNA Messenger RiboNucleic Acid
NDC National Drug Code
NI Non-interventional
NNERC VAMC Northern New England Research Consortium V eterans Affairs Medical
Centers
OR Odds ratio
PASS Post-Authorization Safety Study
PCAFC Program of Comprehensive Assistance for Family Caregivers
PHI Protected Health Information
R&D Research and Development
RCA Rapid cy cle analy sis
RPSS Research Protocol Safety Survey
RR Relative risk
SAP Statistical analy sis plan
SARS -CoV -2 Severe acute respiratory syndrome coronavirus 2
SCRI Self-controlled risk interval
SD Standard deviation
SPEAC Safety Platform for Emergency vACcines
SRSS Subcommittee on Research Safet y and Securit y
US United States
VA Department of Veterans Affairs
VAIRRS Veterans Affairs Innovation and Research Review Sy stem
VHA Veterans Health Administration
VINCI VA Informatics and Computing Infrastructure
VINNE Veteran’s I nstitutional Review Board of Northern New England
VISN Veterans Integrated Service Networks
VSD Vaccine Safet y Datalink
WHO World Health Organization
WOC Without compensation
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 11
FDA-CBER-2021-5683-1076052
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON -INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
3. INVESTIGATORS
Nam e, degree(s) Title Affiliation Address
Yinong Young -Xu,
ScD, MA, MSPrincipal Investigator Veterans Affairs (VA)
Medical Center163 Veterans Drive,
White River Junction,
VT 05009
Cynthia de Luise,
PhD, MPHCo-Investigator Pfizer, Inc. 235 East 42nd Street,
New York, NY 10017
Mei Sheng Duh,
ScD, MPHCo-Investigator Analysis Group, Inc. 111 Huntington Ave
14thFloor
Boston, MA 02199
Harvard T. H. Chan
School of Public Health677 Huntington Ave
Boston, MA 02115
Maral DerSarkissian,
PhD Co-Investigator Analysis Group, Inc. 333 South Hope Street
27th Floor
Los Angeles, CA
90071
Fielding School of
Public Health,
University of California,
Los Angeles650 Charles E Young
Drive South
Los Angeles, CA
90095
Rachel Bhak,
MSCo-Investigator Analysis Group, Inc. 111 Huntington Ave
14thFloor
Boston, MA 02199
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 12
FDA-CBER-2021-5683-1076053
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON -INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
4.OTHER RESPONSIBLE PA RTIES
Not applicable .
5.MILESTONES
Milestone Planned date
VHA CRADA execution 8 January 2021
Determination of IRB exemption[1]10February 2021
Determination of Research Safet y and Securit y
exemption[2]17 February 2021
Approval by Designated Member Review[3]26 February 2021
Registration in the EU PAS register 5 March 2021
Start of data collection 11 March 2021[4]
Interim reports 22June 2021
31December 2021
30June 2022
31 December 2022
End of data colle ction 10June 2023[5]
Final study report 31December 2023
Abbreviations: ACOS, Associate Chief of Staff; COVID -19, Coronavirus disease 2019; CRADA,
Cooperative Research and Data Agreement; IRB, Institutional Revie w Board; EUA, E mergency Use
Authorization; FDA, Food and Drug Administration; NNERC VAMC, Northern New England Research
Consortium VA Medical Centers; R&D, Research and Development; SRSS, Subcommittee on Research
Safety and Security; VA, Veterans Affairs; VAIRRS, VA Innovation and Research Review System; VINNE,
Veteran’s IRB of Northern New England; VHA, Veterans Health Administration ; US, United States .
Notes:
[1] IRB e xemption determination was granted in accordance w ith 38 CFR 16 bytheVeteran’s IRB of
Northern New England (VINNE), White River Junction VA Medical Center, White River Junction, VT for
the signal detection and signal evaluation phases. Prior to progressing to the signal verification phase for
chart review, a second IRB rev iew application will be submitted for an expedited or full review. The tw o-
stage IRB application process is to expedite the initiation of the project.
[2]Research Safety and Security exemption determination was granted by the Subcommittee on Research
Safety and Security (SRSS), VA Innovation and Research Revie w System (VAIRRS) .
[3] Approved by Associate Chief of Staff for Research and Development (ACOS/R&D) and R&D
Committee of the Northern New England Research Consortium VA Medical Centers (NNERC VAMC).
[4] Start of data collection is the date for starting data extraction for the purposes of the study analysis. The
initial data analysis includes Pfizer -BioNTech COVID -19 vaccine exposures from December 11, 2020 (the
EUA approval date by the US FDA) to Marc h 12, 2021 ( the data cutoff date).
[5] End of data collection is the planned date on which Pfizer -BioNTech COVID -19 vaccine exposure data
reached 30 months post -EUA approval.
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 13
FDA-CBER-2021-5683-1076054
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON -INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
6.RATIONALE AND BACKGR OUND
In March 2020, the World Health Organization (WHO) declared a global pandemic for the
coronavirus disease 2019 (COVID -19) due to the severe acute respiratory syndrome
coronavirus 2 (SARS -CoV -2), which was first identified by public health officials in China
in December 2019.1The COVID -19 pandemic presents an unprecedented public health
crisis. As of May 26, 2021 , over 33.1million COVID -19 cases and 590,000 deaths have been
reported in the United States (US) alone.2To date, the cumulative incidence of COVID -19
has continued to rise, largel y among the elderl y and middle -aged individuals, those with
comorbid conditions, and in settings with high noncompliance with public health
measures .3,4,5COVID -19is a well -adapted highly infectious human pathogen that has
evolved over time to develop multiple variants, including those associated with an increased
risk of transmission and death that were first identified in late 2020 .3,6,7,8
On December 11, 2020, the US Food and Drug Administration (FDA) issued itsfirst
emergency use authorization (EUA) for a vaccine for the prevention of COVID -19disease ,
indicated for individuals 16 y ears of age and older.9This vaccine, developed by Pfizer and
BioNTech (BNT162b2; COMI RNATY®),contains synthetic messenger RNA (mRNA) that
instructs cells in the body to produce the virus’ distinctive “spike” protein that triggers an
immune response against SARS -CoV -2.9The EUA for Pfizer -BioNTech COVID -19vaccine
was based on safety and efficacy data from an ongoing Phase 1/2/3 trialsof approximately
44,000 participants aged 12 y ears and older who were randomized 1:1 to receive Pfizer -
BioNTech COVID -19 vaccine or saline control.10,11The FDA review edsafet y data from
37,586 of the participants 16 y ears of age and older who were followed for a median of two
months after receiving their second dose, andefficacy data from 36,523 participants 12 y ears
of age and older after Day seven following vaccination with dose 2.12,13The efficacy data
reviewed b y the FDA indicated that Pfizer- BioN Tech COVID -19 vaccine was 95% effective
in preventing sy mptomatic COVID -19 disease, while the safet y data indicated that the most
commonly reported side effects, which t ypicall y lasted several day s, were pain at the
injection site, tiredness, headache, muscle pain, chills, joint pain, and fever .13No severe
adverse events were reported that would preclude Pfizer -BioNTech COVID-19 vaccine to
meet the criteria for E UA.13Based on the se safety and efficacy data, as well as a review of
manufacturing information regarding product quality and consistency , the FDA determined
that t he known and potential benefits of the vaccine outweighed the known and potential
risks for the prevention of COVID -19 in individuals 16 y ears of age and older.14
As required b y the FDA EUA,13post-authorization observational studies using real -world
data are needed in order to assess the association between Pfizer -BioNTech COVID-19
vaccine and pre -determined safet y events of interest among individuals who received the
vaccine in both the population at large and in populations of interest (e.g.,
immunocompromised individuals, elderly , and those with specific comorbidities).13Such
post-authorization safety evaluations are important for identify ing rare, unexpected, serious
safet y events of interest in larger populations that may not have been detected during clinical
trials (either due to sample size or selected study populations), and monitoring that the
favorable benefit -risk ratio of the vaccine is maintained post-trial.
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 14
FDA-CBER-2021-5683-1076055
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON -INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
On January 27, 2021 ,Pfizer , in collaboration with the US Veterans Health Administration
(VHA) and Anal ysis Gr oup, submitted a study protocol (protocol C4591012 ;Appendix 2)
for post -EUA active safety surveillance of safet y events of interest among individuals 16
years of age and older in the VHA s ystem. Safet y events of interest for the current stud y
include 42safet y outcomes that were selected based primaril yon the Priority List of Adverse
Events of Special Interest from the Brighton Collaboration’s Safet y Platform for Emergency
vACcines (SPEAC) Project and from the preliminary list of safet y events of intere st
presented at the September 22, 2020, meeting of Centers for Disease Control and
Prevention’s (CDC ’s) Advisory Committee on Immunization Practices (ACI P)on the
enhanced safety monitoring of COVID -19 vaccines .15,16
The study uses data from a large -scale electronic medical record (EMR) database from the
VHA to identify and evaluate rapid -cycle, near real -time potential safet y signals associated
with Pfizer -BioNTech COVID -19 vaccine. The Cooperative Research and Data Agreement
(CRADA) was established betwee n Anal ysis Group and White River Junction VA Medical
Center and Veterans Education and Research Association of Northern New England
(VINNE) for this study on January 8, 2021. Data included for this anal ysis commence d on
December 11, 2020 and will continue through June 10, 2023 – i.e., 30 months following the
issuance of the EUA for Pfizer-BioNTech COVID- 19 vaccine. Four interim reports are
planned on June 30, 2021; December 31, 2021; June 30, 2022; and December 31, 2022 , with
a final report to be issued on December 31, 2023.
In this first interim report, the data included for analy sis spans from December 11, 2020 to
March 12, 2021, and the data were locked on April 26, 2021 . This first interim report
describes the selection of two samples of individuals within the VHA: individuals who
received Pfizer -BioNTech COVID- 19 vaccine between December 11, 2020 ( EUA approval
date b y the US FDA) and March 12, 2021 (data cutoff date), and recipients of seasonal
influenza vaccine(s) during the five prior influenza seasons (2014/2015 through 2018/2019).
The demographic characteristics and vaccine utilization patterns among the two samples of
individuals are described pursuant to the secondary study objective. Due to the short time
between the data lock date and the first interim report issuance date, this report does not
include results from the safet y signal analyses pursuant to the primary study objectives. All
references to the study protocol in this first interim report pertain to the study protocol
Version 1.0 dated January 27, 2021 (see Appendix 2). Meanwhile, a protocol amendment is
currentl y under development to address the FDA’s comments on the study protocol Version
1.0, communicated electronically to Pfizer on May 12, 2021.
This non- interventio nal study was designated as a Post -Authori zation Safety Study (PASS)
and isa commitment to the FDA.
7.RESEARCH QUESTION AN D OBJECTIVES
Research question: what are the incidence rates of safet y events of interest (based on adverse
events of special interest [AESI ]) among individuals vaccinated with Pfizer -BioNTech
COVID -19 vaccine within the US VHA system overall and in sub -cohorts of interest a s
compared to expected rates of those events?
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 15
FDA-CBER-2021-5683-1076056
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON -INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
Primary study objectives:
To assess whether individuals in the VHA s ystem experience increased risk of safet y events
of interest following receipt of Pfizer -BioNTech COVID -19 vaccine ;
To assess whether sub- cohorts of interest (i.e., immunocompromised, e lderly , with specific
comorbidities, individuals receiving onl y one dose of Pfizer -BioNTech COVID- 19 vaccine,
and individuals with prior SARS -CoV -2 infection) in the VHA s ystem experience increased
risk of safet y events of interest following receipt of Pfi zer-BioNTech COVID-19 vaccine.
Secondary study objective :
To characterize utilization patterns of Pfizer -BioNTech COVID -19 vaccine among
individuals within the VHA including estimating the proportion of individuals receiving
vaccine , two-dose vaccine completion rate, and distribution of time gaps between the first
and second dose , demographics and health histories of recipients, overall and among the sub -
cohorts of interest.
This first interim report pertains to the secondary study objective.
8.AMENDME NTS AND UPDATES
None.
9. RESEARCH METHODS
9.1.Study Design
The methodology to address the primary study objectives has not yet been implemented and
thus is not covered in this first interim report. As described in greater detail in the study
protocol ( Appendix 2), this post-EUA active safety surveillance program will employ a
rapid -cycle, longitudinal, observational cohort study design to provide early real- world safet y
information .
The self -controlled risk interval (SCRI) design will be used to sequentially monitor
the occurrence of safet y events of interest while controlling for time -invariant
confounders. The SCRI design uses data from cases (i.e., individuals who experience
safet y events of interest following vaccination) to compare the risk interval followi ng
Pfizer -BioNTech COVID-19 vaccination t o pre -or post -vaccination non -risk
intervals (“pre -vaccination control interval” and “post- vaccination control interval” ,
respectivel y) in the same individual.
An active comparator design will be used to sequentia lly monitor the occurrence of
safet y events of interest among individuals who receive Pfizer -BioNTech COVID -19
vaccinations as compared to recipients of influenza vaccine in the VHA during
October 2014 - May 2015 through October 2018 - May 2019 influenza s easons. Data
in peri -COVID time periods from January 2020 to present are excluded because of
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 16
FDA-CBER-2021-5683-1076057
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON -INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
pandemic -associated under -utilization of health resources and under -reporting of
medical events.
Thus, anal yses to address the study primary objectives will rely on two samples :
1. R ecipients of Pfizer -BioNTech COVID- 19 vaccine after December 11 ,2020 , which
will be included in both the SCRI and active comparator design s; and
2. R ecipients of influenza vaccine(s) between the 2014/2015 influenza season and the
2018/2019 influenza season, which will be only included in the active comparator
design .
With both designs, safet y events of interest will be monitored sequentially every two weeks,
and an y signal that is detected will be further evaluated and verified (e.g., by conducting
multivariate adjustment using Poisson regression, assessing temporal clusters, conducting
medical records review). The rapid cy cle analy sis (RCA) has not y et been initiated and thus
is not included in the current interim report .
The study will b e conducted for a period of 30 months, starting on December 11, 2020
onward, with data collection concluding on June 10, 2023.
9.2. Setting
The study population consists of VHA enrollees, which largel y include veterans, and iskept
asbroad as possible under inclusion and exclusion criteria to be representative of the real -
world population at the VHA receiving Pfizer -BioNTech COVID -19 vaccine.
The study relies on secondary data from the Corporate Data Warehouse (CDW) in the
National V eterans Affairs Health Care Network. The CDW data, which are updated dail y,
include standard EMR for all medical encounter information in the V HA s ystem . Information
is also available on date of death, COVID -19 infection status, and COVID- 19 and seasonal
influenza vaccinat ion status.
The VHA oversees the rollout of both COVI D-19 and seasonal influenza vaccination among
individuals enrolled in the VHA. The VHA delivers vaccines through VHA health care
facilities, community urgent care providers in the VHA’s network, and co mmunity
pharmacies in the VHA’s network.17For seasonal influenza, the VHA vaccination rollout
overlaps with the influenza season, which t ypically starts in October and ends in May of the
following year.18For COVID -19, the VHA vaccination rollout started on December 15, 2020
and is still ongoing in a phased approach, as follows:17
Phase 1a includes the following eligible VHA enrollees: individuals who work or live in
VA community living centers and spinal cord units; who live or work in other long-
term care or congregate (group living) settings and do n ot have access to COVID -19
vaccines in those settings ;who work in cemeteries , and who work as health care
personnel ;
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 17
FDA-CBER-2021-5683-1076058
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON -INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
Phase 1b include sthe following eligible VHA enrollees : veterans who a re at least 75
yearsold; individuals who are essential frontline workers ; who experience
homelessness; who receive hemodial ysis care ; who have had a solid organ transplant
or who are being considered for transplant ; who have spinal cord injuries and
disorders ; and who receive chemotherap y treatment in a clinic or hospital ;
Phase 1c includes the following eligible VHA enrollees : veterans who are 65 to 74 years
old; who are younger than 65 years old and have certain health conditions that are
deemed b y the CDC to be associated with a high risk of severe illness from COVID-
19
; and individuals who are considered essential workers by the CDC and were not
included in Phase 1b ;
After Phase 1c is completed , COVID- 19 vaccin ation will be offered free of charge to all
veterans enrolled in the VHA, caregivers of eligible veterans under the Program of
Comprehensive Assistance for Famil y Caregivers (PCAFC ), and other eligible
individuals (e.g., veteran spouses and dependents) under the Civilian Health and
Medical Program of the Department of Veterans Affairs (CHAMPVA )17
As theVHA’s health care delivery system is organized regionall y around 18 Veterans
Integrated Service Networks (VISNs) across the US ,with each VISN responsible for health
care planning and resource allocation in a particular geographical r egion,17regional
variations may impact the timing of vaccine distribution, particularl y for COVID -19 vaccines
where suppl y was not pre -planned.
9.3.Subjects
Inclusion Criteria
9.3.1.1. Pfizer -BioNTech COVID -19 V accine Sample
Individuals with at least one record of Pfizer -BioNTech COVID -19 vaccine during the period
December 11, 2020 to March 12, 2021; and
Individuals with a t least oneyear of continuous enrol lment in VHA benefits (i.e., the baseline
period) prior to their firstPfizer -BioNTech COVID -19 vaccination date .
9.3.1.2. Seasonal Influenza V accine Sample
Individuals with records of one or more seasonal influenza vaccin e from the 2014/2015
influenza season to the 2018/2019 influenza season, where the influenza season was defined
as the period from October 1 of one year until May 31 of the following year;and
Individuals with at least one year of continuous enrollment in VHA benefits (i.e., the baseline
period) prior to at least one seasonal influenza vaccination date .
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 18
FDA-CBER-2021-5683-1076059
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON -INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
Exclusion C riteria
9.3.2.1. Pfizer -BioNTech COVID -19 V accine Sample
Individuals who received at least one dose of COVID -19 vaccine from a manufacturer other
than Pfizer -BioNTech .
While excluded from the study sample, these individuals were described when characteriz ing
the vaccine utilization patterns of Pfizer -BioNTech COVID -19 vaccine (secondary
objective) .
9.3.2.2. Seasonal Influenza Vaccine Sample
Individuals who have records for more than one seasonal influen za vaccine in the same
influenza season were excluded from that influenza season .
Subgroups
Safety surveillance, which is not included in this first interim report ,willbe conducted for
subgroups of interest (i.e.,immunocompromised individuals , different age groups with a
focus on elderl y, individuals with specific comorbidities, individuals receiving onl y one dose
of Pfizer -BioNTech COVID -19 vaccine, individuals with prior SARS -CoV -2 infection, and
individuals likely to receive all their care from VA facilities [i.e., individuals with regular use
of VHA medical care, VA priority group 1 veterans ])as outlined in Section 9.2.3 of the study
protocol ( Appendix 2).
9.4. Variables
This section includes a listing of the key variables for the current stud y, including outcomes,
exposures, and baseline characteristics. For details on the measurement of these variables in
the CDW data ,please see Section 9.5.2.
Outcomes
Outcomes include 42 safety events of interest (Table 15.2 ). The list of outcome safet y events
may be modified over time as new safet y information about the COVID -19 vaccines
emerges.
Safety event sof interest will only be counted as outcom es when observed during a pre-
specified risk interval (e.g., within two days of vaccination for anaph ylaxis; within 42 day s of
vaccination for Bell’s palsy or thrombocy topenia ) without any other diagnosis codes for the
same safet y event of interest in a pr e-specified clean window (e.g., six months before that
date for anaph ylaxis; one y ear before that date for Bell’s pals y or t hrombocy topenia ). The
duration of the risk interval and the duration of the clean window for a given safet y event of
interest were determined based on biological plausibility and precedents in the literature
when the safet y event of interest is vaccine -related (Section 9.3.3 of the study protocol ;
Appendix 2). D etails on the measurement of outcomes in the CDW data are presented in
Section 9.5.2 below.
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 19
FDA-CBER-2021-5683-1076060
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON -INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
Due to the short time between the data lock date and the first interim report issuance date,
this report does not include results from the safet y signal analyses pursuant to the primary
study objectives .
Exposure sof Interest
Vaccination with Pfizer -BioNTech COVID -19 vaccine is the main exposure of interest. Risk
of safet y events of interest during the pre -specified risk window post -Pfizer -BioNTech
COVID- 19 vaccine will be compared with risk during pre -defined pre-and/or post -
vaccination control interval s within the same individuals (SCRI design) or compared to
similar risk intervals post -influenza vaccination among r ecipients of influenza vaccine(s)
between the 2014/2015 through 2018/2019 influenza seasons (active comparator design).
Details on the measurement of Pfizer -BioNTech COVID -19 and seasonal influenza vaccine
receipt in the CDW data are presented in Section 9.5.2 .
9.4.2.1. Pfizer -BioNTech COVID -19 Vaccine Groups of Interest
Some recipients of Pfizer -BioNTech COVID -19 vaccine may have received seasonal
influenza vaccine in the 2020/2021 influenza season , which may impact their observed rates
of safet y events of interest. As described in Section 9.3.1.1 of the study protocol ( Appendix
2),additional analyses will be conducted among subsets of the study population based on (1)
whether they received the influenza vaccine in the 2020/2021 influenza season, and (2) the
timing of the influenza vaccine relative to Pfizer -BioNTech COVID -19vaccine in the
2020/2021 season .
Baseline Characteristics
The following baseline demographic and clinical characteristics were assessed based on a
one-year baseline period prior to the date of vaccination with Pfizer -BioNTech COVID -19
vaccin e and prior to the date of seasonal influenza vaccination for active comparators (unless
otherwise specified) . Operational definitions for baseline characteristics variables listed in
this section are provided in Table 15.1 , while measurement details are provided in
Section 9.5.2.3 .
Demographics:
Age (<16, 16 -64, 65- 74, >74years)
Sex
Race/ethnicit y
VHA service area - US region
Clinical characteristics:
Smoking status
Body mass index (BMI ; measured based on a two -year baseline period , for reasons
described in Section 11.1)
History of anaph ylaxis/allergic reactions
Previous anaph ylaxis of vaccine component
History of hospitalizations
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 20
FDA-CBER-2021-5683-1076061
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON -INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
Charlson comorbidity index (CCI)
Selected comorbidities
Autoimmune disease
Asthma
Bleeding diathesis or condition associated with prolonged bleeding
Cancer
Cardiovascular conditions ( e.g., heart failure, coronary artery disease [CAD] ,
cardiom yopathies)
Chronic kid ney disease/dialy sis
Chronic obstructive pulmonary disease (C OPD )/interstitial lung disease
Diabetes mellitus (i.e., Ty pe 1 or Ty pe 2 diabetes)
Down sy ndrome
Sickle cell disease
Hepatitis B virus infection (HBV)
Hepatitis C virus infection (HCV)
Human immu nodeficiency virus infection (HIV)
Hyperlipidemia
Hypertension
Liver disease
Neurological disease
Other immune deficiencies
Solid organ transplant
Venous thromboembolism (VTE)
Immunization history
Seasonal influenza (during the 2020/2021 influenza season; reported for
recipients of Pfizer -BioNTech COVID -19 vaccine)
Tetanus diphtheria and pertussis (Tdap or Td)
Chickenpox (V aricella)
Shingles (H erpes zoster recombinant and/or live)
Human papillomavirus (HPV)
Pneumococ cal conjugate
Pneumococcal pol ysaccharide
Hepatitis A
Hepatitis B
Meningococcal conjugate (MenACWY) and serogroup B meningococcal
(MenB)
Haemophilus influenza type b
9.5. Data Sources and M easurement
The study relies on secondary EMR data from the VHA CDW , which is a centralized data
warehouse that is updated daily . For this first interim report, the study used data from the
CDW that were available at the time of data cut -off on March 12, 2021.
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 21
FDA-CBER-2021-5683-1076062
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON -INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
VHA EMR Database
The VHA is the largest integrated health care s ystem in the US, providing comprehensive
healthcare services, including primary , specialt y and inpatient care, rehabilitation, long -term
and home care, and other services to over nine million veterans th rough 1,293 health care
facilities, including 171 medical centers and 1, 112outpatient sites of vary ing care
complexity .19In addition to v eterans, VHA enrollees may also include employ ees and certain
categories of famil y members of the veterans, but these are a minority among all VHA
enrollees.
The CDW consolidates data from the VHA’s EMR sy stem and contains information on all
outpatient visits, hospital stays, treatments, dispensed prescriptions, immunizations, and lab
results. Although the VHA may have financ ially covered/reimbursed care provided at non -
VHA facilities, the EMR sy stem (and thus the CDW) does not capture information on visits
at non- VHA facilities. The CDW stores data in separate databases based on ty pe of clinical
information (e.g., inpatient medication, inpatient admission, outpatient medication, outpatient
visit). The VHA also maintains its own mortality data , in which 99% of enrollees’ deaths are
reported within one month of occurrence and which are based on information collected from
multiple sources: family members, VHA hospitals, the National Cemetery Administration,
Medicare vital status file, and the Social Securit y Administration. Death ascertainment from
these sources in the VH A data has be en shown to have 98% sensitivit y.20
Each VHA enrollee is assigned a unique identification number in the CDW, to allow for
longitudinal follow -up as well as for cross- reference across the various separate databases.
For example, in each inpatient admission r ecord, information on the primary discharge
diagnosis (and as man y as 15 secondary diagnoses), date of admission, date of discharge, and
length of stay is available. This record can then be linked to other information pertaining to
that inpatient stay loca ted in other files, including procedures that t he individual underwent
during hospitalization, medical specialty of the provider, and prescriptions dispensed
(inpatient and outpatient). Other files are structured similarly , and therefore can be linked
together to provide comprehensive information about the individual and his/her medical
encounters.
The VHA database is an appropriate data source to provide early data on potential rare safety
events of interest associated with Pfizer -BioNTech COVID -19 vaccine. First, given that
some groups of veterans were prioritized in the first wave of vaccinations,17VHA enrollees
were among the first Pfizer -BioNTech COVID -19 vaccine recipients in the US ,enabling
early safet y anal yses. Second, t he VHA dat a are refreshed daily , and thus enable rapid data
analysis. Third, the VHA population isolder and has more comorbid conditions21than the
general population, thus maximizing the chance of capturing rare safet y events of interest in
early analyses ,following the initial phases of Pfizer -BioNTech COVID -19 va ccine
distribution. Finally , subgroup anal yses will be performed among individuals who are in the
VA priority group 1 (i.e., individuals who have the highest levels of service connected
disability22and are categorized as the highest priority for VHA care ),which will ensure that
the individual is more likely to receive all their care from a VA facility , hence minimizing
the potential for missing data .
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 22
FDA-CBER-2021-5683-1076063
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON -INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
To the extent that the individuals in the VHA population are different from individuals
outside of the VHA, the results may not be generalizable to the broader US population. For
example, the VHA includes predominantl y men (approximately 90%), findings from this
study may not be generalizable to women in the US.
Measurement
9.5.2.1. Outcomes
Operational definitions of the 42 safet y events of interest, based on International
Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM)and
Internation al Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM)
diagnosis codes ,are detailed in Table 15.2 .23,24,25,26,27The list of outcome safet y events may
be modified over time as new safety information about the COVID- 19 vaccines emerges.
Outpatient (including emergency department [ ED]) and/or inpatient settings will be used to
identify safet y events of interest, depending on the type of event , as described in Section
9.3.3 of the protocol ( Appendix 2). Any record of death will be captured, regardless of
whether the individual died in a healthcare or non- healthcare setting.
9.5.2.2. Exposures of Interest
Administration of Pfizer -BioNTech COVID -19 vaccine post -EUA approval and date of
immunization for each dose were identified in the CDW data based on an y of the following
codes:
Current Procedural Terminology (CPT) code s; or
91300, corresponding to severe acute respiratory syndrome coronavirus 2 (SARS -
CoV -2) (coronavirus disease [COVID -19]) vaccine, mRNALNP, spike protein,
preservative free, 30 mcg/0.3mL dosage, diluent reconstituted, for intramuscu lar
use)or
Healthcare Common Procedure Coding S ystem (HCPCS) codes ; or
0001A , corresponding to administration of first dose (ADM SARS -CoV -2 30
mcg/0.3mL 1st)
0002A , corresponding to administration of second dose (ADM SARS -CoV -2 30
mcg/0.3mL 2nd)28,29or
National Drug Codes (NDCs) codes ; or
10-digit NDCs: 59267 -1000 -1, 59267 -1000- 2, 59267 -1000-3)
11-digit NDCs: 59267 -1000 -01, 59267 -1000- 02, 59267- 1000- 0330
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 23
FDA-CBER-2021-5683-1076064
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON -INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
Immunization records that contain data on vaccine code descriptor, vaccine
manufacturer (i.e., Pfizer ), lot number, injection site, and date(s) of immunization.28
Administration of the seasonal influenza vaccine during 2014/2015 through 2018/2019
influenza seasons and date of immunization were identified in the CDW data based on an y of
the following (seeTable 15.3 for additional details) :
CPT codes; or
HCP CS codes; or
10 and 11- digit NDCs; or
Immunization records that contain data on vaccine code descriptor, vaccine
manufacturer, lot number, injection site, and date(s) of immunization.
9.5.2.3. Baseline Characteristics
Operational definitions for all diagnoses, procedures, and immunizations are p rovide d in
Table 15.1. In short, diagnoses were identified b y ICD-10-CM diagnosis codes, procedures
were identified b y ICD-10-PCS (procedure coding sy stem) codes, CPT, or HCPCS procedure
codes, while vaccines were identified by NDC , CPT, and HCPCS codes , and immunization
records .Baseline demographic and clinical characteristics reported in this first interim report
were based on a one -year baseline period ( with two exceptions, specified below ) and
included the following:
Demographic variables included age, sex, race/ethnicity , and VHA service area.
Demographic variables were extracted from the CDW data at the time of the receipt
of the first dose of Pfizer -BioNTech COVID -19 vaccine (for Pfizer -BioNTech
COVID -19 vaccine sample) and at the time of the receipt of the seasonal influenza
vaccine (for the seasonal influenza vaccine sample) , and were well- populated.
BMI was extracted from the CDW based on the most recent BMI record for the
individual in the y ear before the receipt of the first dose of Pfizer -BioNTech COVID-
19 vaccine and/orreceipt of the seasonal influenza vaccine. Given the high proportion
of missing values for BMI in Pfizer -BioNTech COVID-19 vaccine sample, which
was likely due to a higher utilization of telemedicine encounters during the COVID -
19 pandemic ,31BMI was therefore reported based on the two y ears prior to the receipt
of the first dose of Pfizer -BioNTech COVID -19 vaccine and/orreceipt of the seasonal
influenza vaccine.
History of hospitalizations included the number of hospitalizations recorded in the
CDW in the y ear before the receipt of the first dose of Pfizer -BioNTech COVID-19
vaccine and/orreceipt of the seasonal influenza vaccine.
Smoking status, h istory of anaph ylaxis/allergic reactions , previous anaph ylaxis of
vaccine component, comorbidities included in the CCI ,32and other relevant
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 24
FDA-CBER-2021-5683-1076065
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON -INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
comorbidities were identified in the CDW data ( based on diagnosis codes that
conform with the ICD-9-CM and ICD-10 -CM codes) in the y ear before the receipt of
the first dose of Pfizer -BioNTech COVID -19 vaccine and/orreceipt of the seasonal
influenza vaccine ( seeTable 15.1 formore details on the specific codes used).
Other immunizations were identified in the immunization file from the CDW based
on CPT codes, HCPCS codes, NDC codes, and other immunization records (please
see Table 15.1 for more details on the specific codes used).
Non-seasonal immunizations (i.e., all immunizations other than seasonal
influenza) were measured in the y ear preceding the vaccination; seasonal
influenza was measured only among individuals who received Pfizer- BioNTech
COVID -19 vaccine during the influenz a season (i.e., from October 1 to May 31)
that overlaps or precedes the date when the individual received Pfizer -BioNTech
COVID -19 vaccine.
9.6.Bias
Several approaches were incorporated in the stud y design and will be implemented in
forthcoming safet y signal analyses to reduce bias in this study .
First, the SCRI and active comparator designs complement each other in mitigat ingbiasin
the current study . Speci fically , the SCRI design will use individuals as their own controls,
thus removing an y potential confounding bias due to factors that do not change over short
periods of time within an individual (e.g., age, sex , chronic conditions). While the SCRI
design that uses a pre-vaccination control interval may be subject to detection bias because
individuals pay more attention to possible safety events post-vaccination compared to pre -
vaccination , the SCRI design that uses a post -vaccination control interval is not subject to
this bias because both the risk and control intervals are defined post -vaccination .33Despite
the ability to adjust for time -invariant confounders, the SCRI design may have limited power
to estimate expected rates for very rare safety events of interest .34Thus, the SCRI design will
be complemented by an active comparator design that will derive expected rates of safet y
events of interest from historical controls vac cinated for seasonal influenza . To mitigate
potential confounding bias in the active comparator design , historical controls will only
include individuals vaccinated for seasonal influenza (individuals who are open to
vaccination are expected to share similarities) and additional Poisson multivariate adjusted
regression models will be implemented for safet y events of interest that are detected and
persist after conducting quality assurance.
Second, when a signal is detected in the signal detection phase, additional analy ses will be
performed to evaluate the signal and identify other possible sources of bias. For example, the
impact of seasonal variations in the rates of the safety events of interest (e.g., mortalit y rates
vary during the year, with higher rates in winter months and lower rates in summer months34)
will be assessed using a seasonality -adjusted case- centered anal ysis that focuses on the subset
of individuals in Pfizer -BioNTech COVID -19 vaccine sample who experienced a safet y
event of interest (i.e., cases) .Temporal scan statistics will be calculated to empirically
identify temporal clusters of safet y events of interest during the risk interval.
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 25
FDA-CBER-2021-5683-1076066
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON -INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
Third, for both the SCRI and active comparator designs, biasmay result from the
misclassification or imprecision of the time interval during which rates of safet y events of
interest are measured. I t is possible that some safety events of interest do not have a precise
time interval for which to evaluate risk –for example ,if biological plausibility is not well
known or the diagnostic time window is more dela yed than anticipated. In these cases,
misspecification of the risk (and control) intervals could result in outcome misclassification
and introduce bias, often toward the null. For instance, the assumption of a longer risk
interval than is true may result i n “washing out” the signal, and an erroneously short risk
interval may similarly result in underestimation of the effect when using post -vaccination
time intervals for self -control. To address this, the length of the risk intervals may be varied
in sensiti vity anal ysestoincrease the likelihood that the safet y risk is detected accuratel y.
Finally , if individuals receive Pfizer -BioNTech COVID -19 vaccine or the seasonal influenza
vaccine outside of a VHA facility , this information will not be captured in th e VHA EMR
system , resulting in exposure misclassifi cation . Veterans with secondary insurance and
veterans who are 65 y ears of age or older who have Medicare may be more likely to receive
services outside VHA . One study on VHA enrollees in seven different s tates found that
among all individuals admitted to VHA hospitals in 2007, one -fifth also had a non- VHA
hospitalization during that y ear.35To mitigate this limitation , subgroups of individuals who
receive care regularl y at VHA facilities, as well as those w ith priority group 1 status (i.e.,
veterans with service -connected disability that is >50% disabling, veterans who are unable to
work, or veterans who have received the Medal of Honor)22, will be examined to ensure that
their healthcare data are complete to the extent possible in the CDW.
Further discussion of potential sources of bias in the study, including exposure
misclassification, is provided in Section 11.2.
9.7.Study Size
A total of 750,999 individuals received at least one dose of Pfizer -BioNTech COVID- 19
vaccine from December 11, 2020 to March 12, 2021 in the VHA database . The active
comparator group includes a fix ed cohort of 4,277,220 historical seasonal influenza vaccine
recipients who received a total of 10,529,071 seasonal influenza vaccines across successive
influenza seasons between 2014/2015 through 2018/2019.
Power
Power calculations for the safet y signal analyses (study primary objective )will be conducted
for each safet y event of interest using the power calculation feature in the sequential R
package for RCA developed by Kulldorff et al.36The power calculations are not included in
this first interim repo rt as they require the calculation of the background incidence of each
safet y event of interest among the historical seasonal influenza active comparator group as an
input and this analy sishas not y et been performed , and will be included in the second interim
report .
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 26
FDA-CBER-2021-5683-1076067
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON -INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
9.8.Data Transformation
Not applicable.
9.9.Statistical M ethods
Main Summary M easures
9.9.1.1. Baseline Characteristics
Baseline demographics and clinical characteristics were summarized using mean, standard
deviation (SD) ,and median (interquartile range [IQR]) values for continuous variables and
frequency distributions for categorical variables . Baseline demographics and clinical
characteristics were summarized and compared between Pfizer -BioNTech COVID -19
vaccine re cipients (at the time of the first dose of Pfizer -BioNTech COVID -19 vaccine) and
for active comparators who received seasonal influenza vaccination (at the time of the most
recent seasonal influenza vaccine received from the 201 4/2015 to the 2018/2019 influenza
season to facilitate comparison with Pfizer -BioNTech COVID -19 vaccine recipients).
Baseline demographics and clinical characteristics were also summarized at the time of each
seasonal influenza vaccine observed in the seasonal influenza sample from the 201 4/2015 to
the 2018/2019 influenza season (i.e., allowing multiple measurements per individual) as the
background incidence of the safet y events of interest will be assessed in the risk intervals
following all observed seasonal influenza vaccines (to increase the chance of capturing rare
safet y events of interest).
Standardized differences were used to compare baseline demographics and clinical
characteristics between individuals vaccinated with Pfizer -BioNTech COVID -19 vacci ne (at
the time of the first Pfizer -BioNTech COVID -19 vaccine dose) and those vaccinated for
seasonal influenza (at the time of the most recent seasonal influenza vaccine ). For a given
covariate, the standardized difference scales the difference inmeans between the sa mples (if
the covariate is continuous) or the difference in proportions ( ifthe covariate is binary ) by the
standard deviation of that covariate in both samples combined. Because the standardized
difference is a measure of the magnitude of di fference in means/proportions between two
groups that does not depend on sample size ,37it is a more appropriate estimate than statistics
that rely on statistical significance (e.g., t -test for continuous variables or chi -square tests for
binary variables) for studies with very large samples ,such as the current study .
In the current study , a standardized difference >10% was used to identify an imbalance
between charac teristics of recipients of Pfizer -BioNTech COVID -19 vaccine and seasonal
influenza vaccine .38,39The study useda conservative threshold to indicate covariate
imbalance (other authors proposed thresholds ranging from > 10% to > 25%40,41,42,43) to
capture an y possible differences between the study samples that need to be accounted for in
the signal evaluation phase.
9.9.1.2. Pfizer -BioNTech COVID -19 Vaccine Utilization Patterns
Descriptive statistics were used to summarize Pfizer -BioNTech COVID -19 vacc ine
utilization patterns, including the proportion of individuals who received the vaccine, two-
dose completion rate, distribution of time gaps between the first and second vaccine dose,
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 27
FDA-CBER-2021-5683-1076068
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON -INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
and description of care setting where immunization was received (e.g. , outpatient clinic,
pharmacy , inpatient ward, other). These utilization patterns were summarized using the mean
(SD) and median (IQR) values for continuous variables ,and frequency distributions for
categorical variables. Individuals with at least one hea lthcare encounter in the VHA from
December 11, 2020 to March 12, 2021 served as the expected number of individuals who
would be eligible for Pfizer -BioNTech COVID -19 vaccine, as they had been activel y
receiving care through the VHA during the time period w hen Pfizer -BioNTech C OVID -19
vaccine was available. The count and proportion of individuals who received COVID -19
vaccine (s) from different manufacturer sin addition to Pfizer -BioNTech COVID -19 vaccine
were also reported.
9.9.1.3. Safety Signal Analysis
Safety signal anal ysis was not performed in this first interim report . As described in greater
detail in Section 9.7 of the study protocol ( Appendix 2), the safety signal analy sis will rel y on
the following key measures, as appropriate for each study phase :
The s ignal detection phase will be conducted every two weeks for all safety events of
interest , and will include the following anal yses:
For analy ses based on the SCRI design using pre- vaccination control intervals ,
relative risks (RR s) and corresponding confi dence intervals (CIs) will be estimated to
compare the risks of safety events of interest during the risk interval immediately
following Pfizer -BioNTech COVID -19 vaccination and the risks of safet y events of
interest during pre -specified control intervals before Pfizer -BioNTech COVID-19
vaccination . Please see Section 9.9.2 for additional methodological details.
For analy ses based on the active comparator design, RRs and corresponding CIs will
be estimated to com pare the risks of safet y events of interest during the risk interval
immediately following Pfizer -BioNTech COVID- 19 vaccin ation among Pfizer -
BioNTech COVID -19 vaccine recipients andthe risk interval immediately following
seasonal influenza vaccine among historical seasonal influenza vaccine recipients .
The signal evaluation phase will be conducted after a signal is detected (if the signal
persists following post -signal quality assurance ), and will include the following analyses:
For analy ses based on the SCRI design, RRs and corresponding CIs will also be
calculated using post -vaccination control intervals in order to account for potential
detection bias that may impact SCRI anal yses using pre -vaccination control intervals
(due to enhanced vigilance for sa fety events after vaccination compared to the pre-
vaccination period).
For analy ses based on the active comparator design, incidence rate ratios (IRRs) and
corresponding CIs will be calculated using a multivariate adjusted Poisson regression
model to accou nt for baseline differences between Pfizer -BioNTech COVID- 19 and
seasonal influenza vaccinees .
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 28
FDA-CBER-2021-5683-1076069
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON -INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
Temporal scan statistics for each safet y event of interest will be estimated to
determine whether temporal clusters are present in the occurrence of the safety e vents
of interest post -vaccination .
Kaplan -Meier (KM) methods will be used to analy ze time -to-safet y event of interest ,
with censoring at the end of the risk interva l for individuals who did not experience
the safet y event of interest by the end of the ri sk interval .
If a defined COVID- 19 season is established,44additional analy ses will be performed
to address seasonality :
A seasonalit y-adjusted case -centered anal ysis may be conducted to account for
bias caused b y seasonality of safet y events of interest and vaccination.45,46From
this analy sis, odds ratio s(ORs) and corresponding CIs will be reported.
If it is determined in the literature that the COVID -19 pandemic exhibits
seasonality , anal yses may be conducted at the end of the defined COVID- 19
season. This end -of-season anal ysis will use data from the SCRI design with post-
vaccination control intervals, from which RR and corresponding CIs will be
reported . An end-of-season anal ysis using data from the active comparator design
with historical seasonal influenza vaccination recipients may also be conducted ,
from which RRs and corresponding C Iswill be reported.
Finally , the end-of-surveillance safet y analysiswill be a one -time anal ysis conducted
after the final data lock at the study end (July 14, 2023), for safety events of interest with
signals detected, and will include the following analy ses:
Using data from the SCRI design, t he RR for safety events of interest with signals
detected during the risk interval compared to the control interval and corresponding
CIs will be estimated .In addition,
using data from the active comparator design,
safet y events of interest with signals detected in the risk interval among individuals
that received Pfizer -BioNTech COVID -19 vaccine will be compared to sa fety events
of interest observed in the risk intervals among individuals that received seasonal
influenza vaccination in the five prior seasons to estimate RRs and corresponding
CIs.
Main Statistical M ethods
Statistical methods for the safet y signal anal ysishave not been implemented in this first
interim report . As described in greater detail in the study protocol (Appendix 2), the safety
signal analy sis will be performed for signal detection, evaluation, and verification .
In the signal detection phase, the SCRI anal ysis will only include pre -vaccination control
intervals as the post -vaccination control intervals will require a longer time to accumulate
and will be used in the signal evaluation phase. To account for multiple testing and bi- weekl y
review o f the data, the maximized sequential probability ratio test (MaxSPRT) using a
binomial probability model will be applied. For comparison with individuals who received
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 29
FDA-CBER-2021-5683-1076070
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON -INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
seasonal influenza vaccination (active comparator design), the Poisson -based MaxSPRT will
be applied.
For each safet y event of interest, the safet y signal anal ysis will commence once at least 3
events occur. This approach is consistent with the FDA’s COVID- 19 Vaccine Safet y
Surveillance Project to avoid spurious signals from a few earl y event s.47Critical values will
be determined for each safety event of interest based on the historical incidence rate,
expected upper limit of the number of events under the null hypothesis, and pre -specified
significance level and power. Signals will be detecte d if the critical values are reached via the
SCRI or active comparator anal ysis. Incidence rates will also be calculated, and K Mmethods
will be used to anal yze time to safet y event of interest.
If signals are detected for safety events of interest based on the analysis described above,
signal evaluation will be conducted to refine and confirm such detections. This will include
comprehensive quality assurance ( e.g., checking for possible duplicati ons of claims or
medical records, checking for unusual clustering in claim or medical record accrual b y
service date for potential coding issues, check ingfor geographical distribution of cases that
may be related to lot numbers or diagnostic practice) ,and multivariate adjustment using
Poisson regression to account for baseline differences between Pfizer -BioNTech COVID -19
vaccinated and the active comparator cohort . SCRI anal yses using the post -vaccination
control intervals will be conducted as an addition al inferential analysis once enough post-
vaccination time has accumulated. Lastly , the assessment of temporal clustering will also be
conducted.
The signal verification phase will include the d iagnostic validation of the safet y events of
interest detected in the signal evaluation phase ,and will rely on adjudication of medical
records in a representative sample of cases by VHA clinicians for outcome verification. For
rare events, potentiall y all cases may be adjudicated.
End- of-season anal yses (over the cou rse of the 30 -month period, pending if COVID- 19
seasonality is established ) and an end -of-surveillance analy sis (i.e., at 30 months) will also be
conducted.
9.9.2.1. Subgroup Analyses
Separate anal yses of baseline characteristics, vaccine utilization patterns, sig nal detection,
signal evaluation, and signal verification in subgroups of interest (defined in Section 9.3.3)
will be conducted in subseque nt interim reports pending feasibility , sample size, and data
availability .
Missing Values
No VHA members had missing date of birth or sex data. A very small minority of individual s
had both sexes documented. Those members were categorized as “unknown” ( Table 2 ).
Individuals with m issing race/ethnicity or BMI data w erealso categorized as “ unknown ”
(Table 3 ).
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 30
FDA-CBER-2021-5683-1076071
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON -INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
Sensitivity A nalyses
No sensitivity anal yses were performed in this interim report.
Amendments to the Statistical Analysis P lan
Not applicable.
9.10. Quality C ontrol
For this first interim report, data for the stud y wereextracted from EMR databases in the
CDW of the VHA. Each data content area in the CDW wassubjected to similar checks, from
high-level variable name/ty pe checks, to detailed trending comparisons. As an example, the
diagnostic data was subject to the following checks:
Checked that variables referenced in the data dictionary exist and are of appropriate
length and t ype
Checked the diagnosis code type (i.e., ICD -9-CM, ICD -10-CM)wascorrectly
matched with the codes defining specific diagnoses of interest ;
Assessed p ercent ages andrates in the light of literature and substantive knowledge ;
Checked percentages and rates of missing data;
Checked that both inpatient and outpatient (which include emergency room visits)
diagnosis codes were captured .
Data retrieval wascoordinated b y twoexperienced programmer s/anal ysts. The anal yst wrote
programming for retrieval of each data element from the electronic databases. Double
programming w asperformed; results/datasets w erecompared, and discrepancies were
resolved. All tables w ere reviewed b y the project manager and the principal investigator and
evaluate dfor internal consistency of counts and totals. All calculated variables w erechecked
against the component variables (cross tabs) to ensure accuracy. For example, categor ical age
wascompared with continuous age to confirm that each category of age contained only
individuals of the expected age ranges within that category.
9.11. Protection of Human S ubjects
Patient I nformation and Consent
Protected health information (PHI) will not be reused or disclosed to an y other person or
entity except as required by law, for authorized oversight of the research, or for other
research for which the use or disclosure of PHI would be permitted by applicable regulation.
The PHI obtained were th e minimum necessary to conduct the research. Information
regarding Institutional Review Board (IRB) exemption is provided in the below section.
The project isled by the VHA, with Dr. Yinong Young -Xu, Director of the Clinical
Epidemiology Program ( CEP), serving as the Principal Investigator. The CEP at White River
Junction VA Medical Center will conduct this safety surveillance stud y with sponsorship
from Pfizer and ass istance from Anal ysis Group . Analy sis Group employ ees underwent
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 31
FDA-CBER-2021-5683-1076072
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON -INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
background checks b y the VHA and received without compensation employ ee (WOC) status
to access the CDW VHA data files hosted on the VA servers through the VA Informatics and
Computing I nfrastructure (VINCI) platform. CDW VHA data will not be transferred off from
the VA serve rs, to either Pfizer or Anal ysis Group. Only Analy sis Group WOC employ ees
have access to de- identified patient- level data on the VINCI platform and they will only
share summary statistics based on these data with study investigators who are not WOC
employ ees.
All parties complied and will comply with all applicable laws, including laws regarding the
implementation of organizational and technical measures to ensure personal data protection .
Given the sensitive nature of healthcare data, comprehensive securit ymeasures are
implemented to ensure the confidentialit y, integrity , and protection of individuals enrolled in
the VHA ’sprivacy and healthcare data. Only VA employ ees, including those with WOC
employ ee status, who have completed necessary VA training and h ave proper clearance will
access and analyze data on secure VA servers and behind necessary firewalls, under the
direction and supervision of Dr. Young- Xu. Other measures will include omitting individual
names or other directl y identifiable data in an yreports, publications, or other disclosures,
except where required b y applicable laws.
To protect the rights and freedoms of natural individuals with regard to the processing of
personal data, when study data are compiled for transfer to Pfizer and other authorized
parties, an y individual names will be removed and will be replaced b y a single, specific,
numerical code. All other identifiable data transferred to Pfizer or other authorized parties
will be identified by this single, individual -specific code. In case of data transfer, Pfizer will
maintain high standards of confidentialit y and protection of individuals’ personal data
consistent with the vendor contract, and applicable privacy laws.
Independent Ethics Committee (IEC)/Institutional Review Board ( IRB)
The study protocol that outlined the plan for the signal detection and signal evaluation phases
of the study , which includes the anal yses presented in thi s interim study report, was
determined on February 10, 2021 to be exempt from IRB review by the V INNE, White River
Junction VA Medical Center, White River Junction, VT in accordance with 38 CFR 16. Prior
to progressing to the signal verification phase for chart review a second IRB review
application will be submitted for an expedited or full review. The two- stage I RB application
process was implemented to expedite the initiation of the project. On February 17, 2021 the
study protocol was reviewed and determined to be exempt from future r esearch safet y and
securit y review by theSubcommittee on Research Safety and Security (SRSS), VA
Innovation and Research Review Sy stem (VAIRRS) .Finally , on February 26, 2021, the
study protocol was granted approv al by Designated M ember Review of the Northern New
England Research Consortium VA M edical Centers (NNERC VAMC) Research and
Development Committee and the Associate Chief of Staff for Research and Development
(ACOS/R&D) .All correspondence with the IRB was retained and forwarded to Pfizer .
Research Standards of the Study Conduct
The study was conducted in accordance with legal and regulatory requirements, as well as
with scientific purpose, value and rigor and follow generall y accepted research practices
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 32
FDA-CBER-2021-5683-1076073
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON -INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
described in Guidelines for Good Pharmacoepidemiology Practices (GPP) issued by the
International Societ y for Pharmacoepidemiology (ISPE) ,48Good Epidemiological Practice
(GEP) guidelines issued by the International Epidemiological Association (IEA),49
International Ethical Guidelines for Epidemiological Research issued b y the Counci l for
International Organizations of Medical Sciences (CI OMS), European Medicines Agency
(EMA) European Network of Centres for Pharmacoepidemiology and Pharmacovigilance
(ENCePP) Guide on Methodological Standards in Pharmacoepidemiology , and FDA
Guidance for Industry : Good Pharmacovigilance and Pharmacoepidemiologic Assessment,
FDA Guidance for Industry and FDA Staff: Best Practices for Conducting and Reporting of
Pharmacoepidemiologic Safety Studies Using Electronic Healthcare Data Sets.50
10.RESULTS
Figure 1presents a summary of the sample selection for this interim report. After appl ying all
eligibility criteria, the Pfizer -BioNTech COVID -19 vaccine sample consist ed of a total of
750,999 eligible individuals who received their first Pfizer -BioNTech COVID -19 vaccination
from December 11, 2020 to March 12, 2021. The seasonal influenza vaccine sample
consisted of a total of 4,277,220 eligible individuals who received up to five seasonal
influenza vaccines from the 2014/2015 influenza season to the 2018/2019 influenza season
(i.e., one vaccine per influenza season). Among the individuals in the seasonal influenza
sample that satisf iedthe study eligibility criteria , a total of 10,529,071 seasonal influenza
vaccines were observed (for an average of 2.46 seasonal influenza vaccines per individual).
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 33
FDA-CBER-2021-5683-1076074
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON -INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
Figure 1. Sample Selection of Individuals who R eceived Pfizer -BioNTech COVID -19
Vaccine (from Decembe r 11, 2020 to March 12, 2021) or Seasonal Influenza
Vaccine (from October 1, 2014 to May 31, 2019) in the VHA Databas e
Abbreviations: COVID -19, Coronavirus Disease 2019; EUA, Emergency Use Authorization; FDA, Food and
Drug Administration; VHA, Veterans Health Administration.
Notes:
[1] December 11, 2020 is the date w hen the F DAissued the EUA for Pfizer -BioNTech COVID -19 Vaccine;
March 12, 2021 is the date of data cutoff .
[2] All data records (including vaccination records) observed prior to an individu al's date of birth and after an
individual's date of death were considered erroneous and w ere not included.
[3] Influenza seasons started on October 1 of one year and ended on May 31 of the next year (e.g., the
2014/2015 influenza season spanned October 1, 2014 - May 31, 2015).
[4] Individuals who received influenza vaccines in different seasons contributed multiple times to the seasonal
influenza sample. For each individual, eligible influenza vaccines included those from influenza seasons in
which the ind ividual had only a single influenza vaccine record.
[5] Baseline period w as defined as the one year prior to (and not including) the vaccination date.
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 34
FDA-CBER-2021-5683-1076075
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON -INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
Table 1 describes the month and y ear when the first Pfizer -BioNTech COVID -19 vaccine s were administered in Pfizer -BioNTech
COVID -19 vaccine sample and when the seasonal influenza vaccine s were administered in the seasonal influenza vaccine sample. In
the Pfizer -BioNTech COVID-1 9 vaccine sample, most individuals had their first dose of the vaccine in January and February 2021
(39.3% and 37.8%, respectively ). In the seasonal influenza sample, the vaccines were distributed similarly across all influen za
seasons, but with considerab le variation with respect to the month of administration within each influenza season. Specifically,
seasonal influenza vaccines administered in October and November accounted for approximately three quarters of all observed
seasonal influenza vaccines, wh ile the remaining months (December to May ) accounted for only one q uarter of all observed vaccines .
Table 1.Calendar Time Distribution for the Receipt o f Pfizer -BioNTech COVID -19 V accine (from December 11, 2020
to March 12, 2021) or Seasonal Influenza V accine (from 2014/2015 to 2018/ 2019 influenza seasons) in the VHA
Database
Calendar timePfizer -BioNTech
COVID -19 Vaccine
Sample
N = 750,999Seasonal Influenza
Vaccine Sample
N = 4,277,220
First Pfizer-BioNTech
COVID -19 vaccine
dose from December
11, 2020 to March 12,
2021
N = 750,999Most recent seasonal
influenza vaccine
from 2014/2015 to
2018/2019 influenza
seasons
N = 4,277,220All seasonal
influenza vaccine s
from 2014/2015 to
2018/2019 influenza
seasons[1]
N = 10,529,071
Pfizer -BioNTech COVID -19 vaccine
Month when vaccine was received, n (%)
December 2020 (from December 11; 21 day s) 12,880 (1.7) - -
Average number of individuals vaccinated per day[2]613 - -
January 2021 (31 day s) 295,028 (39.3) - -
Average number of individuals vaccinated per day[2]9,517 - -
February 2021 (28 day s) 283,780 (37.8) - -
Average number of individuals vaccinated per day[2]10,135 - -
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 35
FDA-CBER-2021-5683-1076076
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON -INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
Table 1.Calendar Time Distribution for the Receipt o f Pfizer -BioNTech COVID -19 V accine (from December 11, 2020
to March 12, 2021) or Seasonal Influenza V accine (from 2014/2015 to 2018/ 2019 influenza seasons) in the VHA
Database
Calendar timePfizer -BioNTech
COVID -19 Vaccine
Sample
N = 750,999Seasonal Influenza
Vaccine Sample
N = 4,277,220
First Pfizer-BioNTech
COVID -19 vaccine
dose from December
11, 2020 to March 12,
2021
N = 750,999Most recent seasonal
influenza vaccine
from 2014/2015 to
2018/2019 influenza
seasons
N = 4,277,220All seasonal
influenza vaccine s
from 2014/2015 to
2018/2019 influenza
seasons[1]
N = 10,529,071
March 2021 (until March 12; 12 day s) 159,311 (21.2) - -
Average number of individuals vaccinated per day[2]13,276 - -
Seasonal influenza vaccine
Month when vaccine was received (regardless of
year/influenza season)[3], n (%)
October - 2,419,380 (56.6) 5,898,719 (56.0)
November - 886,076 (20.7) 2,269,903 (21.6)
December - 381,404 (8.9) 1,005,034 (9.5)
January - 285,623 (6.7) 672,769 (6.4)
February - 159,617 (3.7) 373,925 (3.6)
March - 94,714 (2.2) 208,398 (2.0)
April - 36,244 (0.8) 73,480 (0.7)
May - 14,162 (0.3) 26,843 (0.3)
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 36
FDA-CBER-2021-5683-1076077
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON -INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
Table 1.Calendar Time Distribution for the Receipt o f Pfizer -BioNTech COVID -19 V accine (from December 11, 2020
to March 12, 2021) or Seasonal Influenza V accine (from 2014/2015 to 2018/ 2019 influenza seasons) in the VHA
Database
Calendar timePfizer -BioNTech
COVID -19 Vaccine
Sample
N = 750,999Seasonal Influenza
Vaccine Sample
N = 4,277,220
First Pfizer-BioNTech
COVID -19 vaccine
dose from December
11, 2020 to March 12,
2021
N = 750,999Most recent seasonal
influenza vaccine
from 2014/2015 to
2018/2019 influenza
seasons
N = 4,277,220All seasonal
influenza vaccine s
from 2014/2015 to
2018/2019 influenza
seasons[1]
N = 10,529,071
Influenza season when vaccine was received[3], n (%)
2014 /2015 - 328,509 (7.7) 2,005,782 (19.0)
2015 /2016 - 391,729 (9.2) 2,066,378 (19.6)
2016 /2017 - 478,070 (11.2) 2,018,667 (19.2)
2017 /2018 - 796,513 (18.6) 2,155,845 (20.5)
2018 /2019 - 2,282,399 (53.4) 2,282,399 (21.7)
Abbreviations: COVID -19, Coronavirus Disease 2019; SD, standard deviation.
Notes:
[1] Individuals who received influenza vaccines in different seasons contributed multiple times to the seasonal influenza sam ple. For each individual,
eligible influenza vaccines included those from influenza seasons in which the individual had only a single influenza vaccine record.
[2] The average number of individuals vaccinated per day was based on all first dose Pfizer- BioNTech COVID -19 vaccinations received in a specific month
divided by the total number of days in the specific month, irrespective of holidays and weekends.
[3] Influenza seasons started on October 1 of one year and ended on May 31 of the next year (e.g., the 2014/2015 influenza se ason spanned O ctober 1, 2014
-May 31, 2015).
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 37
FDA-CBER-2021-5683-1076078
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON -INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
10.1. Descriptive D ata
Baseline Characteristics
10.1.1.1. Pfizer -BioNTech COVID -19 Vaccine Sample
Table 2 and Table 3describe the baseline demographic and clinical characteristics,
respectivel y, of individuals who received Pfizer -BioNTech COVID -19 vaccine andseasonal
influenza vaccine s. The mean age of the r ecipients o f Pfizer -BioNTech COVID -19 vaccine
from Dece mber 11, 2020 to March 12, 2021 was69.8 y ears (median: 72.0 years) and the
sample included 93.2% males and 64.2% White ,non-Hispanics, with the largest proportion
of individuals residing in the South (Table 2 ). Previous and existing s moking status was
documented in the EMR records for 11.4% of individuals and 33.6% ha d a BMI ≥ 30 (obese
and severe obesit y) (Table 2). History of anaph ylaxis/allergic reactions was rare (<1%) . The
mean CCI score was1.0 (median :0.0),and 8.9% individuals were hospitalized in the y ear
preceding Pfizer -BioNTech COVID -19 vaccine. Como rbidities affecting >10% of the sample
included hy pertension (57.8%), hy perlipidemia (49.1%), diabetes (30.8%), cardiovascular
conditions (16.3%; excludes hy pertension), cancer (12.5%), COPD/interstitial lung disease
(12.0%), and chronic kidney disease/dia lysis (11.7%). Approximately one-third of the
individuals in the Pfizer -BioNTech COVID -19 vaccine sample were immunized for seasonal
influenza between October 1, 2020 and the date of their first Pfizer -BioNTech COVID -19
vaccination. Non- seasonal immunizations were rare (<5% users) in the year before Pfizer -
BioNTech COVID -19 vaccine ,except for the S hingles vaccine which was received b y 14.2%
of the individuals in this sample ( Table 3 ).
10.1.1.2. Seasonal Influenza Vaccine Sample
Baseline demographic and clinical characteristics of recipients of the seasonal influenza
vaccine ( atthe time of their most recent seasonal influenza vaccine during the 2014/2015
through 2018/2019 influenza seasons) were generally similar to those of recipients of Pfizer -
BioNTech COVID -19 vaccine sample at the time of their first dose (standardized difference
<10%). However, a few exceptions with standardized differences ≥10% were noted, as
summarized below. With respect to demographic characteristics, compared to the Pfizer -
BioNTech COVID -19 vaccine sample, the seasonal influenza vaccine sample (assessed at the
time of their most recent seasonal influenza vaccine) had a lower proportion of individuals
between 65 and 74 y ears of age (33.8% vs. 41.2%; standardized difference 15.3%) and 75
years of age or older (25.9% vs. 31.6 %; standardized difference 12.5%), a lower proportion
of Blacks (15.4% v s. 20.7%; standardized difference 14.0%), and a higher proportion of
individuals received care in the “Other” (i.e., Puerto Rico) VHA service area (1.1% vs. 0.2%;
standardized difference 10.6%) ( Table 2).Differences were also observed in the history of
other immunizations. The Pfizer -BioNTech COVID -19 vaccine sample had comparable
proportions of comorbidities compared to the seasonal influenza vaccine sample, with the
exception of HBV, which was higher among seasonal influenza vaccine recipients (1.5% vs.
0.2% ; standardized difference 13.6%). As compared to the Pfizer -BioNTech COVID -19
vaccine sample, the seasonal influenza vaccine sample had a higher proportion of individuals
immunized with Tdap or Td, pneumococcal conjugate and pneumococcal
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 38
FDA-CBER-2021-5683-1076079
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON -INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
polysaccharide vaccines (7.5% vs. 3.5%, 7.7% vs. 0.8% and 6.7% vs. 4.3%, respectivel y; standardized differences 17.5%, 35.2% and
10.4%, respectively ) and a lower proportion immunized for Shingles (4.8% vs. 14.2%; standardized difference 32.6%) ( Table 3).
The baseline demographic and clinical characteristics assessed across all seasonal in fluenza vaccinations observed in the seasonal
influenza vaccine sample, (i.e., N = 10,529,071 vaccinations) were numerically similar to those assessed at the time of the m ost recent
seasonal influenza vaccine for individuals in this sample (e.g., mean age: 65.7 y ears vs. 65.4 y ears; males 93.1% vs. 92.6%; White,
non-Hispanics: 70.6% vs. 69.6%; South VHA service area: 43.2 vs. 43.6% [ Table 2]; smoking status: 13.1% vs. 12 .4%; mean BMI:
30.1 vs. 29.9; history of anaph ylaxis/allergic reactions: 0.7% vs. 0.6%; hospitalization in prior y ear: 8.9% vs 9.6%, mean C CI: 0.8 vs.
0.9, respectivel y [Table 3 ]).
Table 2.Baseline Demographic Characteristics of Individuals who Received Pfizer -BioNTech COVID -19 Vaccine or
Seasonal Influenza Vaccine[1]
Characteristics Pfizer -BioNTech
COVID -19
Vaccine SampleSeasonal Influenza
Vaccine Sample[2]Std. Diff. (%)
Pfizer -BioNTech
COVID -19 vs.
Seasonal Influenza
Vaccine SampleSeasonal Influenza
Vaccine Sample[2]
N = 750,999
individualsN = 4,277,220
individualsN = 10,529,071
vaccines
(average 2.46
vaccines/individual[3])
At first dose At most recent
vaccine observed At each vaccine
observed
Age (years), mean ± SD [median][4]69.8 ± 12.3 [72.0] 65.4 ± 15.9 [68.4] 31.1%* 65.7 ± 14.5 [67.9]
Categorical, n (%)
<16 0 (0.0) 1 (0.0) 0.1% 2 (0.0)
16–64 204,189 (27.2) 1,719,739 (40.2) 27.8%* 4,102,639 (39.0)
65–74 309,699 (41.2) 1,447,722 (33.8) 15.3%* 3,926,315 (37.3)
≥75 237,111 (31.6) 1,109,758 (25.9) 12.5%* 2,500,115 (23.7)
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 39
FDA-CBER-2021-5683-1076080
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON -INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
Table 2.Baseline Demographic Characteristics of Individuals who Received Pfizer -BioNTech COVID -19 Vaccine or
Seasonal Influenza Vaccine[1]
Characteristics Pfizer -BioNTech
COVID -19
Vaccine SampleSeasonal Influenza
Vaccine Sample[2]Std. Diff. (%)
Pfizer -BioNTech
COVID -19 vs.
Seasonal Influenza
Vaccine SampleSeasonal Influenza
Vaccine Sample[2]
N = 750,999
individualsN = 4,277,220
individualsN = 10,529,071
vaccines
(average 2.46
vaccines/individual[3])
At first dose At most recent
vaccine observed At each vaccine
observed
Sex, n (%)
Male 700,029 (93.2) 3,959,260 (92.6) 2.5% 9,803,257 (93.1)
Female 50,969 (6.8) 317,955 (7.4) 2.5% 725,802 (6.9)
Unknown 1 (0.0) 5 (0.0) 0.0% 12 (0.0)
Race/ethnicity[5], n (%)
White, non -Hispanic 481,895 (64.2) 2,975,670 (69.6) 11.5%* 7,434,793 (70.6)
Black 155,552 (20.7) 656,649 (15.4) 14.0%* 1,571,550 (14.9)
Hispanic ethnicity , any race 43,650 (5.8) 274,025 (6.4) 2.5% 662,903 (6.3)
Asian 7,212 (1.0) 44,223 (1.0) 0.7% 98,871 (0.9)
Native Hawaiian or Pacific
Islander5,196 (0.7) 32,487 (0.8) 0.8% 80,001 (0.8)
American Indian or Alaskan
Native3,903 (0.5) 28,289 (0.7) 1.8% 67,039 (0.6)
Two or more races 5,122 (0.7) 31,388 (0.7) 0.6% 74,922 (0.7)
Unknown 48,469 (6.5) 234,489 (5.5) 4.1% 538,992 (5.1)
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 40
FDA-CBER-2021-5683-1076081
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON -INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
Table 2.Baseline Demographic Characteristics of Individuals who Received Pfizer -BioNTech COVID -19 Vaccine or
Seasonal Influenza Vaccine[1]
Characteristics Pfizer -BioNTech
COVID -19
Vaccine SampleSeasonal Influenza
Vaccine Sample[2]Std. Diff. (%)
Pfizer -BioNTech
COVID -19 vs.
Seasonal Influenza
Vaccine SampleSeasonal Influenza
Vaccine Sample[2]
N = 750,999
individualsN = 4,277,220
individualsN = 10,529,071
vaccines
(average 2.46
vaccines/individual[3])
At first dose At most recent
vaccine observed At each vaccine
observed
VHA service area -US region[6], n
(%)
South 321,699 (42.8) 1,864,584 (43.6) 1.5% 4,551,767 (43.2)
Midwest 174,882 (23.3) 941,190 (22.0) 3.1% 2,418,497 (23.0)
West 149,526 (19.9) 867,589 (20.3) 0.9% 2,090,837 (19.9)
Northeast 103,061 (13.7) 551,532 (12.9) 2.4% 1,318,221 (12.5)
Other (i.e., Puerto Rico) 1,831 (0.2) 47,366 (1.1) 10.6%* 142,471 (1.4)
Unknown 0 (0.0) 4,959 (0.1) 4.8% 7,278 (0.1)
Abbreviations: SD, standard deviation; Std. Diff., standardized difference; US, United States; VHA, Veterans Health Administration.
Notes:
[1] Baseline period w as defined as the one year prior to (and not including) the vaccination date.
[2] The findings presented for the seasonal influenza vaccine sample for all vaccines observed is informative given that this is the unit of analysis that will be
used in the rapid -cycle safety signal analyses. Standardized differences between the seasonal inf luenza vaccine sample for all vaccines observed and the
Pfizer -BioNTech COVID -19 vaccine sample were not calculated given that they rely on two separate units of analysis (i.e., at the vaccine level vs. at the
individual level). Tw o individuals in the seasonal influenza vaccine sample did not have all information fully extracted at the time of the data lock. These tw o
individuals are currently classified as “Unknown”, “Missing”, or “No” (i.e., as not having the specific characteristic) when data w as unavai lable. Their
information will be updated in subsequent analyses.
[3] Individuals who received influenza vaccines in different seasons contributed multiple times to the seasonal influenza sam ple. For each individual, eligible
influenza vaccines included tho se from influenza seasons in which the individual had only a single influenza vaccine record.
[4] Age on the date of Pfizer -BioNTech COVID -19 vaccination (for Pfizer -BioNTech COVID -19 vaccine recipients) or date of seasonal influenza vaccination
(for activ e com parators), w as reported.
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 41
FDA-CBER-2021-5683-1076082
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON -INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
Table 2.Baseline Demographic Characteristics of Individuals who Received Pfizer -BioNTech COVID -19 Vaccine or
Seasonal Influenza Vaccine[1]
Characteristics Pfizer -BioNTech
COVID -19
Vaccine SampleSeasonal Influenza
Vaccine Sample[2]Std. Diff. (%)
Pfizer -BioNTech
COVID -19 vs.
Seasonal Influenza
Vaccine SampleSeasonal Influenza
Vaccine Sample[2]
N = 750,999
individualsN = 4,277,220
individualsN = 10,529,071
vaccines
(average 2.46
vaccines/individual[3])
At first dose At most recent
vaccine observed At each vaccine
observed
[5] If multiple categories were noted in the data, individuals were classified as two or more races, w ith the exception of Hi spanic ethnicity. If Hispanic
ethnicity was recorded for any individual, they were classified as Hisp anic. Individuals with both known and unknown race categories recorded in the data
were classified into their known category.
[6] The region information associated w ith the most recent healthcare encounte r prior to index date w as used. Midwest included IL, IN, IA, KS, MI, MN, MO,
NE, ND, OH, SD, WI; Northeast included CT, ME, MA, NH, NJ, NY, PA, RI, VT; South included AL, AR, DE, DC, FL, GA, KY, LA, MD, MS, NC, OK,
SC, TN, TX, VA, WV; West included AK, AZ, CA, CO, HI, ID, MT, NV, NM, OR, UT, WA, WY; Other i ncluded Puerto Rico.
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 42
FDA-CBER-2021-5683-1076083
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON -INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
Table 3.Baseline Clinical Characteristics of Individuals who Received Pfizer -BioNTech COVID- 19 Vaccine or Seasonal
Influenza Vaccine[1]
Characteristics Pfizer -BioNTech
COVID -19 Vaccine
SampleSeasonal Influenza
Vaccine Sample[2]Std. Diff. (%)
Pfizer -BioNTech
COVID -19 vs.
Seasonal Influenza
Vaccine SampleSeasonal Influenza
Vaccine Sample[2]
N = 750,999
individualsN = 4,277,220
individualsN = 10,529,071
vaccines
(average 2.46
vaccines/individual[3])
At first dose At most recent
vaccine observedAt each vaccine
observed
Smoking, n (%) 85,251 (11.4) 532,001 (12.4) 3.4% 1,379,342 (13.1)
BMI[4]
BMI known within one -year
baseline period, n (%)296,073 (39.4) 3,018,783 (70.6) 65.9%* 7,571,414 (71.9)
BMI known within two -year
baseline period, n (%)558,911 (74.4) 3,548,170 (83.0) 21.0%* 8,865,904 (84.2)
BMI (kg/m2), mean ± SD
[median]30.0 ± 5.9 [29.3] 29.9 ± 6.0 [29.2] 2.7% 30.1 ± 6.0 [29.4]
BMI category within two -year
baseline period, n (%)
Underweight (<18.5) 4,352 (0.6) 37,046 (0.9) 3.4% 71,330 (0.7)
Normal weight (18.5 –<25) 98,857 (13.2) 681,747 (15.9) 7.9% 1,571,978 (14.9)
Overweight (25– <30) 203,416 (27.1) 1,269,378 (29.7) 5.8% 3,206,893 (30.5)
Obese (30 –<40) 219,554 (29.2) 1,346,430 (31.5) 4.9% 3,464,843 (32.9)
Severe obesit y (≥40) 32,732 (4.4) 213,569 (5.0) 3.0% 550,860 (5.2)
Unknown 192,088 (25.6) 729,050 (17.0) 21.0%* 1,663,167 (15.8)
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 43
FDA-CBER-2021-5683-1076084
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON -INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
Table 3.Baseline Clinical Characteristics of Individuals who Received Pfizer -BioNTech COVID- 19 Vaccine or Seasonal
Influenza Vaccine[1]
Characteristics Pfizer -BioNTech
COVID -19 Vaccine
SampleSeasonal Influenza
Vaccine Sample[2]Std. Diff. (%)
Pfizer -BioNTech
COVID -19 vs.
Seasonal Influenza
Vaccine SampleSeasonal Influenza
Vaccine Sample[2]
N = 750,999
individualsN = 4,277,220
individualsN = 10,529,071
vaccines
(average 2.46
vaccines/individual[3])
At first dose At most recent
vaccine observedAt each vaccine
observed
History of
anaphylaxis/allergic
reactions, n (%)6,755 (0.9) 24,739 (0.6) 3.7% 76,642 (0.7)
Previous anaphylaxis to
vaccine component, n (%)95 (0.0) 233 (0.0) 0.8% 430 (0.0)
History of hospitalizations
Individuals with at least one
hospitalization, n (%)67,009 (8.9) 412,028 (9.6) 2.4% 934,257 (8.9)
Number of hospitalizations,
mean ± SD [median]0.2 ± 0.7 [0.0] 0.2 ± 0.7 [0.0] 2.1% 0.2 ± 0.6 [0.0]
CCI, mean ± SD [median] 1.0 ± 1.6 [0.0] 0.9 ± 1.5 [0.0] 8.3% 0.8 ± 1.4 [0.0]
Comorbidities, n (%)
Hypertension 433,785 (57.8) 2,302,502 (53.8) 7.9% 5,941,440 (56.4)
Hyperlipidemia 368,981 (49.1) 2,037,504 (47.6) 3.0% 5,376,106 (51.1)
Diabetes mellitus (i.e., Ty pe 1
or 2 diabetes)231,010 (30.8) 1,200,288 (28.1) 5.9% 3,125,904 (29.7)
Cardiovascular conditions 122,304 (16.3) 618,950 (14.5) 5.0% 1,395,072 (13.2)
Cancer 93,790 (12.5) 418,659 (9.8) 8.6% 1,078,501 (10.2)
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 44
FDA-CBER-2021-5683-1076085
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON -INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
Table 3.Baseline Clinical Characteristics of Individuals who Received Pfizer -BioNTech COVID- 19 Vaccine or Seasonal
Influenza Vaccine[1]
Characteristics Pfizer -BioNTech
COVID -19 Vaccine
SampleSeasonal Influenza
Vaccine Sample[2]Std. Diff. (%)
Pfizer -BioNTech
COVID -19 vs.
Seasonal Influenza
Vaccine SampleSeasonal Influenza
Vaccine Sample[2]
N = 750,999
individualsN = 4,277,220
individualsN = 10,529,071
vaccines
(average 2.46
vaccines/individual[3])
At first dose At most recent
vaccine observedAt each vaccine
observed
COPD/interstitial lung disease 90,343 (12.0) 543,528 (12.7) 2.1% 1,320,902 (12.5)
Chronic kidney disease/dialy sis 87,644 (11.7) 427,083 (10.0) 5.4% 1,012,975 (9.6)
Neurological disease 51,180 (6.8) 298,956 (7.0) 0.7% 740,193 (7.0)
Liver disease 31,965 (4.3) 133,576 (3.1) 6.0% 297,481 (2.8)
Asthma 28,173 (3.8) 143,231 (3.3) 2.2% 372,693 (3.5)
Autoimmune disease 24,858 (3.3) 134,384 (3.1) 1.0% 401,245 (3.8)
VTE 15,927 (2.1) 70,287 (1.6) 3.5% 167,542 (1.6)
Bleeding diathesis or condition
associated with prolonged
bleeding14,647 (2.0) 76,822 (1.8) 1.1% 181,649 (1.7)
HCV 11,925 (1.6) 91,774 (2.1) 4.1% 212,734 (2.0)
HIV 4,936 (0.7) 22,635 (0.5) 1.7% 63,363 (0.6)
Other immune deficiencies 3,955 (0.5) 18,354 (0.4) 1.4% 52,978 (0.5)
HBV 1,793 (0.2) 63,746 (1.5) 13.6%* 439,674 (4.2)
Sickle cell disease 592 (0.1) 3,356 (0.1) 0.0% 11,220 (0.1)
Solid organ transplant 124 (0.0) 289 (0.0) 0.9% 716 (0.0)
Down sy ndrome 0 (0.0) 88 (0.0) 0.6% 619 (0.0)
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 45
FDA-CBER-2021-5683-1076086
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON -INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
Table 3.Baseline Clinical Characteristics of Individuals who Received Pfizer -BioNTech COVID- 19 Vaccine or Seasonal
Influenza Vaccine[1]
Characteristics Pfizer -BioNTech
COVID -19 Vaccine
SampleSeasonal Influenza
Vaccine Sample[2]Std. Diff. (%)
Pfizer -BioNTech
COVID -19 vs.
Seasonal Influenza
Vaccine SampleSeasonal Influenza
Vaccine Sample[2]
N = 750,999
individualsN = 4,277,220
individualsN = 10,529,071
vaccines
(average 2.46
vaccines/individual[3])
At first dose At most recent
vaccine observedAt each vaccine
observed
Immunization history, n (%)
Seasonal influenza vaccine
(2020/2021 influenza season )[5]283,162 (37.7) - - -
Shingles ( Herpes zoster
recombinant and/or live)106,441 (14.2) 203,315 (4.8) 32.6%* 486,479 (4.6)
Pneumococcal pol ysaccharide 32,542 (4.3) 286,451 (6.7) 10.4%* 759,757 (7.2)
Tdap or Td 26,338 (3.5) 319,721 (7.5) 17.5%* 878,651 (8.3)
Hepatitis B 6,522 (0.9) 35,223 (0.8) 0.5% 85,445 (0.8)
Pneumococcal conjugate 5,682 (0.8) 331,447 (7.7) 35.2%* 1,156,793 (11.0)
Hepatitis A 4,059 (0.5) 25,874 (0.6) 0.9% 58,301 (0.6)
MenACWY and MenB 676 (0.1) 5,230 (0.1) 1.0% 9,189 (0.1)
HPV 442 (0.1) 3,300 (0.1) 0.7% 5,437 (0.1)
Haemophilus influenza ty pe b 194 (0.0) 890 (0.0) 0.3% 2,016 (0.0)
Chickenpox ( Varicella) 134 (0.0) 1,567 (0.0) 1.1% 5,581 (0.1)
Abbreviations: BMI, body mass index; CAD, coronary artery disease; CCI, Charlson Comorbidity Index; COPD, chronic obstructive pulmonary dise ase;
HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; HPV, human papillomavirus; ICD-9/10-CM: International
Classification of Diseases, Ninth/Tenth Revision, Clinical Modification; MenACWY, meningococcal conjugate; MenB, serogroup B meningococcal ;SD,
standard deviation; Std. Diff., standardized difference; Td ap, diphtheria, tetanus and (acellular) pertussis; Td, diphtheria and tetanus; VHA, Veterans Health
Administration; VTE, venous thromboembolism.
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 46
FDA-CBER-2021-5683-1076087
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON -INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
Table 3.Baseline Clinical Characteristics of Individuals who Received Pfizer -BioNTech COVID- 19 Vaccine or Seasonal
Influenza Vaccine[1]
Characteristics Pfizer -BioNTech
COVID -19 Vaccine
SampleSeasonal Influenza
Vaccine Sample[2]Std. Diff. (%)
Pfizer -BioNTech
COVID -19 vs.
Seasonal Influenza
Vaccine SampleSeasonal Influenza
Vaccine Sample[2]
N = 750,999
individualsN = 4,277,220
individualsN = 10,529,071
vaccines
(average 2.46
vaccines/individual[3])
At first dose At most recent
vaccine observedAt each vaccine
observed
Notes:
[1] Baseline period w as defined as the one year prior to (and not including) the vaccination date.
[2] Tw o individuals in the seasonal influenza vaccine sample did not have all information fully extracted at the time of the data lock. These tw o individuals are
currently classified as “Unknown”, “Mi ssing”, or “No” (i.e., as not having the specific characteristic) when data was unavailable. Their information will be
updated in subsequent analyses.
[3] Individuals who received influenza vaccines in different seasons contributed multiple times to the se asonal influenza sample. For each individual, eligible
influenza vaccines included those from influenza seasons in which the individual had only a single influenza vaccine record.
[4] Most recent BMI record during the baseline period prior to vaccination d ate w as included and w as calculated based on individuals height and weight data
as dividing weight in kilograms (kg) by height in meters (m) squared. Individuals with missing BMI or those with BMI <15 or > 60 w ere categorized as
"Unknown".
[5] Vaccinations that were received during the 2020/2021 influenza season between October 1, 2020 and the date of individuals' first Pfizer -BioNTech
COVID -19 vaccination were included.
10.2. Vaccination utilization patterns
The month and y ear of first Pfizer -BioNTech COVID-19 vaccination from December 11 2020 to March 12 2021 were described in
Table 1 inSection 10.1.
Table 4 presents additional details on Pfizer -BioNTech COVID -19 vaccine utilization. Individuals with at least one healthcare
encounter in the VHA from December 11, 2020 to March 12, 2021 served as the expected number of individuals w ho would be
eligible for Pfizer- BioNTech COVID -19 vaccine, as they had been activel y receiving care through the VHA during the time period
when Pfizer-BioNTech COVID- 19 vaccine was available. Among 4,648,524 individuals with at least one healthcare encoun ter during
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 47
FDA-CBER-2021-5683-1076088
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON -INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
the period when administration of Pfizer -BioNTech COVID- 19 vaccines was assessed for this first interim report (i.e., December 11,
2020 to March 12, 2021 assessment period), 793,264 individuals (17.1%) received at least one Pfizer -BioNTech COVID -19 vaccine
dose.Among the latter, 752,904 (94.9%) individuals satisfied the one year of continuous enrollment in VHA healthcare benefits
eligibility criteria , of which most (N = 750,999; 99.7%) only received COVID -19 vaccine(s) from Pfizer -BioNTech and a minority (N
= 1,905; 0.3%) received COVID-19 vaccine (s)from both Pfizer -BioNTech and other manufacturer (s)(96.8% Moderna; 2.9% Johnson
& Johnson; and 0.5% AstraZeneca [ Table 4]) .
Table 4.Vaccine Utilization Patterns among Individuals who Received Pfizer -BioNTech COVID- 19 Vaccine
Individuals with at least one healthcare encounter in the VHA from December 11, 2020 to March 12, 2021 N = 4,648,524
Individuals who received at least one dose of Pfizer-BioNTech COVID- 19 vaccine, n (%) 793,264 (17.1)
Individuals who satisfy the one y ear of continuous enrollment in VHA healthcare benefits sample eligibility
criteria, n (% with at least one dose )752,904 (94.9)
Individuals who received COVID -19 vaccine from Pfizer -BioNTech onl y, n(%with continuous enrollment ) 750,999 (99.7)
Individuals who received COVID -19 vaccine from both Pfizer -BioNTech and another manufacturer[1], n
(%with continuous enrollment )1,905 (0.3)
Moderna , n (% with COVID -19 vaccine from multiple manufacturers ) 1,844 (96.8)
Johnson & Johnson (Janssen) , n (% with COVID -19 vaccine from multiple manufacturers ) 55 (2.9)
AstraZeneca , n (% with COVID -19 vaccine from multiple manufacturers ) 10 (0.5)
Abbreviations: COVID -19, Coronavirus Disease 2019; VHA, Veterans Health Administration .
Note:
[1] Individuals may have had multiple records of COVID -19 vaccines from other manufacturers , which could have been administered either before or after
vaccination with Pfizer -BioNTech COVID -19 vaccine .
Table 5describes the care setting whe rePfizer -BioNTech COVID- 19 vaccine doses were received ,as well as the two -dose
completion rate and timing of doses among Pfizer -BioNTe ch COVID -19 vaccine recipients. T he most common care setting where the
first and second doses of Pfizer -BioNTech COVID- 19 vaccine were received was in outpatient clinics (85.3% and 84.8%,
respectivel y). While onl y 64.6% individuals in the Pfizer -BioNTech C OVID -19 vaccine sample received both doses during the
December 11, 2020 to March 12 , 2021 assessment period, most (94.1%) of those without a second dose had <21 day s follow -up after
the first dose (i.e., less than manufacturer recommended gap between doses) and are therefore considered censored .The two- dose
completion rate among individuals who had ≥21 day s of observation after the first dose was 95.3 %. Of the 485,410 individuals who
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 48
FDA-CBER-2021-5683-1076089
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON -INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
completed two Pfizer-BioNTech COVID- 19 vaccine doses, 70.2% received the second dose exactly 21 day s after the first dose, as
recommended per the product label. Extreme values for the gaps between the two doses (i.e., ≤16 day s or ≥43 day s) were observed for
fewer than 1% of Pfizer -BioNTech COVID -19 vaccine recipients.
Table 5. Vaccine Doses among Individuals who Received Pfizer -BioNTech COVID -19 Vaccine
Pfizer -BioNTech COVID -19 Vaccine Dose 1[1]N = 750,999
Care setting where first Pfizer -BioNTech COVID- 19 vaccine was received, n (%)
Outpatient clinic 640,526 (85.3)
Inpatient ward 1,647 (0.2)
Pharmacy 2 (0.0)
Unknown[2]108,824 (14.5)
Two-dose completion rate[3]
All individuals with first dose, n 750,999
Individuals with two doses observed, n (%) 485,410 (64.6)
Individuals without two doses observed, n (%) 265,589 (35.4)
Individuals with first dose and >21 day s of follow -up between the first dose and data cut -off,
n507,438
Individuals with two doses observed, n (%) 483,555 (95.3)
Individuals without two doses observed, n (%) 23,883 (4.7)
Pfizer -BioNTech COVID -19 Vaccine Dose 2[1]N = 485,410
Care setting where second Pfizer- BioNTech COVID -19 vaccine was received, n (%)
Care setting t ype for second dose
Outpatient clinic 411,644 (84.8)
Inpatient ward 867 (0.2)
Pharmacy 0 (0.0)
Unknown[2]72,899 (15.0)
Different settings for first and second doses, n (%)[4]671 (0.1)
Time gap between first and second Pfizer- BioNTech COVID -19 vaccine doses (day s)
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 49
FDA-CBER-2021-5683-1076090
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON -INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
Table 5. Vaccine Doses among Individuals who Received Pfizer -BioNTech COVID -19 Vaccine
Pfizer -BioNTech COVID -19 Vaccine Dose 1[1]N = 750,999
Mean ± SD 21.3 ± 2.7
Median [I QR] 21.0 [21.0, 21.0]
Categorical, n (%)[5]
≤16 day s 2,494 (0.5)
17-20 day s 63,809 (13.1)
21 day s 340,789 (70.2)
22-27 day s 62,161 (12.8)
28 day s 4,833 (1.0)
29-35 day s 8,657 (1.8)
36-42 day s 1,878 (0.4)
≥43 day s 789 (0.2)
Abbreviations: CDC: US Centers for Disease Control and Prevention; COVID -19, Coronavirus Disease 2019; IQR, interquartile range; SD, standard
deviation.
Notes:
[1] Individuals' first record of Pfizer -BioNTech COVID -19 vaccination was categorized as the first dose. Among individuals with only two Pfizer -BioNTech
COVID -19 vaccination records, the second vaccination record w as categorized as the second dose. Among individuals with more than tw o records of Pfizer -
BioNTech COVID -19 vaccination, the vaccination date closest to 21 days after the first vaccination dose was categorized as the second dose. Among the
750,999 individuals in the Pfizer -BioNTec h COVID -19 vaccine sample, 1,111 (0.1%) individuals had more than tw o records of Pfizer -BioNTech COVID -19
vaccinations.
[2] This category included individuals with vaccination records w ithout care setting information available or indi viduals who had documentation of receiving
one vaccination dose in several different care settings so the care setting could not be determined.
[3] Individuals who received their first COVID -19 vaccine dose in the three weeks prior to March 12, 2021 may no t have had sufficient follow -up time for
their second vaccine dose to be observed.
[4] Individuals who received one of their tw o vaccine doses in an unknown setting were excluded from this count.
[5] According to the CDC's Interim Clinical Considerations f or Use of COVID- 19 Vaccines, the second dose of Pfizer -BioNTech COVID -19 vaccine should
be administered as close to the recommended 21 days after the first dose as possible, but not earlier than 21 days. How ever, second doses administered within
a grace pe riod of 4 days earlier than the recommended date for the second dose are still considered valid. If it is not feasible to adh ere to the recommended
interval and a delay in vaccination is unavoidable, the second dose of Pfizer -BioNTech COVID -19 vaccine may be administered up to 6 w eeks (42 days) after
the first dose .51
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 50
FDA-CBER-2021-5683-1076091
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON- INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
10.3. Safety signal analyses
This interim report focused on baseline demographic and clinical characteristics among
individuals who received Pfizer -BioNTech COVID- 19 vaccine or seasonal influenza vaccine ,
and vaccine utilization patterns among individuals who received Pfizer- BioNTech COVID -
19 vaccine. Results obtained from the real -time, rapid -cycle safet y signal analy ses for Pfizer-
BioNTech COVID -19 vaccine have not y et been initiated and thus are not included in this
first interim report.
10.4. Main results
This interim report focused on baseline demographic and clinical characteristics among
individuals who received Pfizer -BioNTech COVID -19 vaccine or seasonal influenza vaccine ,
and vaccine utilization patterns among individuals who received Pfizer- BioNTech COVID -
19 vaccine. Results obtained from the real -time, rapid -cycle safet y signal analy sesfor Pfizer -
BioNTech COVID -19 vac cine have not y et been initiated due to the short time interval
between the data receipt date and the interim report date, and thus are not included in this
first interim report.
10.5. Other analyses
None.
10.6. Adverse events / adverse reactions
This interim report relies solely on structured data. Thus, the minimum criteria for reporting
an adverse event (i.e., identifiable patient, identifiable reporter, a suspect product, and event)
cannot be met. For additional information regarding adverse event management and
reporting, please see Section 11 of the study protocol ( Appendix 2).
11.DISCUSSION
11.1. Summary of key results
This interim report based on the first three months of the post- EUA experience of Pfizer -
BioNTech COVID -19 vaccine in VHA included 750,999 individuals who received Pfizer -
BioNTech COVID -19 vaccine from December 11, 2020 through March 12, 2021 . The
comparator cohort included 4,277,2 20individuals who received the seasonal influenza
vaccine from the 2014/2015 influenza season to the 2018/2019 influenza seas on. In the
Pfizer -BioNTech COVID- 19 vaccine sample, 72.8% were at least 65 years of age, 93.2%
were males and 64.2% were white, non -Hispanics. While the distribution of sex was
comparable between the two samples (standardized difference 2.5%), individuals in the
Pfizer -BioNTech COVID-19 vaccine sample were older than those in the seasonal influenza
vaccine sample (standardized difference 31.1%). These results are consistent with the CDC
COVID -19 vaccine distribution recommendations, given that the current r eport covers onl y
the first three months of Pfizer -BioNTech COVID-19 vaccine roll out in the VHA, when
older individuals were prioritized for vaccination. The proportion of individuals who were at
least 65 y ears of age in the seasonal influenza vaccine sam ple (59.7 %) is consistent with that
reported b y Luo et al. (2021) in the overall VHA population (59.7%).52As the COVID -19
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 51
FDA-CBER-2021-5683-1076092
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON- INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
vaccination continues to be expanded to y ounger individuals, it is expected that the age gap
will narrow between the Pfizer -BioNTech C OVID -19 vaccine sample and seasonal influenza
sample. Nevertheless, ifdifferences in ages between samples persist, they will be accounted
for in the safety signal analy ses (e.g., by conducting age -stratified safety analy ses or using
standardization method s to age -adjust the expected rates for the adverse events of interest
extracted from the seasonal influenza sample).
While standardized differences for white non- Hispanic and Black categories indicated
imbalance for race/ethnicity between the Pfizer -BioNTech COVID-19 vaccine sample and
the seasonal influenza vaccine sample, the overall race/ethnicity breakdown was largel y
similar in the two samples (W hite, non -Hispanic: 64.2% vs 69.6%, standardized difference
11.5%; Black: 20.7% vs 15.4%, standardized difference 14.0%; all other race/ethnicit y
categories: standardized differences <10%).
A recently published s ystematic review reported that the COVID -19 pand emic decreased
healthcare resource utilization (HRU) b y approximately one -third.53Thereduction in HRU
and enhanced use of telehealth in the US during the COVID- 19 pandemic could have
contributed to the higher proportion of individuals with unknown BMI in the Pfizer -
BioNTech COVID -19 vaccine sample in the one -year period prior to vaccination compared
to the seasonal influenza vaccine sample (standardized difference: 65. 9%), as weight and
height cannot be measured in telehealth settings.54Therefore, a two -year baseline period was
implemented for BM I, which y ielded comparable proportions of obese and severe obesity
categorizations for the two samples (29.2% and 4.4% for the Pfizer -BioNTech COVID -19
vaccine sample and 31.5% and 5.0% for the seasonal influenza samples, respectively ).
Among the estimated 4.6 million individuals with at least one healthcare encounter during
the December 11, 2020 to March 12, 2021 assessment period, the Pfizer- BioNTech COVID -
19 vaccination rate (at least one dose) was 17.1%. While this proportion is lower than the
CDC -reported proportion of individuals greater than 18 y ears of age in the US who received
at least one dose of an y COVID -19 vaccine up until March 12, 2021 in the US (25.5%),55in
the current study only Pfizer -BioNTech CO VID-19 was considered whereas the US statistics
included any COVID -19 vaccine. The two -dose completion rate among individuals who had
≥21 day s of observation after the first dose was 95.3 %.The majorit y of individuals in the
VHA s ystem received Pfizer -BioN Tech COVID -19 vaccination in the outpatient setting
(84.8%). Most individuals in the VHA sy stem who received two doses of Pfizer -BioNTech
COVID -19 vaccine (70.2%) received the second dose precisel y 21 day s following the first
dose, which is consistent with the manufacturer’s guidelines for the Pfizer -BioNTech
COVID -19 vaccine schedule.
11.2. Limitations
While the VHA CDW provides a range of benefits, including its comprehensive structure,
large number of variables, and electronic accessibility , there may be ga ps in the data since
individuals may receive healthcare services outside of VHA facilities that are not recorded in
the CDW . For example, veterans with secondary insurance (e.g., TRICARE t hrough
Department of Defense ,Medicare for those aged 65years of ag e or older ,or Medicaid for
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 52
FDA-CBER-2021-5683-1076093
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON- INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
low socioeconomic group ) may receive health care services outside of VHA facilities . One
study on VHA enrollees in seven states found that of all individuals admitted to VHA
hospitals in 2007, one fifth also had a non -VHA hospit alization during that y ear.35Another
study reported that about 53% of Veterans 65 years of age and older who were duall y eligible
for VHA and Medicare services in 2003 -2004 used both.56As such, if individuals received
Pfizer -BioNTech COVID- 19 vaccine outside of a VHA facility , this information would not
be captured in the data . Similarly , individuals might have also received past seasonal
influenza vaccinations outside of the VHA s ystem, and thus would be misclassified as not
having received vaccine in the current descriptive analysis. Hence, data on vaccination status
may be incomplete. However, this limita tion will be addressed in future study reports by
examining subgroups of individuals who receive care regularl y at VHA fac ilities, as well as
those with VA p riority group 1 status, to minimize healthcare services rendered outside of
the VHA s ystem. Results from the overall VHA group will be compared to these subgroups
with more complete data to examine the extent to which missingness may bias the study
findings. Linkage to Medicare claims data may be sought or the base study population may
be further restri cted to the subgroup of individuals who utilized VHA services regularl y.
The reduction in HRU during the COVID -19 pandemic may also impact the detection of
safet y events of interest and comorbidities identified in the outpatient setting. Given that
none of the safet y events of interest examined in this study will be identified only in the
outpatient setting, the potential for underestimating outcomes in the Pfizer -BioNTech
COVID -19 sample is limited. However, prevalence of some underly ing comorbidities
identified in the outpatient setting may be underestimated in the Pfizer -BioNTech COVID -19
sample.
As with any large EMR or claims database, occasional data entry errors may result in
misclassification of exposures, outcomes, or covariates for some individu als. However, these
are expected to onl y affect a minority of individuals . Furthermore, intensive quality checks
will be performed in the signal evaluation phase for safet yevents of interest for which a
signal is detected in the signal detection phase.
The active comparator study design requires the selection of a historical comparator sample
to calculate the expected rates for each of the safety events of interest. Similar to prior studies
that conducted post -vaccination safet y surveillance (e.g., for H 1N1), this study will use
seasonal influenza recipients a s historical active comparators.46,57The current study will rely
on individuals who received the seasonal influenza vaccine in the five prior seasons in the
VHA s ystem to calculate the expected rates for each of the safet y events of interest. While
seasonal influenza vaccine recipients were deemed to be an appropri ate comparison group
due to similarities in preventative healthcare behaviors and the large number of vaccine
recipients each year,differences in secular trends, coding practices or diagnostic techniques
could lead to potential bias.46To address this, a multivariate Poisson regression analysis will
be conducted as part of signal evaluation to account for potential baseline differences
between Pfizer -BioNTech COVID-1 9 and seasonal influenza vaccinees. Stratified analy ses
will also be used to address confounding and possible heterogeneity in the risk of adverse
events across specific populations of interest.
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 53
FDA-CBER-2021-5683-1076094
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON- INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
11.3. Generali zability
The VHA population included in this interim report is largely male and elderly . Therefore,
this population may not be generalizable to younger men or to women and children in the
US. These findings may also not be generalizable bey ond individuals enrolled in the VHA,
who were eligible to receive t he initial distribution of Pfizer -BioNTech COVID- 19 vaccine.17
Further, the results of this study are specific to Pfizer -BioNTech COVID -19 vaccine and are
not generalizable to COVID -19 vaccines from a manufacturer other than Pfizer -BioNTech.
11.4. Interpretation
This interim report describes sample selection, baseline characteristics and vaccine utilization
patterns among individuals who received P fizer-BioNTech COVID- 19 vaccine within the
VHA s ystem and a historical sample of individuals who received seasonal influenza vaccine
before the COVID -19 pandemic. M ost baseline characteristics were well -balanced between
the study sample s, suggesting that seasonal influenza vaccine from the five prior seasons is
an appropriate active comparator for the safet y surveillance of Pfizer -BioNTech COVID-19
vaccine .
Since CDC’s COVID -19 vaccine rollout recommendations gave priority to individuals 65
years and olde r in phases 1a through 1c, the higher proportion of older individuals with
Pfizer -BioNTech COVID-19 vaccine in the current sample was expected.58This distribution
of age will likely change in subsequent interim reports as y ounger individuals become
eligibl e to be vaccinated in the VH A. The higher proportion of men in this study was also
expected, as the VHA population is predominantly male (approximately 90%). The lower
proportion of individuals from Puerto Rico in the Pfizer-BioNTech COVID-19 vaccine
sampl e can be attributed to delay s in vaccine distribution to Puerto Rico, which was delay ed
by onemonth as compared to o ther VHA service areas, with access to COVID-19
vaccinations starting in January 2021 rather than December 2020.59
Recipients of Pfizer- BioNTech COVID -19 vaccine from December 11, 2020 to March 12,
2021 had a higher prevalence of the Shingles vaccine during the one -year prior to Pfizer -
BioNTech COVID -19 vaccination, as compared to the seasonal influenza comparator
sample. Given the higher pr oportion of older individuals in the Pfizer -BioNTech COVID -19
vaccine sample, the higher proportion of individuals with concurrent S hingles immuniza tion
is not surprising, as the S hingles vaccine is recommended for adults 50 y ears of age or
older.60Conversel y, seasonal influenza vaccinees had a higher prevalence of Tdap or Td and
pneumococcal conjugate vaccines during the one -year prior to seasonal influenza
vaccination, as compared to the Pfizer -BioNTech COVID- 19 sample. These differences are
likely explained by changes over time in immunization guidel ines for the elderly .61,62
The demographic and clinical characteristics of the Pfizer -BioNTech COVID -19 vaccine
sample were consistent with existing data in the US population, which suggests that vaccine
administration within the VHA s ystem aligned with CDC’s vaccine rollout recommendations
to prioritize the elderly population and individuals with underly ing medical conditions.58
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 54
FDA-CBER-2021-5683-1076095
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON- INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
12.OTHER INFORMATION
While this interim report focused on baseline demographic and clinical characteristics among
individuals who received Pfizer -BioNTech COVID- 19 vaccine or seasonal influenza vaccine ,
and vaccine utilization patterns among individuals who received Pfizer- BioNTech COVID -
19 vaccine , results for the real -time, rapid -cycle safet y signal analyses are forthcoming in the
next report. The second interim report, to be submitted in December 2021, w ill include
updated baseline descriptive data (with the additionally accrued data) , updated vaccination
utilization pattern s, and results from the safet y signal anal ysis, which will come from both
the signal detection and safet y evaluation anal yses. Additionally , findings from the sig nal
verification phase are expected to be included in the third interim report, to be submitted in
June 2022.
13.CONCLUSIONS
Among the 750,999 eligible VHA enrollees who received at least one dose of Pfizer -
BioNTech COVID -19 vaccine from December 11, 2020 to March 12, 2021, 64.6% were
administered two doses , with the two-dose vaccination completion rate among individuals
with ≥21 day s of observation after the first dose was 9 5.3%. Most individuals in the VHA
received Pfizer-BioNTech COVID- 19 vaccine in the ou tpatient setting (84.8%). The majorit y
of individuals who received two doses of the vaccine received the second dose precisel y 21
days following the first dose (70.2%) .Very few individuals (N = 1,905; 0.3%) of VHA
enrollees received mixed doses of COVID -19 vaccines - receiving a different vaccine brand
as a second dose from the first dose of Pfizer -BioNTech COVID- 19 vaccine . Overall, Pfizer -
BioNTech COVID -19 and seasonal influenza vaccinees within the VHA s ystem were
comparable based on both baseline demographic and clinical characteristics, supporting the
use of seasonal influenza vaccinees from the five prior seasons as an appropriate active
comparator group for the safet y surveillance of Pfizer -BioNTech COVID -19 vaccine.
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 55
FDA-CBER-2021-5683-1076096
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON- INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
14.REFERENCES
1World Health Organization (WHO). WHO Director-General’s opening remarks at the
media briefi ng on COVID -19 -11 March 2020 [I nternet]. W HO; 2020 [cited 2020 Nov 11].
Available from: https://www.who.int/dg/speeches/detail/who- director -general -s-opening -
remarks -at-the-media -briefing -on-covid -19---11-march -2020
2Johns Hopkins Coronavirus Resource Center. Home [I nternet]. Johns Hopkins
Coronavirus Resource Center; 2020 [cited 2020 Nov 10]. Available from:
https://coronavirus.jhu.edu/
3Centers for Disease Control and Prevention (CDC). About Variants of the Virus that
Causes COVID -19 [Internet]. CDC; 2021 [updated 2021 Apr 2; cited 2021 Apr 21].
Available from: https://www.cdc.gov/coronavirus/2019 -ncov/transmission/variant.html
4Schoeni RF, Wiemers EE, Seltzer JA, L anga KM. Association Between Risk Factors
for Complications From COVID- 19, Perceived Chances of Infection and Complications, and
Protective Behavior in the US. JAMA Netw O pen. 2021;4(3):e213984.
5Centers for Disease Control and Prevention (CDC). People with Certain Medical
Conditions [Internet]. CDC; 2020 [updated 2020 Dec 29; cited 2021 Jan 4]. Available from:
https://www.cdc.gov/coronavirus/2019 -ncov/need -extra -precautions/people- with-medical -
conditions.html
6Challen R, Brooks- Pollock E, Read JM, Dy son L, Tsaneva -Atanasova K, Danon L.
Risk of mortality in patients infected with SARS -CoV -2 variant of concern 202012/1:
matched cohort stud y. BMJ .2021;372 :n579 .
7Davies NG, Jarvis CI , CMMI D COVID -19 Working Group , Edmunds WJ, Jewell
NP, Diaz -Ordaz K, Keogh RH. I ncreased mortality in community -tested cases of SARS -
CoV -2 lineage B. 1.1. 7. Nature. 2021 May;593(7858):270 -274.
8Kirby T. New variant of SARS -CoV -2 in UK causes surge of COVID -19.
Lancet Respir Med. 2021;9(2):e20- e21.
9U.S. Food and Dr ug Administration (FDA). Pf izer-BioN Tech COVID -19 Vaccine
[Internet]. FDA; 2021 [cited 2021 Apr 21 ]. Available from: https://www.fda.gov/emergency -
preparedness -and-response/coronavirus- disease -2019 -covid- 19/pfizer -biontech -covid-19-
vaccine
10Walsh EE, Frenck RW, Jr., Falsey AR, Kitchin N, Absalon J, Gurtman A , et al.
Safety and Immunogenicity of Two RNA -Based Covid -19 Vaccine Candidates. N Engl J
Med. 2020 Dec 17;383(25):2439-50.
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 56
FDA-CBER-2021-5683-1076097
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON- INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
11Clinicaltrials.gov . Study to Describe the Safet y, Tolerability, Immunogenicity, and
Efficacy of RNA Vaccine Candidates Against COVID- 19 in Healthy Individuals
(NCT04368728 ) [Internet] .Clinicaltrials.gov; 2020 [cited 2020 Apr 23]. Available from:
https://clinicaltrials.gov/ct2/show/NCT04368728
12U.S. Food and Drug Administration (FDA). Vaccines and Related Bio logical
Products Advisory Committee Meeting: Pfizer -BioN Tech COVID -19 Vaccine FDA Briefing
Document . FDA; 2020 [cited 2021 Apr 23]. Available from:
https://www.fda.gov/media/144245/download
13U.S. Food & Drug Administration (FDA). Pfizer COVID- 19 Vaccine EUA Letter of
Auth orization reissued 12-23- 20. 2020 [cited 2021 Apr 23]. Available from:
https://www.fda.gov/media/144412/download
14U.S. Food and Drug Administration (FDA). FDA Takes Key Action in Fight Against
COVID -19 By Issuing Emergency Use Authorization for First COVID- 19 Vaccine
[Internet]. December 10, 2020 [cited April 21, 2021]. Available from:
https://www.fda.gov/news -events/press -announcements/fda -takes -key-action -fight -against -
covid-19- issuing- emergency -use-authorization- first-covid-19
15Law B. SO2 -D2.1.2 Priority List of COVID -19 Adverse Events of special interest:
Quarterl y update [I nternet]. Brightoncollaboration.us; 2020 [cited 2021 Apr 23] .Available
from: https://brightoncollaboration.us/wp-
content/uploads/2021/01/SO2_D2.1.2_V1. 2_COVID -19_AESI -update -23Dec2020 -
review_final.pdf
16Shimabukuro T. Enhanced safet y monitoring for COVID -19 vaccines in early phase
vaccination. National Center for Immunization & Respiratory Diseases ; 2020. Available
from: https://www.cdc.gov/vaccines/acip/meetings/downloads/slides -2020 -09/COVI D-03 -
Shimabukuro.pdf
17U.S. Department of Veterans Affairs. COVID -19 vaccines at VA [Internet] . U.S.
Department of Veterans Affairs; 2021 [cited 2021 Apr 23]. Available from:
https://www.va.gov/health- care/covid -19-vaccine/
18U.S. Department of Veterans Affairs National Center for Health Promotion and
Disease Prevention . Influenza (flu) [I nternet] .U.S. Department of Veterans Affairs ; 2020
[cited 2021 Apr 23]. Available from: https://www.prevention.va.gov/flu/
19U.S. Department of Veterans Affairs. Veterans Health Administration. Providing
Health Care for Veterans [Internet]. U.S. Department of Veterans Affairs ; 2020 [cited 2021
Apr 23]. Available from: https://www.va.gov/health/
20Sohn MW, Arnold N, May nard C, Hynes DM. Accuracy and completeness of
mortality data in the Department of Veterans Affairs. Population health metr . 2006;4:2.
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 57
FDA-CBER-2021-5683-1076098
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON- INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
21Agha Z, Lofgren RP, VanRuiswy k JV, L ayde PM. Are patients at Veterans Affairs
medical centers sicker? A comparative anal ysis of health status and medical resource use.
Arch Intern Med. 2000;160(21):3252-3257.
22U.S. Department of Veterans Aff airs. VA priority groups [Internet]. U.S. Department
of Veterans Aff airs; 2020 [cited 2021 Apr 23]. Available from: https://www.va.gov/heal th-
care/eligibility /priority- groups/
23Baxter R, Eaton A, Hansen J, Aukes L , Caspard H, Ambrose CS. Safet y of
quadrivalent live attenuated influenza vaccine in subjects aged 2 –49 years. Vaccine. 2017
Mar 1;35(9):1254-8.
24Johns Hopkins Vasculitis Center. Types of Vasculitis [I nternet]. 2021 [cited 2021
January 19]. Available from: https://www.hopkinsvasculitis.org/t ypes-
vasculitis/#:~:text=%E2%80%9CAngiitis%E2%80%9D%20and%20%E2%80%9CArteritis
%E2%80%9D,lit'%20i%20deez%E2%80%9D
25OptumI nsight, Inc. Guide t o Clinical Validation, Documentation and Coding: Acute
Kidney Injury [Internet]. 2013 [cited 2021 Jan 17]. Available from:
https://www.optum360coding.com/upload/pdf/ECDCG14/CDCG14_v2.pdf
26U.S. Department of Health and Human Services. Common Terminology Criteria for
Adverse Events (CTCAE) [I ntenet]. 2017 [cited 2021 Jan 17]. Available from:
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick
Reference_5x7.pdf
27Forns J, Cainzos ‐Achirica M, Hellfritzsch M, Morros R, Poblador ‐Plou B, Hallas J, et
al. Validity of ICD‐9 and I CD‐10 codes used to identify acute liver injury : A study in three
European data sources. Pharmacoepidemio Drug Saf 2019 Jul;28(7):965 -75.
28American Medical Association (AMA). Appendix Q: Severe Ac ute Respiratory
Syndrome Coronavirus 2 (SARS -CoV -2) (coronavirus disease [COVID- 19]) Vaccines
[Internet]. AMA; 2021 [cited 2021 Jan 12] .Available from: https://www.ama -
assn.org/sy stem/files/2020 -11/covid -19-immunizations -appendix -q-table.pdf
29Centers for Medicare & Medicaid Services (CMS) . COVID -19 Vaccines and
Monoclonal Antibodies [Internet]. CMS; 2020 [cited 2021 Jan14]. Available from:
https://www.cms.gov/medicare/medicare -part-b-drug-average -sales -price/covid -19-vaccines-
and-monoclonal -antibodies
30Centers for Disease Control and Prevention (CDC). NDC11 to NDC10 Crosswalk
Reference [Internet]. CDC; 2021 [cited April 30, 2021]. Available from:
https://www2.cdc.gov/vaccines/iis/iisstandards/downloads/NDC/NDC_Reference_1110 -
tag508.pdf
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 58
FDA-CBER-2021-5683-1076099
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON- INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
31Lieneck C, Ga rvey J, Collins C, Graham D, Loving C, Pearson R. Rapid Telehealth
Implementation during the COVID -19 Global Pandemic: A Rapid Review. Healthcare
(Basel). 2020 Nov 29;8(4):517.
32Menendez ME, Neuhaus V, van Dijk CN, Ring D. The Elixhauser comorbidity
method outperforms the Charlson index in predicting inpatient death after orthopaedic
surgery . Clin Orthop Relat Res . 2014; 472(9):2878-2886.
33Hoffman KB, Demakas AR, Dimbil M, Tatonetti NP, Erdman CB. Stimulated
reporting: the impact of US food and dru g administration -issued alerts on the adverse event
reporting s ystem (FAERS). Drug Saf. 2014;37(11):971 -980.
34Centers for Disease Control and Prevention (CDC). QuickStats: Average Daily
Number of Deaths, by Month —United States, 2017 [I nternet]. CDC; 2019 [cited 2021 Apr
23]. Available from: https://www.cdc.gov/mmwr/volumes/68/wr/mm6826a5.htm
35West AN, Charlton ME, Vaughan -Sarrazin M. Dual use of VA and non -VA hospitals
by Veterans with multiple hospitalizations. BMC Health Serv Res. 2015 Sep;15(1): 431.
36Kulldorff M, Davis RL, Kolczak† M, Lewis E, L ieu T, Platt R. A maximized
sequential probability ratio test for drug and vaccine safety surveillance. Seq Anal. 2011
Jan;30(1):58 -78.
37Flury BK, Riedwy l H. Standard distance in univariate and multivariate analy sis.Am
Stat. 1986 Aug;40(3):249–51.
38Austin PC. Using the standardized difference to compare the prevalence of a binary
variable between two groups in observational research. Commun Stat-Simul Comput . 2009
Apr;38(6):1228 -34.
39Ahmed A, Perry GJ, Fleg JL , Love TE, Goff Jr DC, Kitzman DW. Outcomes in
ambulatory chronic s ystolic and diastolic heart failure: a propensity score analy sis. American
heart journal. 2006 Nov 1;152(5):956 -66.
40Cohen J. Statistical power anal ysis for the behavioral sciences. 2nd ed. Hillsdale, NJ:
Lawrence Earlbaum Associates; 1988. p . 20–6.
41Yang D, Dalton JE. A unified approach to measuring the effect size between two
groups using SAS. SAS Global Forum 2012 [I nternet] . 2012 [ cited 2021 April 23]. SAS
Institute Inc. Available from: https://support.sas.com/resources/papers/proceedings12/335 -
2012.pdf
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 59
FDA-CBER-2021-5683-1076100
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON- INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
42Harder VS, Stuart EA, Anthony JC. Propensity score techniques and the assessment
of measured covariate balance to test causal associations in psy chologica l research. Psy chol
Methods. 2010 Sep ;15(3):234-49.
43Stuart EA, Lee BK, Leacy FP. Prognostic score -based balance measures can be a
useful diagnostic for propensity score methods in comparative effectiveness research. J Clin
Epidemiol . 2013 Aug;66(8 Suppl ):S84- S90.e1.
44Li Y, Wang X, Nair H. Global Seasonality of Human Seasonal Coronaviruses: A
Clue for Postpandemic Circulating Season of Severe Acute Respiratory Syndrome
Coronavirus 2? J Infect Dis . 2020 Sep ;222(7):1090 -7.
45Baker MA, Lieu TA, Li L, Hua W, Qiang Y, Kawai AT ,et al. A vaccine study design
selection framework for the postlicensure rapid immunization safety monitoring program.
Am J Epidemiol . 2015 Apr;181(8):608-18.
46Lee GM, Greene SK, Weintraub ES, Baggs J, Kulldorff M, Fireman BH , et al. H1N1
andseasonal influenza vaccine safet y in the vaccine safet y datalink project. Am J Prev Med.
2011 Aug;41(2):121 -8.
47U.S. Food and Drug Administration (FDA). COVID- 19 Vaccine Safet y Surveillance :
Active Monitoring Master Protocol [Internet] . 2021 F ebruary 10 [cited 2021 April 23].
Available from: https://www.bestinitiative.org/wp -content/uploads/2021/02/C19 -Vaccine -
Safety -Protocol -2021.pdf
48International Societ y for Pharmacoepidemiology (ISPE). Guidelines for good
pharmacoepidemiology practices (G PP). Pharmacoepidemiol Drug Saf. 2008 Feb;17(2):200 -
8.
49International Epidemiological Association (IEA). Good Epidemiological Practice
(GEP), IEA Guidelines for Proper Conduct of Epidemiological Research [Internet]. 2007
[cited 2021 January 25]. Available from:
https://ieaweb.org/IEAWeb /Content/I EA_Publications.aspx
50U.S. Food and Drug Administration (FDA) Center for Drug Evaluation and Research
(CDER). Best Practices for Conducting and Reporting Pharmacoepidemiologic Safet y
Studies Using El ectronic Healthcare Data [I nternet]. 2013 [cited 2021 January 19].Available
from: https://www.fda.gov/media/79922/download
51Centers for Disease Control and Prevention (CDC). Interim Clinical Considerations
for Use of COVID -19 Vaccines Currently Authorized i n the United States [Internet]. 2021
May 14 [cited 2021 May 17]. Available from: https://www.cdc.gov/vaccines/covid- 19/info-
by-product/clinical -considerations.html
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 60
FDA-CBER-2021-5683-1076101
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON- INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
52Luo J, Jey apalina S, Stoddard GJ, Kwok AC, Agarwal JP. Coronavirus disease 2019
in veterans receiving care at Veterans Health Administration facilities. Ann Epidemiol . 2021
Mar;55:10 -4.
53Moy nihan R, Sanders S, Michaleff ZA, Scott AM, Clark J, To EJ, et al. Impact of
COVID -19 pandemic on utilisation of healthcare services: a s ystematic review. BMJ open.
2021 Mar 1;11(3):e045343.
54Lieneck C, Garvey J, Collins C, Graham D, Loving C, Pearson R. Rapid telehealth
implementation during the COVID -19 g lobal pandemic: A rapid r eview. Healthcare (Basel).
2020 Nov 29;8(4):517.
55Center for Disease Control and Prevention (CDC) . COVID -19 vaccinations in the
United States [Internet] . 2021 [cited 2021 April 4]. Available from:
https://covid.cdc.gov/covid -data-track er/#vaccinations
56Petersen LA, By rne MM, Daw CN, Hasche J, Reis B, Pietz K. Relationship between
clinical conditions and use of Veterans Affairs health care among Medicare -enrolled
veterans. Health Serv Res. 2010;45(3):762-791.
57Yih WK, L ee GM, Lieu T A, Ball R, Kulldorff M, Rett M, et al. Surveillance for
adverse events following receipt of pandemic 2009 H1N1 vaccine in the Post -Licensure
Rapid I mmunization Safety Monitoring (PRI SM) Sy stem, 2009- 2010. Am J Epidemiol. 2012
Jun;175(11):1120 -8.
58Center for Disease Control and Prevention (CDC) . CDC’s COVID -19 Vaccine
Rollout Recommendations [Internet] . 2021 [cited 2021 April 15]. Available from:
https://www.cdc.gov/coronavirus/2019 -ncov/vaccines/recommendations.html
59U.S. Department of Veterans Affairs. VA Caribbean Healthcare S ystem [I nternet] .
2021 [cited 2021 January 15]. Available from:
https://www.caribbean.va.gov/pressreleases/COVID -19_Moderna_Vaccine.asp
60Center for Disease Control and Prevention (CDC). Shingles Vaccination [Internet] .
2021 [cited 2021 April 15]. Available from:
https://www.cdc.gov/vaccines/vpd/shingles/public/shingrix/index.html#:~:text=CDC%20rec
ommends%20that%20healthy %20adults,shot%20in%20y our%20upper%20arm
61Center for Disease Control and Prevention (CDC) . Updated Recomm endations for
Use of Tetanus Toxoid, Reduced Diphtheria Toxoid, and Acellular Pertussis (Tdap) Vaccine
in Adults Aged 65 Years and Older — Advisory Committee on I mmunization Practices
(ACI P)[Internet] , 2012 [cited 2021 April 15]. Available from:
https://www.cdc.gov/mmwr/preview/mmwrhtml/mm6125a4.htm
62American Association of Retired Persons (AARP) . Recommendation for Pneumonia
Vaccine Revised [Internet] . 2019 [cited 2021 April 15]. Available from:
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 61
FDA-CBER-2021-5683-1076102
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON- INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
https://www.aarp.org/health/conditions -treatments/info -2019/pneumonia -vaccine -
recommendation.html
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 62
FDA-CBER-2021-5683-1076103
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON- INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
15.LIST OF SOURCE TABLES AND FI GURES
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 63
FDA-CBER-2021-5683-1076104
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON- INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
Table 15.1.Operational Definitions of Demographic and Clinical Characteristics
Variable Description Operational definition
Demographic Characteristics
Age Continuous variable;
Categorical variable:
<16
16–64
65–74
≥75Age on the date of Pfizer- BioNTech
COVID -19 vaccination (and/or date of
seasonal influenza vaccination for
active comparators)
Sex Categorical variable:
Male
Female
Unknown
Race/ethnicit yCategorical variable:
White, non -Hispanic
Black
Hispanic ethnicity , any
race
Asian
Native Hawaiian or
Pacific Islander
American Indian or
Alaskan native
Two or more races
Unknown
VHA service
areaGeographic regions in the US ;
Categorical variable:
South
Midwest
West
Northeast
Other
UnknownRegion associated with the most recent
healthcare encounter prior to index date
Clinical Characteristics
Smoking Status Dichotomous variable ICD-9-CM codes:
305.1, Tobacco use disorder
V15.82, History of tobacco use
ICD-10-CM codes:
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 64
FDA-CBER-2021-5683-1076105
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON- INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
Table 15.1.Operational Definitions of Demographic and Clinical Characteristics
Variable Description Operational definition
F17.200, Nicotine dependence,
unspecified, uncomplicated
Z7.20, Tobacco use
Z87.891, Personal history of
nicotine dependence
Body mass
index (BMI)*Continuous variable;
Categorical variable:
Underweight (<18.5)
Normal weight (18.5 –<25)
Overweight (25– <30)
Obese (30 –<40)
Severe obesit y (≥40)
UnknownCalculated from height and weight data
(kg/m2)
History of
anaph ylaxis/
allergic
reactionsDichotomous variable ICD-9-CM code:
V13.81, Personal history of
anaph ylaxis
V14.0–V14.6, V14.8, V14.9,
Personal history of allergy to
drugs, medications and
biological substances, excluding
serum and vaccine
V15.0x, Other allergy
525.66, Allergy to existing
dental restorative material
995, Other anaph ylactic shock,
not elsewhere classified
995.1, Ang ioneurotic edema,
not elsewhere classified
995.21, Arthus phenomenon
999.27, Other drug allergy
995.3, Allergy , unspecified, not
elsewhere classified
995.6x, Anaphy lactic shock due
to food
999.41, Anaph ylactic reaction
due to administration of blood
and bl ood products
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 65
FDA-CBER-2021-5683-1076106
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON- INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
Table 15.1.Operational Definitions of Demographic and Clinical Characteristics
Variable Description Operational definition
999.49, Anaph ylactic reaction
due to other serum
ICD-10-CM code:
Z87.892 Personal history of
anaph ylaxis
Z88.0 –Z88.6, Z88.8, Z88.9,
Allergy status to drugs,
medications and biological
substances, excluding serum and
vaccine
T78.00xx –T78.09xx,
Anaph ylactic reaction due to
food, initial encounter,
subsequent encounter and
sequela
T78.2xxx, Anaphy lactic shock,
initial encounter, subsequent
encounter and sequela
T78.3xxx, Angioneurotic
edema, initial encounter,
subsequent encount er and
sequela
T78.41xx, Arthus phenomenon
T80.51xx, Anaphy lactic
reaction due to administration of
blood and blood products, initial
encounter, subsequent encounter
and sequela
T80.59xx, Anaphy lactic
reaction due to other serum,
initial encounter, subseq uent
encounter and sequela
T88.6xxx, Anaphy lactic
reaction due to adverse effect of
correct drug or medicament
properl y administered, initial
encounter, subsequent encounter
and sequela
Previous
anaph ylaxis of Dichotomous variable ICD-9-CM code:
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 66
FDA-CBER-2021-5683-1076107
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON- INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
Table 15.1.Operational Definitions of Demographic and Clinical Characteristics
Variable Description Operational definition
vaccine
component999.42, Anaph ylactic reaction
due to vaccination
V14.7, Personal history of
allergy to serum or vaccine
ICD-10-CM codes:
T80.52xx, Anaphy lactic
reaction due to vaccination,
initial encounter, subsequent
encounter and sequela
Z28.04, Immuniza tion not
carried out because of patient
allergy to vaccine or component
Z88.7, Allergy status to serum
and vaccine
History of
hospitalizations Dichotomous variable;
Continuous variableDefined b y having any hospitalizations
(dichotomous) and number of
hospitalizations (continuous)
Charlson
Comorbidity
Index (CCI )32Continuous variable ICD-9-CM codes:
410.x, 412.x, My ocardial
infarction
398.91, 402.01, 402.11, 402.91,
404.01, 404.03, 404.11, 404.13,
404.91, 404.93, 425.4 –425.9,
428.x, Congestive heart failure
093.0, 437.3, 440.x, 441.x,
443.1 –443.9, 447.1, 557.1,
557.9, V43.4, Peripheral
vascular disease
362.34, 430.x– 438.x,
Cerebrovascular disease
290.x, 294.1, 331.2, Dementia
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 67
FDA-CBER-2021-5683-1076108
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON- INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
Table 15.1.Operational Definitions of Demographic and Clinical Characteristics
Variable Description Operational definition
416.8, 416.9, 490.x– 505.x,
506.4, 508.1, 508.8, Chronic
pulmonary disease
446.5, 710.0 –710.4, 714.0 –
714.2, 714.8, 725.x, Rheumatic
disease
531.x– 534.x, Peptic ulcer
disease
070.22, 070.23, 070.32, 070.33,
070.44, 070.54, 070.6, 070.9,
570.x, 571.x, 573.3, 573.4,
573.8, 573.9, V42.7, Mild liver
disease
250.0 –250.3, 250.8, 250.9,
Diabetes without chronic
complication
250.4 –250.7, Diabetes with
chronic complication
334.1, 342.x, 343.x, 344.0 –
344.6, 344.9, Hemiplegia or
paraplegia
403.01, 403.11, 403.91, 404.02,
404.03, 404.12, 404.13, 404.92,
404.93, 582.x, 583.0–583.7,
585.x, 586.x , 588.0, V42.0,
V45.1, V56.x, Renal disease
140.x– 172.x, 174.x –195.8,
200.x– 208.x, 238.6, Any
malignancy , including
lymphoma and leukemia, except
malignant neoplasm of skin
456.0 –456.2, 572.2 –572.8,
Moderate or severe liver disease
196.x– 199.x, Metastatic solid
tumor
042.x– 044.x, Acquired
immunodeficiency syndrome
(AIDS)/Human
immunodeficiency virus (HIV)
ICD-10-CM codes:
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 68
FDA-CBER-2021-5683-1076109
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON- INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
Table 15.1.Operational Definitions of Demographic and Clinical Characteristics
Variable Description Operational definition
I21.x, I21.xx, I 22.x, I 25.2,
Myocardial infarction
I09.9, I11.0, I13.0, I13.2, I25.5,
I42.0, I42.5 –I42.9, I43, I43.x,
I50.x, I50.xx, Cong estive heart
failure
I70.x, I71.x, I 73.1, I73.8, I 73.9,
I77.1, I79.0, I79.2, K55.1,
K55.8, K55.9, Z95.8, Z95.9,
Peripheral vascular disease
G45, G45.x, G46.x, H34.0,
I60.x –I63.x, I 60.xx –I63.xx,
I60.xxx –I63.xxx, I 65.x– I69.x,
I65.xx –I69.xx, I 65.xxx –I69.xxx,
Cerebrovascular disease
F00.x –F03.x, F00.xx –F03.xx,
F05, F05.1, G30.x, G31.1,
Dementia
I27.8, I27.9, J40.x –J47.x,
J40.xx –J47.xx, J40.xxx –
J47.xxx, J60.x –J67.x, J68.4,
J70.1, J70.3, Chronic pulmonary
disease
M05, M05.x, M05.xx, M05.xxx,
M06, M06.x, M06.xx, M06.xxx,
M31.5, M32.x –M34.x, M32.xx –
M34.xx, M35.1, M35.3, M36.0,
Rheumatic disease
K25.x –K28.x, Peptic ulcer
disease
B18.x, K70.0– K70.3, K70.9,
K71.3–K71.5, K71.7, K73.x,
K74.x, K74.xx, K76.0, K76.2–
K76.4, K76.8, K76.9, Z94.4,
Mild liver disease
E10.0, E10.1x, E10.6x,
E10.6xx, E10.8, E10.9, E11.0x,
E11.1x, E11.6x, E11.6xx,
E11.8, E11.9, E12.0, E12.1,
E12.6, E12.8, E12.9, E13.0x,
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 69
FDA-CBER-2021-5683-1076110
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON- INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
Table 15.1.Operational Definitions of Demographic and Clinical Characteristics
Variable Description Operational definition
E13.1x, E13.6x, E13.6xx,
E13.8, E13.9, E14.0, E14.1,
E14.6, E14.8, E14.9, Diabetes
without chronic complication
E10.2x –E10.5x, E10.2xx –
E10.5xx, E10.7, E11.2x –
E11.5x, E11.2xx –E11.5xx,
E11.7, E12.2 –E12.5, E12.7,
E13.2–E13.5x, E13.7, E14.2 –
E14.5, E14.7, Diabetes with
chronic complication
G04.1, G11.4, G80.1, G80.2,
G81.x, G81.xx, G82.x, G82.xx,
G83.0, G83.1–G83.3, G83.1x –
G83.3x, G83.4, G83.9,
Hemiplegia or paraplegia
I12.0, I13.1x, N03.2–N03.7,
N05.2–N05.7, N18.x, N19,
N25.0, Z49.0x –Z49.3x, Z94.0,
Z99.2, Renal disease
C00–C75, C00.x –C75.x,
C00.xx –C75.xx (excluding C44,
C44.x and C44.xx), C7A.,
C7A.x, C7A.xx, C7B., C7B.x,
C7B.xx, C76–C80, C76.x –
C80.x, C76.xx –C80.xx, C81–
C96, C81.x –C96.x, C81.xx –
C96.xx, Any malignancy,
including l ymphoma and
leukemia, except malignant
neoplasm of skin
I85.0, I85.9, I86.4, I98.2,
K70.4x, K71.1x, K72.1x,
K72.9x, K76.5, K76.6, K76.7,
Moderate or severe liver d isease
C77.x –C80.x, C77.xx –C80.xx,
Metastatic solid tumor
B20, B97.35, AIDS/HIV
Comorbidities Categorical variable:
Autoimmune disease Autoimmune disease
(immunocompromised state [weakened
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 70
FDA-CBER-2021-5683-1076111
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON- INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
Table 15.1.Operational Definitions of Demographic and Clinical Characteristics
Variable Description Operational definition
Asthma
Bleeding diathesis or
condition associated
with prolonged
bleeding
Cancer
Cardiovascular
conditions (e.g.,
heart failure, CAD,
cardiom yopathies)
Chronic kidney
disease/dial ysis
COPD/interstitial
lung disease
Diabetes mellitus
Down sy ndrome
Sickle cell disease
HBV
HCV
HIV
Hyperlipidemia
Hypertension
Liver disease
Neurological disease
Other immune
deficiencies
Solid organ
transplant
VTEimmune sy stem] from solid organ
transplant):
ICD-9-CM codes:
245.2, Chronic ly mphocytic
thyroiditis
340, Multiple sclerosis
357, Acute infective
polyneuritis
357.4, Polyneuropathy in
other diseases classified
elsewhere
696.1, Other psoriasis
694.3, I mpetigo
herpetiformis
696.1, Other psoriasis
696, Psoriatic arthropathy
695.4, L upus ery thematosus
714, 714.x, 714.xx,
Rheumatoid arthritis and
other inflammatory
polyarthropathies
359.6, Sy mptomatic
inflammatory myopathy in
diseases classified elsewhere
357.1, Poly neuropathy in
collagen vascular disease
714.89, Other specified
inflammatory
polyarthropathies
714.9, Unspecified
inflammatory
polyarthropathy
446.5, Giant cell arteritis
710.2, Sicca s yndrome
ICD-10-CM codes:
D69.3, I mmune
thrombocy topenic purpura
E06.3, Autoimmune
thyroiditis
G35, MS
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 71
FDA-CBER-2021-5683-1076112
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON- INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
Table 15.1.Operational Definitions of Demographic and Clinical Characteristics
Variable Description Operational definition
G61.0 and G65.0, GBS and
sequelae of GBS
L40.x, L 40.5x, Psoriasis
L93.x, L upus ery thematosus
M05.x, M05.xx, M05.xxx,
Rheumatoid arthritis with
rheumatoid factor
M06.x, M06.xx, M06.xxx,
Other rheumatoid arthritis
M31.5, M31.6, Giant cell
arteritis
M35.0x, Sicca (Sjogren’s)
syndrome
N05.9, Glomerulonephritis
D84.9, I mmunodeficiency ,
unspecified
Asthma:
ICD-9-CM codes:
o493.xx, Asthm a
ICD-10-CM codes:
oJ45.2x –J45.3x, Mild
intermittent asthma
oJ45.4x, Moderate
persistent asthma
oJ45.5x, Severe
persistent asthma
oJ45.9x , Other and
unspecified asthma
Bleeding diathesis or condition
associated with prolonged bleeding:
ICD-9-CM codes:
o286.x, Coagulation
defects
o289.8x, Other
specified diseases of
blood and blood -
forming organs
o287, 287.x, 287.xx,
Purpura and other
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 72
FDA-CBER-2021-5683-1076113
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON- INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
Table 15.1.Operational Definitions of Demographic and Clinical Characteristics
Variable Description Operational definition
hemorrhagic
conditions
ICD-10-CM codes:
oD65, Disseminated
intravascular
coagulation
oD66, Hereditary
factor VIII
deficiency
oD67, He reditary
factor IX deficiency
oD68, D68.x, D68.xx,
Other coagulation
defects
oD69, D69.x, D69.xx,
Purpura and other
hemorrhagic
conditions
Cancer:
ICD-9-CM codes:
o140.x– 149.x,
Malignant neoplasm
of lip, oral cavit y,
and phary nx
o150.x– 159.x,
Malignant neoplasm
of digestive organs
and peritoneum
o160.x– 165.x,
Malignant neoplasm
of respiratory and
intrathoracic organs
o170.x– 176.x,
Malignant neoplasm
of bone, connective
tissue, skin, and
breast
o179.x– 189.x,
Malignant neoplasm
of genitourinary
organs
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 73
FDA-CBER-2021-5683-1076114
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON- INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
Table 15.1.Operational Definitions of Demographic and Clinical Characteristics
Variable Description Operational definition
o190.x– 199.x,
Malignant neoplasm
of other unspecified
sites
o200.xx– 208.xx,
Malignant neoplasm
of lymphatic and
hematopoietic tissue
o209.0x– 209.3x,
Malignant
neuroendocrine
tumors
o230.x– 234.x,
Carcinoma in situ of
digestive organs
ICD-10-CM codes:
oC00–C75, C00.x –
C75.x, C00.xx –
C75.xx, C7A.,
C7A.x, C7A.xx,
C7B., C7B.x,
C7B.xx, Malignant
neoplasms, stated or
presumed to be
primary (of specified
sites), and certain
specified histologies,
except
neuroendocrine, and
of lymphoid,
hematopoietic and
related tissue
oC76–C80, C76.x –
C80.x, C76.xx –
C80.xx, Malignant
neoplasms of ill-
defined, other
secondary and
unspecified sites
oC81–-C96, C81.x –
C96.x, C81.xx –
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 74
FDA-CBER-2021-5683-1076115
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON- INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
Table 15.1.Operational Definitions of Demographic and Clinical Characteristics
Variable Description Operational definition
C96.xx, Malignant
neoplasms of
lymphoid,
hematopoietic and
related tissue
Cardiovascular conditions (e.g., heart
failure, coronary artery disease [CAD],
cardiom yopathies):
ICD-9-CM codes:
o428.xx, Heart failure
o414.01, 429.2, 411.1,
413.9, 414.11,
414.12, 414.05,
414.02, 414.0 3,
414.0 4, 414.06,
414.07, 414.2,
411.81, 411.89, CAD
o425.xx,
Cardiomy opath y
ICD-10-CM codes:
o150.x, 1 50.xx, Heart
failure
oI24.0, I24.8, I24.9,
I25.10, I25.110,
I25.111, I25.118,
I25.119, I25.41,
I25.42, I25.700,
I25.701, I25.708,
I25.709, I25.710,
I25.711, I25.718,
I25.719, I25.720,
I25.721, I25.728,
I25.729, I25.730,
I25.731, I25.738,
I25.739, I25.750,
I25.751, I25.758,
I25.759, I25.760,
I25.761, I25.768,
I25.769, I25.790,
I25.791, I25.798,
I25.799, I25.810,
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 75
FDA-CBER-2021-5683-1076116
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON- INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
Table 15.1.Operational Definitions of Demographic and Clinical Characteristics
Variable Description Operational definition
I25.811, I25.812,
CAD
oI42.x,
Cardiomy opath y
Chronic kidney disease/dialy sis:
ICD-9-CM codes:
o283.11, Hemoly tic-
uremic s yndrome
o403, 403.x, 403.xx,
Hypertensive chronic
kidney disease
o404, 404.x, 404.xx,
Hypertensive heart
and chronic kidney
disease
o440.1,
Atherosclerosis of
renal artery
o442.1, Aneury sm of
renal artery
o572.4, Hepatorenal
syndrome
o274.1, Gouty
nephropath y,
unspecified
o710, Sy stemic lupus
erythematosus
o710.2, Sicca
syndrome
o580, 580.x, 580.xx,
Acute
glomerulonephritis
o581.x, 581.xx,
Nephrotic s yndrome
o582, 582.x, 582.xx,
Chronic
glomerulonephritis
o583, 583.x, 583. xx,
Nephritis and
nephropath y, not
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 76
FDA-CBER-2021-5683-1076117
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON- INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
Table 15.1.Operational Definitions of Demographic and Clinical Characteristics
Variable Description Operational definition
specified as acute or
chronic
o591, Hy dronephrosis
o593.3, Stricture or
kinking of ureter
o592, Calculus of
kidney
o592.1, Calculus of
ureter
o590.9, I nfection of
kidney , unspecified
o584.x, Acute kidney
failure
o585.x, Chronic
kidney disease
o588.x, 588.xx,
Disorders resulting
from impaired renal
function
o587, Renal sclerosis,
unspecified
o753.1x, Cy stic
kidney disease
o753.2, 753.2x,
Obstructive defects
of renal pelvis and
ureter
ICD-10-CM codes:
oD59.3, Hemoly tic-
uremic s yndrome
oI12.x, Hy pertensive
chronic kidney
disease
oI13.x, I13.xx,
Hypertensive heart
and chronic kidney
disease
oI70.1,
Atherosclerosis of
renal artery
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 77
FDA-CBER-2021-5683-1076118
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON- INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
Table 15.1.Operational Definitions of Demographic and Clinical Characteristics
Variable Description Operational definition
oI72.2 Aneury sm of
renal artery
oK76.7, Hepatorenal
syndrome
oM10.30–M10.39,
M10.30x –M10.37x,
Gout due to renal
impairment
oM32.14, Glomerular
disease in s ystemic
lupus ery thematosus
oM32.15, Tubulo-
interstitial
nephropath y in
systemic lupus
erythematosus
oM35.04, Sicca
syndrome with
tubulo -interstitial
nephropath y
oN00.x –N07.x, N08,
Glomerular diseases
oN13.1, N13.2,
N13.3x, Obstructive
and reflux uropath y
oN14.x, Nephropathy
oN15.x, Other renal
tubulo -interstitial
diseases
oN16, Renal tubulo-
interstitial disorders
in diseases classified
elsewhere
oN17.x, N18.x, N19,
Acute kidney failure
and chronic kidney
disease
oN25.x, N26.x,
N25.xx, Other
disorders of kidney
and ureter
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 78
FDA-CBER-2021-5683-1076119
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON- INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
Table 15.1.Operational Definitions of Demographic and Clinical Characteristics
Variable Description Operational definition
oQ61.02, Q61.11x,
Q61.2–Q61 .9, Cy stic
kidney disease
oQ62.x, Q62.xx,
Congenital
obstructive defects of
renal pelvis and
congenital
malformation of
ureter
COPD/interstitial lung disease:
ICD-9-CM codes:
o491.9, Unspecified
chronic bronchitis
o492.8, Other
emphy sema
o491.x, 491.xx,
Chronic bronchitis
o493.2, Chronic
obstructive asthma,
unspecified
o496, Chronic airway
obstruction, not
elsewhere classified
o516, 516.x, 516.xx,
Other alveolar and
parietoalveolar
pneumonopathy
o515,
Postinflammatory
pulmonary fibrosis
o518.x, 518.xx, Other
diseases of lung
o714.81, Rheumatoid
lung
ICD-10-CM codes:
oJ41.x Simple and
mucopurulent
chronic bronchitis
oJ42, Unspecified
chronic bronchitis
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 79
FDA-CBER-2021-5683-1076120
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON- INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
Table 15.1.Operational Definitions of Demographic and Clinical Characteristics
Variable Description Operational definition
oJ43.x, Emphy sema
oJ44.x, Other COPD
oJ80, J81.x, J82.xx,
J84.xx, J84.xxx,
Other respiratory
diseases principall y
affecting the
interstitium
oM05.10, Rheumatoid
lung disease with
rheumatoid arthritis
of unspecified site
Diabetes mellitus:
ICD-9-CM codes:
o250.xx, Diabetes
mellitus
ICD-10-CM codes:
oE10.x, E10.xx,
E10.xxx, Ty pe 1
diabetes mellitus
oE11.x, E11.xx,
E11.xxx, Type 2
diabetes mellitus
Down sy ndrome:
ICD-9-CM codes:
o758.x, Down
syndrome
ICD-10-CM codes:
oQ90.x, Down
syndrome
Sickle cell disease:
ICD-9-CM codes:
o282.xx, Sickle -cell
disease
ICD-10-CM codes:
oD57, D57.x, D57.xx,
D57.xxx, Sickle -cell
disorders
HBV:
ICD-9-CM codes:
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 80
FDA-CBER-2021-5683-1076121
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON- INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
Table 15.1.Operational Definitions of Demographic and Clinical Characteristics
Variable Description Operational definition
o70.33, Chronic viral
hepatitis B without
mention of hepatic
coma with hepatitis
delta
o70.32, Chronic viral
hepatitis B without
mention of hepatic
coma without
mention of hepatitis
delta
o70.3, Viral hepatitis
B without mention of
hepatic coma, acute
or unspecified,
without mention of
hepatitis delta
o70.2, Viral hepatitis
B with hepatic coma,
acute or unspecified,
without mention of
hepatitis delta
ICD-10-CM codes:
oB18.0, B18.1,
Chronic viral
hepatitis B
oB19.1, B19.1x,
Unspecified viral
hepatitis B
HCV:
ICD-9-CM codes:
o70.7, Unspecified
viral hepatitis C
without hepatic coma
o70.71, Unspecified
viral hepatitis C with
hepatic coma
o70.54, Chronic
hepatitis C without
mention of hepatic
coma
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 81
FDA-CBER-2021-5683-1076122
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON- INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
Table 15.1.Operational Definitions of Demographic and Clinical Characteristics
Variable Description Operational definition
ICD-10-CM codes:
oB18.2, Chronic viral
hepatitis C
oB19.2 x, Unspecified
viral hepatitis C
HIV:
ICD-9-CM codes:
o42, HIV disease
o79.53, HIV t ype 2
ICD-10-CM codes:
oB20, HIV disease
oB97.35, HIV t ype 2
as the cause of
diseases classified
elsewhere
Hyperlipidemia
ICD-9-CM codes:
o272.0x, Pure
hypercholesterolemia
o272.1x, Pure
hypergly ceridemia
o272.2x, Mixed
hyperlipidemia
o272.4x,
Hyperlipidemia,
NOS
ICD-10-CM codes:
oE78.0–E78.5,
E78.0x, E78.4x,
Hyperlipidemia
Hypertension:
ICD-9-CM codes:
o401.1, Benign
essential
hypertension
o401.9, Essential
hypertension, NOS
o405.1, Benign
secondary
hypertension
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 82
FDA-CBER-2021-5683-1076123
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON- INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
Table 15.1.Operational Definitions of Demographic and Clinical Characteristics
Variable Description Operational definition
o405.9, Secondary
hypertension, NOS
o997.91,
Hypertension, NOS
ICD-10-CM codes:
oH35.03x,
Hypertensive
retinopathy
oI10, I11.x –I16.x,
I13.xx, Hy pertensive
diseases
oI67.4, Hy pertensive
encephalopath y
diseases
Liver disease:
ICD-9-CM codes:
o571, 571.x,
Alcoholic fatt y liver
o572, 572.x, Hepatic
encephalopath y
o573.x, Other disorder
of liver
o570, Acute and
subacute necrosis of
liver
ICD-10-CM codes:
oK70.x, K70.xx,
Alcoholic fatt y liver
oK71.x, K71.xx,
Toxic liver disease
oK72.xx, Hepatic
failure, not
elsewhere classified
oK73.x, Chronic
hepatitis, not
elsewhere specified
oK74.x, K74.xx,
Fibrosis and cirrhosis
of liver
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 83
FDA-CBER-2021-5683-1076124
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON- INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
Table 15.1.Operational Definitions of Demographic and Clinical Characteristics
Variable Description Operational definition
oK75.x, K75.xx,
Other inflammatory
liver diseases
oK76.x, K76.xx,
Other diseases of
liver
oK77, L iver disorders
in disea ses classified
elsewhere
Neurological disease:
ICD-9-CM codes:
o780.97, Altered
mental status
o780.93, Memory loss
o781.8, Neurologic
neglect s yndrome
o797, Senility without
mention of psy chosis
oV62.89, Other
psychological or
physical stress, not
elsewhere cla ssified
o799.5x, Signs and
symptoms involving
cognition
o780.99, Other
general s ymptoms
o780.4, Dizziness and
giddiness
o781.1, Disturbances
of sensation of smell
and taste
oV41.5, Problems
with smell and taste
o368.16,
Psychoph ysical
visual disturbances
o307.9, Other and
unspecified special
symptoms or
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 84
FDA-CBER-2021-5683-1076125
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON- INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
Table 15.1.Operational Definitions of Demographic and Clinical Characteristics
Variable Description Operational definition
syndromes, not
elsewhere classified
o300.9, Unspecified
nonpsy chotic mental
disorder
o308.9, Unspecified
acute reaction to
stress
o307.9, Other and
unspecified special
symptoms or
syndromes, not
elsewhere classified
oV62.85, Homicidal
ideation
oV62.84, Suicidal
ideation
o799.24, Emotional
lability
o799.23,
Impulsiveness
o799.29, Other signs
and sy mptoms
involving emotional
state
oV40.39, Other
specified behavioral
problem
ICD-10-CM codes:
oR41, R41.x, R41.xx,
Other s ymptoms and
signs involving
cognitive functions
and awareness
oR42, Dizziness and
giddiness
oR43, R43.x,
Disturbances of
smell and taste
oR44, R44.x, Other
symptoms and signs
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 85
FDA-CBER-2021-5683-1076126
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON- INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
Table 15.1.Operational Definitions of Demographic and Clinical Characteristics
Variable Description Operational definition
involving general
sensations and
perceptions
oR45, R45.x, R45.xx,
Symptoms and signs
involving emotional
state
oR46, R46.x, R46.xx,
Symptoms and signs
involving appearance
and behavior
Other immune deficiencies:
ICD-9-CM codes:
o279.x, 279.xx,
Deficiency of
humoral immunity
o135, Sarcoidosis
o273.x, Disorders of
plasma protein
metabolism
ICD-10-CM codes:
oD80, D80.x,
Immunodeficiency
with predominantly
antibody defects
oD81, D81.x, D81.xx,
Combined
immunodeficiencies
oD82, D82.x,
Immunodeficiency
associated with other
major defects
oD83, D83.x,
Common variable
immunodeficiency
oD84, D84.x, D84. xx,
Other
immunodeficiencies
oD86, D86.x, D86.xx,
Sarcoidosis
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 86
FDA-CBER-2021-5683-1076127
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON- INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
Table 15.1.Operational Definitions of Demographic and Clinical Characteristics
Variable Description Operational definition
oD89, D89.x, D89.xx,
Other disorders
involving the
immune mechanism,
not elsewhere
classified
Solid organ transplant:
CPT codes:
o32850 –32856,
Transplantation of
lung
o33930 –33945,
Transplantation of
heart
o44132, 44133,
47133, 47135,
47140 –47147,
Transplantation of
liver
o44135 –44137,
44715, 44720,
44721,
Transplantation of
intestine
o48160, 48550 –
48552, 48554,
48556,
Transplantation of
pancreas
o50300, 50320,
50323, 50325,
50327, 50328,
50329, 50340,
50360, 50365,
50370, 50380, Renal
transplantation
ICD-9-PCS codes:
o00.91 –00.93,
Transplant from
donor or cadaver
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 87
FDA-CBER-2021-5683-1076128
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON- INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
Table 15.1.Operational Definitions of Demographic and Clinical Characteristics
Variable Description Operational definition
o37.51, Heart
transplantation
o33.51, Unilateral
lung transplantation
o33.52, Bilateral lung
transplantation
o46.97, Transplant of
intestine
o50.59, Other
transplant of
intestine
o52.82,
Homotransplant of
pancreas
o55.69, Other kidney
transplant
ICD-10-PCS codes:
o02YA0Z0,
02YA0Z1,
Transplantation of
heart
o0BYC0Z0,
0BYC0Z1,
0BYD0Z0,
0BYD0Z1,
0BYF0Z0,
0BYF0Z1,
0BYG0Z0,
0BYG0Z1,
0BYH0Z0,
0BYH0Z1,
0BYJ0Z0,
0BYJ0Z1,
0BYK0Z0,
0BYK0Z1,
0BYL0Z0,
0BYL0Z1,
0BYM0Z0,
0BYM0Z1,
Transplantation of
lung
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 88
FDA-CBER-2021-5683-1076129
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON- INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
Table 15.1.Operational Definitions of Demographic and Clinical Characteristics
Variable Description Operational definition
o0DY60Z0,
0DY60Z1,
Transplantation of
stomach
o0DY80Z0,
0DY80Z1,
Transplantation of
small intestine
o0DYE0Z0,
0DYE0Z1,
Transplantation of
large intestine
o0FY00Z0, 0FY00 Z1,
Transplantation of
liver
o0FYG0Z0,
0FYG0Z1,
Transplantation of
pancreas
o0TY00Z0,
0TY00Z1,
0TY10Z0,
0TY10Z1,
Transplantation of
kidney
VTE:
ICD-9-CM codes:
o415.1x, Pulmonary
embolism and
infarction
o451.x, 451.xx,
Phlebitis and
thrombophlebitis
o452, Portal vein
thrombosis
o453.x, 453.xx, Other
venous embolism
and thrombosis
ICD-10-CM codes:
oI26, I26.x, I 26.xx,
Pulmonary embolism
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 89
FDA-CBER-2021-5683-1076130
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON- INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
Table 15.1.Operational Definitions of Demographic and Clinical Characteristics
Variable Description Operational definition
oI80, I80.x, I 80.xx,
I80.xxx, Phlebitis
and thrombophlebitis
oI81, Portal vein
thrombosis
oI82, I82.x, I 82.xx,
I82.xxx Other
venous embolism
and thrombosis
Immunization
history Categorical variable:
Seasonal influenza
Tetanus diphtheria and
pertussis (Tdap or Td)
Chickenpox (Varicella)
Shingles (Herpes Zoster
recombinant and/or live)
Human papillomavirus
(HPV)
Pneumococcal conjugate
Pneumococcal
polysaccharide
Hepatitis A
Hepatitis B
Meningococcal
conjugate (MenACWY)
and serogroup B
meningococcal (MenB)
Haemophilus influenza
type bSeasonal influenza:
See Table 15.3
Tetanus diphtheria and pertussis (Tdap
or Td):
CPT codes:
o90714, Tetanus and diphtheria
toxoids adsorbed (Td),
preservative free, when
administered to individuals 7
years or older, for
intramuscular use
o90715, Tdap administered to
individuals 7 y ears or older,
for intramuscular use
o90718, Tetanus and
diphtheria toxoids (Td)
adsorbed when administered
to individuals 7 y ears or
older, for intramuscular use
Chickenpox (Varicella)
CPT codes:
o90396, Varicella -zoster
immune globulin, human, for
intramuscular use
o90716, Varicella virus
vaccine, l ive, for subcutaneous
use
Shingles (Herpes Zoster recombinant
and/or live)
CPT codes:
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 90
FDA-CBER-2021-5683-1076131
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON- INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
Table 15.1.Operational Definitions of Demographic and Clinical Characteristics
Variable Description Operational definition
o90396, Varicella -zoster
immune globulin, human, for
intramuscular use
o90736, Zoster (shingles)
vaccine (HZV), live, for
subcutaneous injection
o90750, Zoster (shingles)
vaccine (HZV), recombinant,
subunit, adjuvanted, for
intramuscular use
Human papillomavirus (HPV)
CPT codes:
o90649, Human Papillomavirus
vaccine, t ypes 6, 11, 16, 18,
quadrivalent (4vHPV), 3 dose
schedule, for intramuscular
use
o90650, Human Papillomavirus
vaccine, t ypes 16, 18, bivalent
(2vHPV), 3 dose schedule, for
intramuscular use
o90651, Human Papillomavirus
vaccine t ypes 6, 11, 16, 18, 31,
33, 45, 52, 58, nonavalent
(9vHPV), 2 or 3 dose
schedule, for intramuscular
use
Pneumococcal conjugate
CPT codes:
o90669, Pneumococcal
conjugate vaccine, 7 valent,
for intramuscular use
o90670, Pneumococcal
conjugate vaccine, 13 valent
(PCV13), for intramuscular
use
HCPCS codes (used
pneumococcal conjugate and
polysaccharide):
oG0009, Administration of
pneumococcal vaccin e
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 91
FDA-CBER-2021-5683-1076132
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON- INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
Table 15.1.Operational Definitions of Demographic and Clinical Characteristics
Variable Description Operational definition
oG8864, Code for
Pneumococcal vaccine
administered or previously
received
Pneumococcal pol ysaccharide:
CPT code:
o90732, Pneumococcal
polysaccharide vaccine, 23 -
valent (PPSV23), adult or
immunosuppressed patient
dosage, when administered to
individuals 2 y ears or older,
for subcutaneous or
intramuscular use
Hepatitis A
CPT codes
o90632, Hepatitis A vaccine,
adult dosage, for
intramuscular use
o90633, Hepatitis A vaccine
(HepA), pediatric/adolescent
dosage -2 dose schedule, for
intramuscular use
o90634, Hepatitis A vaccine
(HepA), pediatric/adolescent
dosage -3 dose schedule, for
intramuscular use
o90730, Hepatitis A vaccine
o90636, Hepatitis A and
hepatitis B vaccine (HepA -
HepB), adult dosage, for
intramuscular use
Hepatitis B
CPT codes:
o90731, Hepatitis B vaccine
o90739, Hepatitis B vaccine
(HepB), adult dosage, 2 dose
schedule, for intramuscular
use
o90740, Hepatitis B vaccine
(HepB), dial ysis or
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 92
FDA-CBER-2021-5683-1076133
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON- INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
Table 15.1.Operational Definitions of Demographic and Clinical Characteristics
Variable Description Operational definition
immunosuppressed patient
dosage, 3 dose schedule, for
intramuscular use
o90743, Hepatitis B vaccine
(HepB), adolescent, 2 dose
schedule, for intramuscular
use
o90744, Hepatitis B vaccine
(HepB), pediatric/adolescent
dosage, 3 dose schedule, for
intramuscular use
o90745, Hepatitis B vaccine,
adolescent/high risk infant
dosage, for intramuscular use
o90746, Hepatitis B vaccine
(HepB), adult dosage, 3 dose
schedule, for intramuscular
use
o90747, Hepatitis B vaccine
(HepB), dial ysis or
immunosuppressed patient
dosage, 4 dose schedule, for
intramuscular use
HCPCS codes:
oG0010, Administration of
Hepatitis B vaccine
Meningococcal conjuga te (MenACWY)
and serogroup B meningococcal
(MenB)
CPT codes:
o90619, Meningococcal
conjugate vaccine, serogroups
A, C, W, Y, quadrivalent,
tetanus toxoid carrier
(MenACWY -TT), for
intramuscular use
o90620, Meningococcal
recombinant protein and outer
membrane vesicle vaccine,
serogroup B (MenB -4C), 2
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 93
FDA-CBER-2021-5683-1076134
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON- INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
Table 15.1.Operational Definitions of Demographic and Clinical Characteristics
Variable Description Operational definition
dose schedule, for
intramuscular use
o90621, Meningococcal
recombinant lipoprotein
vaccine, serogroup B (MenB -
FHbp), 2 or 3 dose schedule,
for intramuscular use
o90733, Meningococcal
polysaccharide vaccine,
serogrou ps A, C, Y, W- 135,
quadrivalent (MPSV4), for
subcutaneous use
o90734, Meningococcal
conjugate vaccine, serogroups
A, C, W, Y, quadrivalent,
diphtheria toxoid carrier
(MenACWY -D) or CRM197
carrier (MenACWY -CRM),
for intramuscular use
Haemophilus influenza typ e b
CPT codes:
o90645, Hemophilus influenza
b vaccine (Hib), HbOC
conjugate (4 dose schedule),
for intramuscular use
o90646, Hemophilus influenza
b vaccine (Hib), PRP -D
conjugate, for booster use
only, intramuscular use
o90647, Haemophilus
influenzae ty pe b vaccine
(Hib), PRP -OMP conjugate, 3
dose schedule, for
intramuscular use
o90648, Haemophilus
influenzae ty pe b vaccine
(Hib), PRP -T conjugate, 4
dose schedule, for
intramuscular use
o90737, Hemophilus influenza
B
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 94
FDA-CBER-2021-5683-1076135
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON- INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
Table 15.1.Operational Definitions of Demographic and Clinical Characteristics
Variable Description Operational definition
o90748, Hepatitis B and
Haemophilus influenza e type
b vaccine (Hib -HepB), for
intramuscular use
*BMI was assessed within the one -year and tw o-year baseline periods, respectively. BMI at the time of the
most recent encounter within the baseline period prior to vaccination date was included and w as ca lculated
based on patient height and weight data as dividing weight in kilograms (kg) by height in meters (m) squared.
Patients with missing BMI or those with BMI <15 or > 60were categorized as "Unknown"
.
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 95
FDA-CBER-2021-5683-1076136
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON- INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
Table 15.2.Operation Definitions of Safety Events of Interest
Variable Operational Definition
Defined b y the presence of an y of the following
ICD-9-CM codes (inclusive)*:Defined b y the presence of an y of the
following ICD -10-CM codes
(inclusive)*:
Neurologic
Generalized convulsions/seizures44,57345, Epilepsy and recurrent seizures
780.3, Convulsions
780.31, Febrile convulsion s (simple),
unspecified
780.39, Other convulsions
780.32, Complex febrile convulsionsG40.A01, Absence epileptic
syndrome, not intractable, with
status epilepticus
G40.A09, Absence epileptic
syndrome, not intractable, without
status epilepticus
G40.A11, Absence epileptic
syndrome, intractable, with status
epilepticus
G40.A19, Absence epileptic
syndrome, intractable, without
status epilepticus
G40.101, L ocalization -related
(focal) (partial) sy mptomatic
epilepsy and epileptic s yndromes
with simple partial seizures, not
intractable, with status epilepticus
G40.109, L ocalization -related
(focal) (partial) sy mptomatic
epilepsy and epileptic s yndromes
with simple partial seizures, not
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 96
FDA-CBER-2021-5683-1076137
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON- INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
Table 15.2.Operation Definitions of Safety Events of Interest
Variable Operational Definition
Defined b y the presence of an y of the following
ICD-9-CM codes (inclusive)*:Defined b y the presence of an y of the
following ICD -10-CM codes
(inclusive)*:
intractable, without status
epilepticus
G40.111, L ocalization -related
(focal) ( partial) sy mptomatic
epilepsy and epileptic s yndromes
with simple partial seizures,
intractable, with status epilepticus
G40.119, L ocalization -related
(focal) (partial) sy mptomatic
epilepsy and epileptic s yndromes
with simple partial seizures,
intractable, without status
epilepticus
G40.201, L ocalization -related
(focal) (partial) sy mptomatic
epilepsy and epileptic s yndromes
with complex partial seizures, not
intractable, with status epilepticus
G40.209, L ocalization -related
(focal) (partial) sy mptomatic
epilepsy and epileptic s yndromes
with complex partial seizures, not
intractable, without status
epilepticus
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 97
FDA-CBER-2021-5683-1076138
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON- INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
Table 15.2.Operation Definitions of Safety Events of Interest
Variable Operational Definition
Defined b y the presence of an y of the following
ICD-9-CM codes (inclusive)*:Defined b y the presence of an y of the
following ICD -10-CM codes
(inclusive)*:
G40.211, L ocalization -related
(focal) (partial) sy mptomatic
epilepsy and epileptic s yndromes
with complex partial seizures,
intractable, with status ep ilepticus
G40.219, L ocalization -related
(focal) (partial) sy mptomatic
epilepsy and epileptic s yndromes
with complex partial seizures,
intractable, without status
epilepticus
G40.309, Generalized idiopathic
epilepsy and epileptic s yndromes,
not intractable, without status
epilepticus
G40.311, Generalized idiopathic
epilepsy and epileptic s yndromes,
intractable, with status epilepticus
G40.401, Other generalized
epilepsy and epileptic s yndromes,
not intractable, with status
epilepticus
G40.409, Other generali zed
epilepsy and epileptic s yndromes,
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 98
FDA-CBER-2021-5683-1076139
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON- INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
Table 15.2.Operation Definitions of Safety Events of Interest
Variable Operational Definition
Defined b y the presence of an y of the following
ICD-9-CM codes (inclusive)*:Defined b y the presence of an y of the
following ICD -10-CM codes
(inclusive)*:
not intractable, without status
epilepticus
G40.411, Other generalized
epilepsy and epileptic s yndromes,
intractable, with status epilepticus
G40.419, Other generalized
epilepsy and epileptic s yndromes,
intractable, wi thout status
epilepticus
G40.501, Epileptic seizures
related to external causes, not
intractable, with status epilepticus
G40.509, Epileptic seizures
related to external causes, not
intractable, without status
epilepticus
G40.802, Other epileps y, not
intractable, without status
epilepticus
G40.804, Other epileps y,
intractable, without status
epilepticus
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 99
FDA-CBER-2021-5683-1076140
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON- INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
Table 15.2.Operation Definitions of Safety Events of Interest
Variable Operational Definition
Defined b y the presence of an y of the following
ICD-9-CM codes (inclusive)*:Defined b y the presence of an y of the
following ICD -10-CM codes
(inclusive)*:
G40.821, Epileptic spasms, not
intractable, with status epilepticus
G40.822, Epileptic spasms, not
intractable, without status
epilepticus
G40.823, Epileptic spasms,
intractable, with status epilepticus
G40.824, Epileptic spasms,
intractable, without status
epilepticus
G40.901, Epilepsy , unspecified,
not intractable, with status
epilepticus
G40.909, Epilepsy , unspecified,
not intractable, without status
epilepticus
R56.00, Simple febrile
convulsions
R56.01, Complex febrile
convulsions
R56.9, Unspecified convulsions
Guillain -Barré syndrome (GBS)44,57357.0, Guillain -Barre s yndrome G61.0, Guillain -Barre syndrome
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 100
FDA-CBER-2021-5683-1076141
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON- INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
Table 15.2.Operation Definitions of Safety Events of Interest
Variable Operational Definition
Defined b y the presence of an y of the following
ICD-9-CM codes (inclusive)*:Defined b y the presence of an y of the
following ICD -10-CM codes
(inclusive)*:
Aseptic meningitis29322.1, Eosinophilic meningitis
322.9, Meningitis, unspecifiedG03.8, Meningitis due to other
specified causes
G03.9, Meningitis, unspecified
Encephalitis/encephalomyelitis44,57323.5, Encephalitis, my elitis, and
encephalomy elitis following immunization
procedures
323.51, Encephalitis and encephalomy elitis
following immunization procedures
323.52, My elitis following immunization
procedures
323.62, Other postinfectious encephalitis
and encephalom yelitis
323.81, Other causes of encephalitis and
encephalomy elitis
323.9, Unspecified causes of encephalitis,
myelitis, and encephalomyelitis
323.41, Other encephalitis and
encephalomy elitis due to infection
classified elsewhereG04.00, Acute disseminated
encephalitis and
encephalomy elitis, unspecified
G04.02, Postimmunization acute
disseminated encephalitis, my elitis
and encephalom yelitis
G04.81, Other encephalitis and
encephalomy elitis
G04.90, Encephalitis and
encephalomy elitis, unspecified
G05.3, Encephalitis and
encep halomy elitis in diseases
classified elsewhere
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 101
FDA-CBER-2021-5683-1076142
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON- INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
Table 15.2.Operation Definitions of Safety Events of Interest
Variable Operational Definition
Defined b y the presence of an y of the following
ICD-9-CM codes (inclusive)*:Defined b y the presence of an y of the
following ICD -10-CM codes
(inclusive)*:
Other acute dem yelinating diseases
(excluding those limited as separate
outcomes)44,57341.0, Neurom yelitis optica
341.1, Schilder's disease
341.8, Other dem yelinating diseases of
central nervous s ystem
341.9, Demy elinating disease of central
nervous s ystem, unspecified
357.81, Chronic inflammatory
demy elinating pol yneuritisG37.1, Central dem yelination of
corpus callosum
G37.2, Central pontine
myelinol ysis
G37.8, Other specified
demy elinating diseases of central
nervous s ystem
G37.9, Dem yelinating disease of
central nervous s ystem,
unspecified
G61.81, Chronic inflammatory
demy elinating pol yneuritis
Transverse m yelitis (TM)44,57341.2, Acute (transverse) my elitis G37.3, Acute transverse my elitis
in demy elinating disease of central
nervous s ystem
Multiple sclerosis (MS)44,57340, Multiple sclerosis G35, Multiple sclerosis
Optic neuritis (ON)44,57377.30, Optic neuritis, unspecified
377.31, Optic papillitis
377.32, Retrobulbar n euritis (acute)
377.34, Toxic optic neuropathy
377.39, Other optic neuritisG36.0, Neurom yelitis optica
[Devic]
H46.00, Optic papillitis,
unspecified ey e
H46.01, Optic papillitis, right ey e
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 102
FDA-CBER-2021-5683-1076143
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON- INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
Table 15.2.Operation Definitions of Safety Events of Interest
Variable Operational Definition
Defined b y the presence of an y of the following
ICD-9-CM codes (inclusive)*:Defined b y the presence of an y of the
following ICD -10-CM codes
(inclusive)*:
H46.02, Optic papillitis, left ey e
H46.03, Optic papillitis, bilateral
H46.10, Retrobulbar neuritis,
unspecified ey e
H46.11, Retrobulbar neuritis, right
eye
H46.12, Retrobulbar neuritis, left
eye
H46.13, Retrobulbar neuritis,
bilateral
H46.3, Toxic optic neuropathy
H46.8, Other optic neuritis
H46.9, Unspecified opti c neuritis
Bell’s pals y44,57351.0, Bell’s Pals y
351.8, Other facial nerve disorders
351.9, Facial nerve disorder, unspecifiedG51.0, Bell's pals y
G51.8, Other disorders of facial
nerve
G51.9, Disorder of facial nerve,
unspecified
Immunologic
Anaph ylaxis44,57999.4, Anaph ylactic shock due to serum not
elsewhere specifiedT78.2XXA, Anaph ylactic shock,
unspecified, initial encounter
090177e1975eec19\Approved\Approved On: 23-Jun-2021 02:25 (GMT)
Page 103
FDA-CBER-2021-5683-1076144
Pfizer -BioNTech COVID -19 vaccine
C4591012 NON- INTERVENTIONAL STUDY INTERIM REPORT
22June 2021
PFIZER CONFIDENTIAL
Table 15.2.Operation Definitions of Safety Events of Interest
Variable Operational Definition
Defined b y the presence of an y of the following
ICD-9-CM codes (inclusive)*:Defined b y the presence of an y of the
following ICD -10-CM codes
(inclusive)*:
995.0, Other anaph ylactic reaction T80.52XA, Anaph ylactic reaction
due to vaccination, initial
encounter
Vasculitides (excluding those limited
as separate outcomes)23,24136.1, Behcet’s disease
273.2, Other paraproteinemias
287.0, Allergic purpura (Henoch -Schonlein
Purpura)
443.1, Thromboangiitis obliterans
(Buerger’s disease)
446.0, Poly arteritis nodosa
446.4, Wegener’s granulamatosis
446.5, Giant cell arteritis
446.7, Takay asu’s disease
447.6, Arteritis, unspecifiedD69.0, Allergic purpura (Henoch -
Schonlein Purpura)
D89.1, Cry oglobulinemia
I73.1, Thromboangiitis obliterans
(Buerger’s di
…[truncated]