Document text
PF-07302048 (BNT162b2 RNA -Based COVID -19 Vaccine)
Protocol C4591020
Protocol, 18January2021
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (15 May 2020)
Page 1
A PHASE 3, RANDOMIZE D, OBSERVER -BLIND ST UDY TO EVALUATE THE
SAFETY, TOLERABILITY , AND IMMUNOGENICITY OF A LYOPHILIZED
FORMULATION OFTHE VACCINE CANDIDA TEBNT162b2 AGAINST
COVID-19 INHEALTHY ADULTS 18 T HROUGH 55 YEARS OF A GE
Study Sponsor: BioNTech
Study Conducted By: Pfizer
Study Intervention Number: PF-07302048
Study Intervention Name: BNT162b2 RNA -Based COVID -19 Vaccine
USINDNumber: 19736
EudraCT Number: 2020-002641-42
Protocol Number: C4591020
Phase: 3
Short Title: A Phase 3 Study to Evaluate the Safety , Tolerability , and Immunogenicity of a
LyophilizedFormulation of BNT162 b2 Against COVID -19 in Healthy Adults
This document and accompanying materials contain confidential information belonging to Pfizer. Except as
otherwise agreed to in writing, by accepting or reviewing these document s, you agree to hold this information in
confidence and not copy or disclose it to others (except where required by app licable law ) or use it for
unauthorized purposes. In the event of any actual or suspected breach of this obligation, Pfizer must be
promptly notified.
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PF-07302048 (BNT162b2 RNA -Based COVID -19 Vaccine)
Protocol C4591020
Protocol, 18January2021
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (15 May 2020)
Page 2Protocol Amendment Summary of Changes Table
Document History
Document Version Date Summary and Rationale for Changes
Originalprotocol 18Jan2021 N/A
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FDA-CBER-2021-5683-1073381
PF-07302048 (BNT162b2 RNA -Based COVID -19 Vaccine)
Protocol C4591020
Protocol, 18January2021
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (15 May 2020)
Page 3TABLE OF CONTENTS
LIST OF TABLES ................................ ................................ ................................ ..................... 7
1. PROTOCOL SUMMARY ................................ ................................ ................................ .....8
1.1. Synopsis................................ ................................ ................................ .................... 8
1.2. Schema ................................ ................................ ................................ .................... 11
1.3. Schedule of Activities ................................ ................................ ............................. 12
2. INTRODUCTION ................................ ................................ ................................ ...............14
2.1. Study Rationale ................................ ................................ ................................ .......14
2.2. Background ................................ ................................ ................................ .............14
2.2.1. Clinical Overview ................................ ................................ ....................... 15
2.3. Benefit/Risk Assessment ................................ ................................ ......................... 17
2.3.1. Risk Assessment................................ ................................ ......................... 19
2.3.2. Benefit Assessment ................................ ................................ ..................... 21
2.3.3. Overall Benefit/Risk Conclusion ................................ ................................ 21
3. OBJECTI VES, ESTIMANDS, AND ENDPOINTS...........................................................21
4. STUDY DESIGN ................................ ................................ ................................ ................. 22
4.1. Overall Design ................................ ................................ ................................ .........22
4.2. Scientific Rationale for Study Design................................ ................................ .....22
4.3. Justification for Dose ................................ ................................ .............................. 23
4.4. End of Study Definition ................................ ................................ .......................... 23
5. STUDY POPUL ATION................................ ................................ ................................ ......23
5.1. Inclusion Criteria ................................ ................................ ................................ .....23
5.2. Exclusion Criteria ................................ ................................ ................................ ....24
5.3. Lifestyle Considerations ................................ ................................ .......................... 25
5.3.1. Contraception ................................ ................................ .............................. 25
5.4. Screen Failures ................................ ................................ ................................ ........25
5.5. Criteria for Temporarily Delaying Enrollment/Randomization/Study
Intervention Administration ................................ ................................ ...................... 26
6. STUDY INTERVENTIO N................................ ................................ ................................ ..27
6.1. Study Intervention(s) Administered ................................ ................................ ........27
6.1.1. Administration ................................ ................................ ............................ 27
6.2. Preparation/Handling/Storage/Accountability ................................ ........................ 28
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Protocol C4591020
Protocol, 18January2021
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CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (15 May 2020)
Page 46.2.1. Preparation and Dispensing ................................ ................................ ........29
6.3. Measures to Minimize Bias: Randomization and Blinding ................................ .....29
6.3.1. Allocation to Study Intervention ................................ ................................ 29
6.3.2. Blinding of Site Personnel ................................ ................................ ..........30
6.3.3. Blinding of the Sponsor................................ ................................ ..............30
6.3.4. Breaking the Blind ................................ ................................ ...................... 30
6.4. Study Intervention Compliance ................................ ................................ ...............31
6.5. Concomitant Therapy ................................ ................................ .............................. 31
6.5.1. Prohibited During the Study ................................ ................................ .......31
6.5.2. Permitted During the Study ................................ ................................ ........32
6.6. Dose Modification ................................ ................................ ................................ ...32
6.7. Intervention After the End of the Study ................................ ................................ ..32
7. DISCONTINUATION O F STUDY INTERVENTION AND PAR TICIPANT
DISCONTINUATION/WI THDRAWAL ................................ ................................ ...........32
7.1. Discontinuation of Study Intervention ................................ ................................ ....32
7.2. Participant Discontinuation/Withdrawal From the Study ................................ .......33
7.2.1. Withdrawal of Consent ................................ ................................ ...............34
7.3. Lost to Follow -up................................ ................................ ................................ ....34
8. STUDY ASSESSMENTS AND PROCEDURES ................................ ............................... 35
8.1. Efficacy and/or Immunogenicty Assessments ................................ ........................ 35
8.1.1. Biological Samples ................................ ................................ ..................... 36
8.2. Safet y Assessments ................................ ................................ ................................ .36
8.2.1. Clinical Safety Laboratory Assessments ................................ .................... 37
8.2.2. Electronic Diary ................................ ................................ .......................... 37
8.2.2.1. Grading Scales ................................ ................................ ...........37
8.2.2.2. L ocal Reactions ................................ ................................ .........37
8.2.2.3. Sy stemic Events ................................ ................................ ........38
8.2.2.4. Fever ................................ ................................ .......................... 39
8.2.2.5. Antipy retic Medication ................................ ............................. 40
8.2.3. Pregnancy Testing................................ ................................ ...................... 40
8.3. Adverse Events and Serious Adverse Events................................ .......................... 40
8.3.1. Time Period and Frequency for Collecting AE and SAE Information .......41
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Page 58.3.1.1. Reporting SAEs to Pfizer Safety ................................ ...............41
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF................... 42
8.3.2. Method of Detecting AEs and SAEs ................................ .......................... 42
8.3.3. Follow -up of AEs and SAEs ................................ ................................ .......42
8.3.4. Regulatory Reporting Requirements for SAEs ................................ ...........42
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational
Exposure ................................ ................................ ................................ ..........43
8.3.5.1. Exposure During Pregnancy ................................ ...................... 43
8.3.5.2. Exposure During Breastfeeding ................................ ................ 44
8.3.5.3. Occupational Exposure ................................ ............................. 45
8.3.6. Cardiovascular and Death Events ................................ ............................... 45
8.3.7. Disease -Related Events and/or Disease -Related Outcomes Not
Qualifying as AEs or SAEs ................................ ................................ ..............45
8.3.8. Adverse Events of Special Interest................................ ............................. 45
8.3.8.1. Lack of Efficacy ................................ ................................ ........46
8.3.9. Medical Device Deficiencies ................................ ................................ ......46
8.3.10. Medication Errors ................................ ................................ ..................... 46
8.4. Treatment of Overdose................................ ................................ ............................ 47
8.5. Pharmacokinetics ................................ ................................ ................................ ....47
8.6. Pharmacod ynamics................................ ................................ ................................ ..47
8.7.Genetics................................ ................................ ................................ ................... 47
8.8. Biomarkers ................................ ................................ ................................ ..............47
8.9. Immunogenicit y Assessments ................................ ................................ ................. 47
8.10. Health Economics ................................ ................................ ................................ .48
8.11. Study Procedures ................................ ................................ ................................ ...48
8.11.1. Visit 1 – Vaccination 1 (Day 1)................................ ................................ 48
8.11.2. Visit 2 – Vaccination 2 (19 to 23 Day s After Visit 1) .............................. 50
8.11.3. Visit 3 – 1- Month Follow -up (28 to 35 Days After Visit 2)..................... 52
8.11.4. Unscheduled Visits for a Grade 3 or Suspected Grade 4 Reaction.......... 53
9. STATI STICAL CONSI DERATIONS ................................ ................................ ................ 54
9.1. Estimands and Statistical Hy potheses................................ ................................ .....54
9.1.1. Estimands ................................ ................................ ................................ ....54
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CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (15 May 2020)
Page 69.1.2. Statistical Hy pothesis................................ ................................ .................. 55
9.1.3. Multiplicity Considerations................................ ................................ ........55
9.2. Sample Size Determination ................................ ................................ ..................... 55
9.3. Analy sis Sets................................ ................................ ................................ ...........56
9.4. Statistical Analy ses................................ ................................ ................................ .57
9.4.1. General Considerations ................................ ................................ ...............57
9.4.1.1. Analy sis for Binary Data................................ ........................... 57
9.4.1.2. Analy sis for Continuous Data ................................ ................... 58
9.4.2. Primary Endpoint(s) ................................ ................................ .................... 58
9.4.3. Secondary Endpoint(s) ................................ ................................ ................ 59
9.5.Interim Anal yses................................ ................................ ................................ .....59
9.6. Data Monitoring Committee or Other Independent Oversight Committee .............60
10. SUPPORTING DOCUM ENTATION AND OPERATI ONAL
CONSIDERATIONS................................ ................................ ................................ ..........61
10.1. Appendix 1: Regulatory , Ethical, and Study Oversight Considerations ...............61
10.1.1.Regulatory and Ethical Considerations ................................ .................... 61
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the
Protocol or I CH GCP................................ ................................ .........61
10.1.2. Financial Disclosure ................................ ................................ ................. 62
10.1.3. Informed Consent Process ................................ ................................ ........62
10.1.4. Data Protection ................................ ................................ ......................... 63
10.1.5. Dissemination of Clinical Study Data................................ ...................... 63
10.1.6. Data Qualit y Assurance ................................ ................................ ............65
10.1.7. Source Documents ................................ ................................ .................... 66
10.1.8. Study and Site Start and Closure ................................ .............................. 66
10.1.9. Publication Policy................................ ................................ ..................... 67
10.1.10. Sponsor’s Qualified Medical Personnel ................................ ................. 68
10.2.Appendix 2: Clinical Laboratory Tests................................ ................................ .68
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording,
Evaluating, Follow -up, and Reporting ................................ ................................ ......69
10.3.1. Definition of AE ................................ ................................ ....................... 69
10.3.2. Definition of SAE ................................ ................................ ..................... 70
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Page 710.3.3. Recording/Reporting and Follow- up of AEs and/or SAEs ....................... 72
10.3.4. Reporting of SAEs................................ ................................ .................... 75
10.4. Appendix 4: Contraceptive Guidance ................................ ................................ ...76
10.4.1. Male Participant Reproductive Inclusion Criteria................................ ....76
10.4.2. Female Participant Reproductive Inclusion Criteria ................................ .76
10.4.3. Woman of Childbearing Potential ................................ ............................ 77
10.4.4. Contraception Methods ................................ ................................ .............78
10.5. Appendix 5: L iver Safety : Suggested Actions and Follow -up Assessments ........80
10.6. Appendix 6: Abbreviations................................ ................................ ................... 82
11. REFERENCES ................................ ................................ ................................ .................. 85
LIST OF TABLES
Table1. Local Reaction Grading Scale................................ ................................ ..38
Table2. Systemic Event Grading Scale ................................ ................................ ..39
Table3. Scale for Fever ................................ ................................ .......................... 40
Table4. Power Anal ysis for Noninferiorit y Assessment ................................ .......56
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PFIZER CONFIDENTIAL
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Page 81.PROTOCOL SUMMARY
1.1.Synopsis
Short Title: A Phase 3 Study to Evaluate the Safety , Tolerability , and Immunogenicity of a
LyophilizedFormulation of BNT162 b2 Against COVID -19 in Healthy Adults
Rationale
A pneumonia of unknown cause detected in Wuhan, China, was first reported in
December 2019. In January2020, the pathogen causing this outbreak was identified as a
novel coronavirus 2019. The outbreak was declared a Public Health Emergency of
International Concern on 30 January2020. On 12 February 2020, the virus was officiall y
named as severe acu te respiratory syndrome coronavirus 2 (SARS -CoV-2), and the WHO
officially named the disease caused b y SARS-CoV-2 as coronavirus disease 2019
(COVID-19). On 11 March 2020, the WHO upgraded the status of the COVID- 19 outbreak
from epidemic to pandemic, whi ch continues to spread globally at high speed.
There are currently no licensed vaccines to prevent infection with SARS -CoV-2 or the
disease it causes, COVID -19. Based on Phase 2/3 safet y, immunogenicity, and efficacy data,
BNT162b2 was shown to be effecti ve and has been authorized for temporary or emergency
usein multiple countries,eg, UK, US, Canada, Mexico, and Bahrain .
The Pfizer-BioNTech COVID-19 vaccine (also referred to as BNT162b2 ) is administered
intramuscularl y as a 2-dose series spaced 21 day s apart at a dose of 30 μg each. Study
C4591001 (NCT04368728) is an ongoing Phase 1/2/3 trial in ~44,000 participants designed
to generate safet y, tolerability , immunogenicit y, and efficacy data from a novel RNA -based
vaccine candidate. The trial is being conducted in a heterogeneous study population: eligible
participants ≥12years of age, healthy participants, including those participants with stable
chronic medical conditions, including HIV-, HCV-, and HBV -positive participants. The
study consists of 2 parts: Phase 1: to identify the preferred vaccine candidate (BNT162b1 or
BNT162b2) and dose level (10 µg, 20µg, 30µg, or 100 µg [for BNT162b1]); Phase 2/3: an
expanded -cohort and efficac ypart for the selected vaccine candidate (BNT162b2).
BNT162b2 was selected from the Phase 1 part of this study based on the overall safety ,
tolerability, and immunogenicity .Vaccine efficacy from Phase 2/3 for the primary endpoint
against confirmed COVID -19 occurring at least 7 day s after the second dose was 95% with
8COVID-19 cases in the active vaccine group compared to 162 COVID-19 cases in the
placebo group. Data from approximately 38,000 participants randomized 1:1 with a median
of 2months of follow- up after the second dose of vaccine showed a favorable safet y profile
at a dose of 30 μg in participants 16 y ears of age and older.
To optimize storage and distribution of this vaccine on a wide scale ,a lyophilized
formulation that will be stable at standard refrigerator temperatures isrequired. Therefore,
this study will compare the safety andtolerability of lyophilized BNT162b2 presented in
SDVsto those of frozen -liquid BNT162b2 in MDVs, and demonstrate that the immune
response is nonin ferior.An alternative MDVpresentation of the ly ophilized BNT162b2 may
also be studied in a separate comparison to frozen -liquidBNT162b2 in MDV s.
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CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (15 May 2020)
Page 9Objectives , Estimands, and Endpoints
Objectives Estimands Endpoints
Primary Immunogenicity
To demonstrate that the immune
response induced by lyophilized
BNT162b2 in SDVsisnoninferior to
the immune response induced by
frozen-liquid BNT162b2 in MDVs in
participants without evidence of
SARS-CoV-2 infection during the
studyIn participants complying with the key
protocol criteria (evaluable participants):
GMR from lyophilized formulation
in SDVsto frozen-liquid
formulation in MDVs 1 month after
Dose2Full-length S-binding IgG levels
To demonstrate that the immune
response induced by lyophilized
BNT162b2 in MDVs is noninferior to
the immune response induced by
frozen-liquid BNT162b2 in MDVs in
participants without evidence of
SARS-CoV-2 infection during the
studyIn participants complying with the key
protocol criteria (evaluable participants):
GMR from lyophiliz ed formulation
in MDVs to frozen -liquid
formulation in MDVs 1 month after
Dose2Full-length S-binding IgG levels
Primary Safety
To evaluate the safety of BNT162b2
when administered on a 2 -dose
schedule in healthy adults 18 through
55 years of ageIn participants receiving at least 1 dose
of study intervention from each vaccine
group, the percentage of participants
reporting:
Local reactions for up to 7 days
following each dose
Systemic events for up to 7 days
following each dose
AEs and SAEs from Dose 1 through
1month after Dose 2Local reactions (pain at the
injection site, redness, and
swelling)
Systemic events (fever, fatigue,
headache, chills, vomiting,
diarrhea, new or worsened muscle
pain, and new or worsened joint
pain)
AEs
SAEs
Secondary Immu nogenicity
To describe the immune responses
induced by BNT162b2In evaluable participants from each
vaccine group:
GMCsat baseline (before Dose 1)
and 1 month after Dose 2
GMFR from baseline (before
Dose1) through 1 month after Dose
2Full-length S-binding IgG levels
OverallDesign
This is a P hase 3, randomized, observer -blind study to evaluate the safet y, tolerability , and
immunogenicit y of a lyophilized formulation of BNT162B2 , an RNA -based COVID -19
vaccine, administered on a 2 -dose schedule in healthy adults 18 through 55 y ears of age.
Participants will receive either lyophilized BNT162b2 in SDVs or frozen -liquid BNT162b2
in MDVs. Separately, lyophilized BNT162b2 presented in MDVs may also be st udied,
where participants will receive either ly ophilized or frozen- liquid BNT162b2 in MDVs .
Participants will be randomized in a 1:1 ratio to 1 of the 2groups(lyophilized SDV or
frozen-liquidMDVcontrolfor lyophilized SDV );if lyophilized MDV is studied,participants
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PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (15 May 2020)
Page 10will be randomized in a 1:1 ratio to 1 of the 2 groups separately (lyophilized MDV or
frozen-liquid MDV controlfor lyophilized MDV ). The duration of the study for each
participant will be approximately 2months. The study will be conducted in the United States
with potential to expand to other countries .
Number of Participants
Approximately 275 participants will be randoml y assigned to each of the 2 or 4vaccine
groups(lyophilized SDV, frozen- liquid MDV control for ly ophilized SDV, ly ophilized
MDV, or frozen- liquid MDV control for l yophilized MDV) ,for a total of approximately 550
or 1100randomized participants. I t is expected that approximately 440 or 880evaluable
participants will complete the study , based on a 20% nonevaluable rate.
Data Monitoring Committee or Other Independent Oversight Committee : Yes
This study will use a DMC. The DMC is independent of the study team and includes
external members. The DMC charter describes the role of the DMC in more detail.
The DMC will be responsible for ongoing monitoring of the safety of participants in the
study according to the charter. This may include, but is not limited to:
Contemporaneous review of related AEs up to 1 month after completion of the
vaccination schedule,
Contemporaneous review of all SAEs up to 1 month after completion of the
vaccination schedule.
The recommendations made b y the DMC to alter the conduct of the stud y will be forwarded
to the appropriate Pfizer personnel for final decisio n. Pfizer will forward such decisions,
which may include summaries of aggregate analy ses of safety data, to regulatory authorities,
as appropriate.
Statistical Methods
There are 2 primary immunogenicity objectives; each will be evaluated separately by a
formal hypothesis test for nonin feriority ofthe full-length S-binding IgG levels induced b y
lyophilized SDV or MDV BNT162b2 compared to the corresponding frozen-liquid MDV
BNT162b2 control. GMRs will be provided along with associated 2 -sided 95% CI s.
Noninferiorit y will be declared if the lower bound of the 2 -sided 95% CIfor the GMR of
lyophilized BNT162b2 relative to frozen -liquid MDV BNT162b2 is greater than 0.67 ( using
a 1.5-fold noninferiority criterion).
With 220evaluable participants per group, the study has a power of 9 0.1% for declaring
noninferiority for each comparison. Assuming a nonevaluable rate of 20%, the study will
randomize approximately 275participants in each groupto achieve the required number of
evaluable participants.
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Page 11The secondary immunogenicity objectives will be evaluated descriptivel y by GMCs,
GMFRs, and the associated 95% CIs for the full- length S-binding IgG levels for each vaccine
group.
The primary safety objective will be evaluated b y descriptive statistics includi ng counts and
percentages of participants and the associated Clopper-Pearson 95% CIs for local reactions,
systemic events, and AEs/SAEs, for each vaccine group.
1.2.Schema
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Page 121.3. Schedule of Activ ities
The SoAtable provides an overview of the protocol visits and procedures. Refer to the STUDY ASSE SSMENTS AND
PROCEDURES section of the protocol for detailed information on each procedure and assessment required for compliance with the
protocol.
The investiga tor may schedule visits (unplanned visits) in addition to those listed i n the SoA table, in order to conduct evaluations or
assessments required to protect the well -being of the participant .
Visit Number 1 2 3
Visit Description Vaccination 1 Vaccination 2 1-Month Follow -up Visit
Visit Window Day 1a 19 to 23 Days After Visit 1 28 to 35 Days After Visit 2
Obtain informed consent X
Assign participant number X
Obtain demography and medical history data X
Perform clinical assessmentb X
Measure height and weight X
Measure temperature (body) X X
Perform urine pregnancy test (if appropriate) X X
Confirm use of contraceptives (if appropriate) X X X
Collect nonstudy vaccine information X X X
Collect prohibited medication use X X
Confirm eligibility X X
Review temporary delay criteria X X
Collect blood sample for immunogenicity assessment & for
serological testing for prior COVID -19 infectionc~20 mL ~20 mL
Obtain nasal (midturbinate) swab for determination of current
SARS-CoV-2 statuscX X
Obtain randomization number and study intervention allocation X
Administer study intervention X X
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Page 13Visit Number 1 2 3
Visit Description Vaccination 1 Vaccination 2 1-Month Follow -up Visit
Visit Window Day 1a 19 to 23 Days After Visit 1 28 to 35 Days After Visit 2
Assess acute reactions for at least 30 minutes after study intervention
administrationX X
Explain/review participant communication methods (including for
reactogenicity e -diary completion), assist the participant with
downloading the app, or issue provisioned device, if requiredX X
Provide/ensure participant has a thermometer and measuring device X X
Review reactogenicity e -diary data (daily review is optimal during
the active diary period)X X
Review ongoing reactogenicity e -diary symptoms with participant
and obtain stop datesX X
Collect AEs and SAEs X X Xd
Collect e-diary or assist the participant to delete the application X
Abbreviations: = continuous/ongoing event; e -diary = electronic diary.
a.The visit may be conducted across 2 consecutive days; if so, all steps from assessing the inclusion and exclusion criteria on ward must be conducted on the
same day.
b.Including, if indicated, a physical examination.
c.Administration of study intervention is not dependent on test result s.
d.Any AEs occurring up to 48 hours after blood draw and nasal swab collection must be recorded.
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Page 142.INTRODUCTION
BNT162b2 is an RNA -based COVID-19 vaccine that is currentl y being investigated for the
prevention of COVID -19 in individuals ≥12 years of age .On 02 December 2020, the MHRA
in the UK granted a temporary authorization. The distribution of the vaccine in the UK will
be prioriti zed according to the populations identified in advice from the JCVI. On
11December 2020, the US FDA issued an EUA for use in individuals 16 years of age and
older. Other countries have also granted EUA ( eg, Canada, Mexico, Bahrain ), andPfizer and
BioNTech are anticipating further regulatory decisions in other countries.
2.1.Study Rationale
The purpose of this stud y is to demonstrate that the immune response induced by the
refrigerator -stable lyophilized formulation of BNT162b2 is noninferior to the frozen -liquid
formulation of BNT162b2 in MDVs, and to describe the safety and tolerability of these
different vaccine formulations in healthy adults, there bysupporting refrigerated storage and
distribution at commercial scale.
2.2.Background
In December 2019, a pneumonia outbreak of unknown cause occurred in Wuhan, China.
InJanuary 2020, it became clear that a novel coronavirus (2019 -nCoV) was the underl ying
cause. Later in January , the genetic sequence of the 2019 -nCoV became available to the
WHO and the publ ic (MN908947.3), and the virus was categorized in the Betacoronavirus
subfamily . By sequence anal ysis, the phy logenetic tree revealed a closer relationship to
SARS virus isolates than to another coronavirus infecting humans, the MERS virus.1,2
The outbrea k was declared a Public Health Emergency of International Concern on
30January2020.3 On 12 February 2020, the virus was officiall y named as severe acute
respiratory syndrome coronavirus 2 (SARS -CoV-2), and the WHO officially named the
disease caused b y SARS-CoV-2 as coronavirus disease 2019 (COVID -19).3 SARS-CoV-2
infections and the resulting disease, COVID -19, have spread globall y and on 11 March 2020,
the WHO characterized the COVID- 19 outbreak as a pandemic.4 On 08 January 2021, The
Center for S ystems Science and Engineering at Johns Hopkins University reported more than
88million cases globall y, with over 1.9 million deaths from 1 91 countries. The
UnitedStates has reported more than 21.6 million cases and over 366,000 deaths.5 Since fall
of 2020, the incidence of COVID -19 illnesses is increasing dramaticall y in many northern
hemisphere countries, including the United States, France, German y, Italy, and theUnited
Kingdom, raising the specter that as temperatures have fallen and the “respiratory virus
season” has started, cases may dramaticall y increase, potentially overwhelming healthcare
infrastructures. This possibility highlights the importance of develo ping a COVID -19 vaccine
as quickly as possible while ensuring that all safety measures are met.
There are currently nolicensedvaccines to prevent, or effective antiviral drugs to treat,
SARS-CoV-2 infections or the disease it causes, COVID -19.6 A prophylactic, RNA -based
SARS-CoV-2 vaccine provides one of the most flexible and fastest approaches available to
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Page 15immunize against the emerging virus.7,8In an attempt to prevent the spread of disease and to
control the pandemic, numerous COVID -19 vaccine candidates are in development.
The development of an RNA -based vaccine encoding a viral antigen, which is then expressed
by the vaccine recipient as a protein capable of eliciting protective immune responses,
provides significant advantages over more tr aditional vaccine approaches. Unlike live
attenuated vaccines, RNA vaccines do not carry the risks associated with infection and may
be given to people who cannot be administered live virus (eg, pregnant women and
immunocompromised persons). RNA -based vaccines are manufactured via a cell -free
invitro transcription process, which allows an easy and rapid production and the prospect of
producing high numbers of vaccination doses within a shorter time period than achieved with
traditional vaccine approaches . This capability is pivotal to enable the most effective
response in outbreak scenarios.7,8
BNT162b2 is a SARS -CoV-2–RNA-LNP vaccine based on a platform of modRNA with
blunted innate immune sensor –activating capacit y and augmented expression encoding P2 S.
2.2.1. Clinical Overview
Study C4591001 (NCT04368728) is an ongoing Phase 1 /2/3 trialin ~44,000 particip ants
designed to generate safety , tolerabilit y, immunogenicity, and efficacy data from a novel
RNA-based vaccine candidate.9 The trial is being conducted in a heterogeneous study
population: eligible participants ≥12years of age, healthy participants, including those
participants with stable chronic medical conditions, including HIV-, HCV-, and
HBV-positive participants. The study consists of 2 parts: Phase 1: to identify the preferred
vaccine candidate (BNT162b1 or BNT162b2) and dose level (10 µg, 20 µg, 30 µg, or 100 µg
[for BNT162b1]); Phase 2/3: an expanded- cohort and efficacy part for the selected vaccine
candidate (BNT162b2). BNT162b2 was selected from the Phase 1 part of this study based on
the overall safet y,tolerability , and immunogenicity . In a mid- November 2020 anal ysis of
36,621 participants randomized 1:1 to vaccine or placebo who were included in the
per-protocol efficacy analysis population of participants without evidence of SARS -CoV-2
infection prio r to 7 day s after completion of the vaccination schedule, efficacy in preventing
confirmed COVID -19 occurring at least 7 day s after the second dose of vaccine was 95.0%,
with 8 COVI D-19 cases in the active vaccine group and 162 COVID -19 cases in the placeb o
group. Subgroup anal yses of the primary efficacy endpoint showed similar efficacy point
estimates across age groups, sexes, racial and ethnic groups, and participants with medical
comorbidities associated with high risk of severe COVID -19. Secondary efficacy analyses
suggested benefit of the vaccine in preventing severe COVID-19, in preventing COVID-19
following the first dose, and in preventing COVID -19 in individuals with prior SARS -CoV-2
infection, although available data for these outcomes did not all ow for firm conclusions.10
Safety data from approximately 38,000 participants at least 16 y ears of age randomized 1:1
to vaccine or placebo with a median of 2 months of follow-up after the second dose suggest a
favorable safety profile. Available safet y data from all participants enrolled through the
14 November 2020 data cutoff (N=43,252, which includes late enrollment of additional
adolescent and adult participants) w ereconsistent with the safet y profile for the
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Page 16approximately 38,000 participants with a median follow -up of 2 months and also did not
raise specific safet y concerns.10
The most common solicited adverse reactions were injection site reactions (84.1%), fat igue
(62.9%), headache (55.1%), muscle pain (38.3%), chills (31.9%), joint pain (23.6%), and
fever (14.2%); severe adverse reactions occurred in 0.0% to 4.6% of participants, were more
frequent after Dose 2 than after Dose 1, and were generall y less freque nt in participants
≥55years of age ( ≤2.8%) as compared to y ounger participants (≤4.6%). The frequency of
SAEs was low (<0.5%), without meaningful imbalances between stud y arms. Among
nonserious unsolicited AEs, there was a numerical imbalance of 4cases of Bell’s pals y in the
active vaccine group com pared with no cases in the placebo group, though the 4cases in the
active vaccine group do not represent a frequency above that expected in the general
population. Otherwise, there were no notable patterns or numerical imbalances between
vaccinegroups for specific categories of nonserious AEs (including other neurologic,
neuroinflammatory , and thrombotic events) that would suggest a causal relationship to
BNT162b2. With the exception of more frequent, generally mild to moderate reactogenicit y
in participants <55 years of age, the safet y profile of BNT162b2 was generally similar across
age groups, sexe s, ethnic and racial groups, participants with or without medical
comorbidities, and participants with o r without evidence of prior SARS -CoV-2 infection at
enrollment .10
In the C4591001 stud y, the Phase 1 population included health y participants 18 through 55
and 65 through 85 years of age. Enrollment in Phase 1 is complete and, although follow -up
continues, the available safet y data from Phase 1 participants show that BNT162b2
reactogenicity , AEs, and laboratory results were consistent with those commonly associated
with vaccination. The observed reactogenicity was generall y mild or moderate (primarily
pain at the injection site) and short-lived. The local reactions tended to be more frequent
after the second dose. There was no redness or swelling reported b y participants in the
65-through 85 -year age group who received BNT162b2.11
Regarding s ystemic events, 17% of the 18- through 55 -year age group and 8% of those in the
65-through 85 -year age group reported fever ( ≥38.0°C to 38.9°C) after the second dose of
30µgof BNT162b2. Severe s ystemic events (fatigue, headache, chills, muscle pain, and
joint pain) were reported in small numbers of y ounger recipients of this vaccine candidate,
but no severe s ystemic events were reported in older recipients, and there were n o Grade 4
systemic events reported.11
No unexpected AEs or SAEs were reported. Through 1 month after receipt of the second
vaccination, AEs that were considered b yinvestigators to be related to the study intervention
were reported in 25% of participants 18 through 55 y ears of age who received 30 µg of
BNT162b2; no AEs were reported by the older population who received the same dose.11
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Page 17The available immunogenicity data from Phase 1 participants show that BNT162b2 induced
a robust IgG -binding response to S1 and a SARS -CoV-2–neutralizing response.
Immunogenicit y substantially increased following the second dose of vaccine. BNT162b2
induces a strong antigen -specific Th 1–skewed CD4+ response and a strong antigen-specific
CD8+ response.
Based on the safety , tolerability , and immunogenicity data generated from Phase 1, the
vaccine candidate selected for the Phase 2/3 part of the study wasBNT162b2 at a dose
of30µg. This phase of the study is currentl y ongoing and is evaluating the efficacy of the
study intervention .
The Phase 2/3 portion of C4591001 was initiated in 18 -through 85 -year-old adults but was
amended in September 2020 to include participants ≥16 years of age. It is intended that a
minimum of 40% of participants will be in the >55 -year stratum. A further protoc ol
amendment in October 2020 added a stratum of 2000 participants (1000 active vaccine)
12through 15 years of age. The first 360 participants in the Phase 2/3 part of the study will
be considered the Phase 2 segment but will also contribute to the effica cy endpoint.
There are 2 primary efficacy endpoints in the Phase 2/3 part of the study. The first is to
evaluate the efficacy of prophy lactic BNT162b2 against confirmed COVID- 19 in participants
without evidence of infection before vaccination and the seco nd is to evaluate the efficacy of
prophylactic BNT162b2 against confirmed COVID -19 in participants regardless of evidence
of infection before vaccination. Cases of COVID -19 are defined b y the presence of specified
symptoms plus anNAATfor SARS -CoV-2 at least 7 day s following the second dose of
vaccine. Effectiveness in 12 -to 15-year-old participants will be inferred b y immune
noninferiority to that in 16-to 25-year-old participants based on SARS -CoV-2–neutralizing
GMTs.
The primary safety objectives in clude definition of the safet y profile of prophylactic
BNT162b2 in the first 360 participants in the Phase 2 population, in all participants
randomized in Phase 2/3, and in12 -to 15-year-old participants. Reactogenicity will be
assessed b y e-diary in allparticipants in Phase 1, in at least 6000 participants in Phase 2/3,
and in all participants 12 through 15 years of age.
The scale of the BNT162b2 manufacturing has been increased to support future supply .
Therefore, in the C4591001 Phase 2/3 phase of th e study, BNT162b2 generated using the
manufacturing process supporting an increased supply (“Process 2”) was administered to
approximately 250 participants 16 through 55 years of age, per lot.
The currently available safet y and immunogenicity data are pres ented in the BNT162 IB.12
2.3.Benefit/Risk Assessment
There is an ongoing global pandemic of COVID -19 with no approved or licensed preventive
or therapeutic options available. However, ba sed on the data available from the C4591001
study,multiple temporary or emergency use authorizations have been granted. The available
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Page 18safety and immunogenicitydata from the ongoing Pfizer/BioNTech clinical trial combined
with available nonclinical data with BNT162 vaccines, and data from nonclinical studies and
clinical trial s with the same or related RNA components, or antigens, support a favorable
benefit/risk profile and support continued clinical development of BNT162b2.
In the C4591001 stud y, BNT162b2has been shown to elicit increased local and sy stemic
adverse reactions as compared to those in the placebo arm, usuall y lasting a few days. The
most common solicited adverse reactions were injection site reactions (84.1%), fatigue
(62.9%), headache (55.1 %), muscle pain (38.3%), chills (31.9%), joint pain (23.6%), and
fever (14.2%).10Adverse reactions characterized as reactogenicit y were generall y mild to
moderate. The number of participant s reporting h ypersensitivity -related AEs was numerically
higher in the active vaccine group compared with the placebo group (137 [0.63%] vs 111
[0.51%]). Severe adverse reactions occurred in 0.0 % to 4.6% of participants, were mor e
frequent after Dose 2 than after Dose 1 ,and were generall y less frequent in older adults
(>55years of age) (<2.8%) as compared to younger participants ( ≤4.6%). Among reported
unsolicited AE s, lymphadenopathy occurred much more frequently in the active vaccine
group than the placebo group and is plausibly related to vaccination. S AEs, while uncommon
(<1.0%), represented medical events that occur in the general population at similar frequency
as observed in the study .10
No specific safet y concerns were identified in subgroup anal yses by age, race, ethnicit y,
medical comorbidities, or prior SARS -CoV-2 infection. Although participants 16 through
17years of age were enrolled in the P hase 3 trial, safet y data for this age group arelimited.
However, available data are consistent with the safety profile in the adult population, and it is
biologicall y reasonable to extrapolate the greater safet y experience in adults, in particular
younger adults, to the oldest pediatric age group of 16 through17 years. The potential risks
are based on the observed safet y profile to date, which shows mostly mild reactogenicity , low
incidence of severe or serious events, and no clinically concerning safet y observations. The
preponderance of severe cases of COVID -19 in the placebo group relative to the BNT162b2
group (9 of 10) suggests no evidence of VAED.10Continued clinical investigation is
justified given:
the urgent need to optimize storage and distribution of a COVID-19 vaccine on a
wide scale usinga lyophilized formulation that will be stable at standard refrigerator
temperatures,
the threat posed b y the increasing number of globally distributed outbreaks of
SARS-CoV-2 infection,
the potential of the BioNTech platform of RNA -based vaccines to rapidly deliver
high numbers of vaccine doses in a single production campaign.
More detailed information about the known and expected benefits and risks and reasonabl y
expected AEs of BNT162b2 may be found in the IB, which is the SRSD for this study .
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Page 192.3.1.Risk Assessment
Potential Risk of Clinical Significance Summary of Data/Rationale for Risk Mitigation Strategy
Study Intervention: BNT162b2 RNA -Based COVID- 19 Vaccine
Potential for local reactions (injection site redness,
injection site swelling, and injection site pain) and
systemic events (fever, fatigue, headache, chills,
vomiting, diarrhea, muscle pain, and joint pain)
following vaccination.These are common adverse reactions seen with other
vaccines, as noted in the FDA CBER guidelines on
toxicity grading scales for healthy adult volunteers
enrolled in preventive vaccine clinical trials.13The
most common events reported in C4591001 w ere
mild to moderate pain at the injection site, fatigue,
and headache.10The study employ s the use of a reactogenicity
e-diary to monitor local reactions and systemic
events in real time.
All study participants will be observed for at
least 30 minutes after vaccination.
Safety profile of a novel vaccine not yet fully
characterized.Data available from the C4591001 study showed
low incidence of severe or serious events, and no
clinically concerning safety observations. The
vaccine appears to be safe and w ell-tolerated across
the safety population and within demographic
subgroups based on age, sex, race/ethnicity, country,
and baseline SARS -CoV-2 status.AE and SAE reports will be collected from
signing of the ICD through1month after the
second dose of vaccine.
A DMCwill be employed throughout the study
to review all safety data.
Allparticipants will be observed for at least
30minutes after vaccination.
Potential for COVID -19 enhancement. Disease enhancement has been seen following
vaccination with RSV, feline coronavirus, and
Dengue virus vaccines. No evidence of disease
enhancement has been seen in large -scale clinical
study of BNT162b2 in humans.9Eligibility criteria will exclude any participants
who have had a previous clinical
(signs/symptoms only) or microbiological
(signs/symptoms and positive SARS -CoV-2
NAAT result) diagnosis of COVID -19. This
will minimize the low risk of potential disease
enhancement and ensure that the immune
response evaluated in the study is not impacted
by serological changes due to previous
COVID-19 disease.
The study will include m onitoring for cases o f
COVID-19 developing during the study, which
will be reported as AESIs.
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Page 20Potential Risk of Clinical Significance Summary of Data/Rationale for Risk Mitigation Strategy
Study Procedures
Participants will be required to attend healthcare
facilities during the global SARS -CoV-2 pandemic.Without appropriate social distancing and PPE, there
is a potential for increased exposure to
SARS-CoV-2.Pfizer will work with sites to ensure an
appropriate COVID -19 prevention strategy.
The study will include m onitoring for cases of
COVID-19 developing during the study, which
will be reported as AESIs.
Venipuncture will be performed during the study. There is the risk of bleeding, bruising, hematoma
formation, and infection at the venipuncture site.Only appropriately qualified personnel will obtain
the blood draw .
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Page 212.3.2.Benefit Assessment
Benefits to individual participants may include:
Receipt of a n efficacious or potentially efficacious COVID -19 vaccine during a
global pandemic
Access to COVID -19 diagnostic testing
Contributing to research to help others in a time of global pan demic
2.3.3.Overall Benefit /Risk Conclusion
Taking into account the measures taken to minimize risk sto participants participating in this
study, the potential risks identified in association with BNT162b2 are justified by the
anticipated benefits that may be afforded to healthy participants.
3.OBJECTIVES , ESTIMANDS ,AND ENDPOINTS
Objectives Estimands Endpoints
Primary Immunogenicity
To demonstrate that the immune
response induced by lyophilized
BNT162b2 in SDVs is noninferior to
the immune response induced by
frozen-liquid BNT162b2 in MDVs in
participants without evidence of
SARS-CoV-2 infection during the
studyIn participants complying with the key
protocol criteria (evaluable participants):
GMR from lyophiliz ed formulation
in SDVs to frozen -liquid
formulation in MDVs 1 month after
Dose2Full-length S-binding IgG levels
To demonstrate that the immune
response induced by lyophilized
BNT162b2 in MDVs is noninferior to
the immune response induced by
frozen-liquid BNT162b2 in MDVs in
participants without evidence of
SARS-CoV-2 infection during the
studyIn participants complying with the key
protocol criteria (evaluable participants):
GMR from lyophilized formulation
in MDVs to frozen -liquid
formulation in MDVs 1 month after
Dose2Full-length S-binding IgG levels
Primary Safety
To evaluate the safety of BNT162b2
when administered on a 2 -dose
schedule in healthy adults 18 through
55 years of ageIn participants receiving at least 1 dose
of study intervention from each vaccine
group, the percentage of participants
reporting:
Local reactions for up to 7 days
following each dose
Systemic events for up to 7 days
following each dose
AEs and SAEs from Dose 1 through
1month after Dose 2Local reactions (pain at the
injection site, redness, and
swelling)
Systemic events (fever, fatigue,
headache, chills, vomiting,
diarrhea, new or worsened muscle
pain, and new or worsened joint
pain)
AEs
SAEs
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Page 22Objectives Estimands Endpoints
Secondary Immunogenicity
To describe the immune responses
induced by BNT162b2In evaluable participants from each
vaccine group:
GMCs at baseline (before Dose 1)
and 1 month after Dose 2
GMFR from baseline (before
Dose1) through 1 month after
Dose2Full-length S-binding IgG levels
4.STUDY DESIGN
4.1.Overall Design
This is a Phase 3, randomized, observer- blind study to evaluate the safet y, tolerability , and
immunogenicit y of a lyophilized formulation of BNT162 b2, an RNA -based COVID -19
vaccine, administered on a 2 -dose schedule in healthy adults 18 through 55 y ears ofage.The
study will be conducted in the United States with potential to expand to other countries .
Participants will receive either ly ophilized BNT162b2 in SDVs or frozen -liquid BNT162b2
in MDVs. Separately, lyophilized BNT162b2 presented in MDVs may alsobe studied, where
participants will receive either ly ophilized or frozen- liquid BNT162b2 in MDVs .Participants
will be randomized in a 1:1 ratio to 1 of the 2 groups (ly ophilized SDV or frozen- liquid
MDV control for l yophilized SDV) ;if lyophilized MDV is studied,participants will be
randomized in a 1:1 ratio to 1 of the 2 groups separatel y (lyophilized MDV or frozen- liquid
MDV control for l yophilized MDV). The duration of the study for each participant will be
approximately 2 months. Approximately 275participants will be randoml y assigned to each
of the 2 or 4 vaccine groups (ly ophilized SDV, frozen- liquid MDV control for ly ophilized
SDV, lyophilized MDV, or frozen- liquid MDV control for ly ophilized MDV) , for a total of
approximately 550or 1100randomized participants. I t is expected that approximately 440 or
880 evaluable participants will complete the study, based on a 20% nonevaluable rate.
4.2.Scientific Rationale for Study Design
This study contains assessments that could be considered standard for a vaccine
noninferiority study. Blood samples taken for immunogenicit y will establish the level of
immune response elicited by each formulation to provide the necessary data to meet the
primary endpoint of the study . Immunogenicit y will be assessed b y thefull-length S-binding
IgG assay . To establish if a participant has as ymptomatic SARS -CoV-2 infection, nasal
swabs for SARS -CoV-2 nucleic acid amplification testing (ie, NAAT) and blood samples to
measure N -binding antibody levels will be taken. A positi ve result on either test will result
in the immunogenicity data from that participant being excluded from the evaluable portion
of the study population. All reactogenicity and safety assessments are standard for a study of
this nature.
This study will notinclude a placebo, as the aim and design of this study are not to
demonstrate efficacy .
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Page 23Human reproductive safety data are not available for BNT162b2, but there is no suspicion of
human teratogenicit y based on the intended mechanism of action of the compo und.
Therefore, the use of a highl y effective method of contraception is required (see Appendix 4 ).
4.3.Justification for Dose
Based on data from the Phase 1 component of clinical trial C4591001 and available
nonclinical data , the modRNA BNT162b2 vaccine candidate was selected at a dose of 30 µg
for Phase 2/3 evaluation of safety, immunogenicity, and efficacy. This is the dose that has
shown to be effective and has been authorized for temporary or emergency use.
4.4.End of Study Definition
A participant is considered to have completed the study if he/she has completed all phases of
the study, including the last visit.
The end of the stud y is defined as the date of the last visit of the last participant in the study.
5.STUDY POPULATION
This study can fulfill its objectives only if appropriate participant s are enrolled. The
following eligibility criteria are designed to select participant s for whom participation in the
study is considered appropriate. All relevant medic al and nonmedical conditions should be
taken into consideration when deciding whether a particular participant is suitable for this
protocol.
Prospective approval of protocol deviations to recruitment and enrollment criteria ,also
known as protocol waiver s or exemptions, is not permitted .
5.1. Inclusion Criteria
Participants are eligible to be included in the study onl y if all of the following criteria appl y:
Ageand Sex:
1.Male or female participants between the ages of 18 and 55 y ears, inclusive, at Visit 1
(Day 1).
Refer to Section 10.4 for reproductive criteria for male ( Section 10.4.1) and
female (Section 10.4.2) participants.
Type of Participant and Disease Characteristics:
2.Participants who are will ing and able to comply with all scheduled visits, treatment
plan, laboratory tests, lifesty le considerations, and other study procedures.
3.Healthy participants who are determined b y medical history, ph ysical examination
(ifrequired), and clinical judgment of the investigator to be eligible for inclusion in
the study.
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Page 24Note: Health y participants with preexisting stable disease, defined as disease not
requiring significant change in therap y or hospitalization for worsening disease
during the 6 weeks before enr ollment, can be included.
Informed Consent:
4.Capable of giving personal signed informed consent as described in Appendix 1 ,
which includes compliance with the requirements and restrictions listed in the I CD
and inthis protocol.
5.2. Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply :
Medical Conditions:
1.Other medical or psy chiatric condition including recent (within the past year) or
active suicidal ideation/behavior or laboratory abnormality that may increase the risk
of study participation or, in the investigator’s judgment, make the participant
inappropriate for the study .
2.Known infection with HIV, HCV, or HBV.
3.History of severe adverse reaction associated with a vaccine and/or severe allergic
reaction (eg, anaph ylaxis) to any component of the study intervention(s).
4.Previous clinical (based on COVID -19 symptoms/signs alone, if a SARS -CoV-2
NAAT result was not available) or microbiological (based on COVID -19
symptoms/signs and a positive SARS -CoV-2 NAAT result) diagnosis of COVID -19.
5. Immunocompromised individuals with known or suspected immunodeficiency , as
determined b y history and/or laboratory /physical examination.
6. Bleeding diathesis or condition associated with p rolonged bleeding that would, in the
opinion of the investigator, contraindicate intramuscular injection.
7.Women who are pregnant or breastfeeding.
Prior/Concomitant Therapy:
8.Previous vaccination with any coronavirus vaccine.
9.Receipt of medications intended to prevent COVID -19.
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Page 2510.Individuals who receive treatment with radiotherapy or immunosuppressive therap y,
including cytotoxic agents or sy stemic corticosteroids (if sy stemic corticosteroids are
administered for ≥14 days at a dose of ≥20 mg/day of prednisone or equivalent),
eg,for cancer or an autoimmune disease, or planned receipt throughout the study .
Inhaled/nebulized, intra -articular, intrabursal, or topical (skin or ey es) corticosteroids
are permitted.
11.Receipt of blood/plasma products or immunoglobulin,from 60 day s before study
intervention administration or planned receipt throughout the stud y.
Prior/Concurrent Clinical Study Experience:
12.Participation in other studies involving study intervention within 28 day s prior to
study entry and/or during study participation.
13.Previous participation in other studies involving study intervention containing LNPs.
Other Exclusions:
14.Investigator site staff or Pfizer/BioNTech employees directly involved in the conduct
of the study , site staff otherwise supervised by the investigator, and their respective
family members.
5.3.Lifestyle Considerations
5.3.1.Contraception
The investigator or his or her designee, in consultation with the participant, will confirm that
the participant has selected an appropriate method of contraception for the individual
participant and his or her partner(s) from the permitted list of contraception methods
(seeSection 10.4.4) and will confirm that the participant has been instructed in its consistent
and correct use.
At time points indicated in the SoA, the investigator or designee will inform the participant
of the need to use highl y effective contraception consistently and correctly and document the
conversation and the participant’s affirmation in the participant’s chart (participants need to
affirm their consistent and correct use of at least 1 of the selected methods of contraception).
In addition, the investigator or designee will instruct the participant to call immediately if the
selected contraception method is discontinued or if pregnancy is known or suspected in the
participant or partner.
5.4.Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but
are not subsequently randomly assigned to study intervention. A minimal set of screen
failure information is required to ensure transparent reporting of screen failure participants to
meetthe CONSORT publishing requirements and to respond to queries from regulatory
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Page 26authorities. Minimal information includes demography , screen failure details, eligibility
criteria, and an y SAEs.
Individuals who do not meet the criteria for participation in this study (screen failure) may be
rescreened under a different participant number.
5.5. Criteria for Temporarily Delaying Enrollment/Randomization/Study Intervention
Administration
The following conditions are temporary or self-limiting and a participant may be vaccinated
once the condition(s) has/have resolved and no other exclusion criteria are met.
1.Current febrile illness (body temperature ≥100.4°F [≥38.0°C]) or other acute illness
within 48 hours before study intervention administration. This includes cur rent
symptoms that could represent a potential COVID -19 illness:
New or increased cough;
New or increased shortness of breath;
Chills;
New or increased muscle pain;
New loss of taste/smell;
Sore throat;
Diarrhea;
Vomiting.
2.Receipt of any seasonal or pandem ic influenza vaccine within 14 day s, or any other
nonstudy vaccine within 28 days, before study intervention administration.
3. Anticipated receipt of any seasonal or pandemic influenza vaccine within 14 day s, or
any other nonstudy vaccine within 28 days, aft er study intervention administration.
4.Receipt of short -term (<14 day s) systemic corticosteroids. Study intervention
administration should be delay ed until sy stemic corticosteroid use has been
discontinued for at least 28 day s. Inhaled/nebulized, intra -articular, intrabursal, or
topical (skin or ey es) corticosteroids are permitted.
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Page 276.STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s),
placebo, medical device(s), or study procedure(s) intended to be ad ministered to a study
participant according to the study protocol.
For the purposes of this protocol, study intervention refers to BNT162b2, an RNA -based
vaccine for immunization against COVID -19. One of 2 formulations of BNT162b2
(lyophilized or frozen -liquid) will be administered to each participant. The study will
evaluate a 2 -dose (separated by 21days) schedule in healthy adults 18 through 55 y ears of
age.
6.1.Study Intervention(s) Administered
Intervention Name BNT162b2
(BNT162 RNA- LNP
vaccine utilizin g modRNA)BNT162b2
(BNT162 RNA- LNP
vaccine utilizing modRNA)BNT162b2
(BNT162 RNA- LNP
vaccine utilizing modRNA)
Arm Name
(group of participants
receiving a specific
vaccine or no vaccine)Frozen-liquid MDV Lyophilized SDV Lyophilized MDVa
Type Vaccine Vaccine Vaccine
Dose Form ulation modRNA modRNA modRNA
Dosage Level 30-µg 30-µg 30-µg
Route of
AdministrationIntramuscular injection Intramuscular injection Intramuscular injection
Use Experimental Experimental Experimental
IMP or NIMP IMP IMP IMP
Sourcing Provided centrally by the
sponsorProvided centrally by the
sponsorProvided centrally by the
sponsor
Packaging and
LabelingStudy intervention will be
provided in a glass vial.
Each vial will be labeled as
required per country
requirement.Study intervention will be
provided in a glass vial.
Each vial will be labeled as
required per country
requirement.Study intervention will be
provided in a glass vial.
Each vial will be labeled as
required per country
requirement.
a.May contain 2-phenoxyethanol (2 -PE) as a preservative.
6.1.1.Administration
Participants will receive 1 dose of study intervention as randomized at each vaccination visit
(Visits 1 and 2) separated by 21 days in accordance with the study ’s SoA. Full details are
described in the IP manual.
Study intervention should be administered intramuscularl y into the deltoid muscle, preferabl y
of the nondominant arm, by an unblinded administrator.
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Page 28Standard vaccination practices must be observed and vaccine must not be injected into blood
vessels. Appropri ate medication and other supportive measures for management of an acute
hypersensitivity reaction should be available in accordance with local guidelines for standard
immunization practices.
Administration of study interventions should be performed b y an appropriately qualified,
GCP-trained, and vaccine- experienced member of the study staff (eg, ph ysician, nurse,
physician’s assistant, nurse practitioner, pharmacist, or medical assistant) as allowed by
local, state, and institutional guidance.
Study intervention administration details will be recorded on the CRF.
6.2.Preparation/Handling/Storage/Accountability
1. The investigator or designee must confirm appropriate temperature conditions have
been maintained during transit for all study interventions received and an y
discrepancies are reported and resolved before use of the study intervention.
2.Only participants enrolled in the study may receive study intervention and only
authorized site staff may supply or administer study intervention. All study
interventions mu st be stored in a secure, environmentally controlled, and monitored
(manual or automated recording) area in accordance with the labeled storage
conditions with access limited to the investigator and authorized site staff. The
temperature of all locations where study intervention is stored at a clinical site must
be monitored continuously . At a minimum, daily minimum and maximum
temperatures for all site storage locations must be documented and available upon
request. Data for nonworking day s must indicate the minimum and maximum
temperatures since previously documented for all site storage locations upon return to
business.
3.Any excursions from the study intervention label storage conditions should be
reported to Pfizer upon discovery along with an y actions taken. The site should
actively pursue options for returning the stud y intervention to the storage conditions
described in the labeling, as soon as possible. Once an excursion is identified, the
study intervention must be quarantined and not used until Pfizer provides permission
to use the study intervention. Specific details regarding the definition of an excursion
and information the site should report for each excursion will be provided to the site
in the IP manual.
4.Any storage conditions stated in the SRSD will be superseded b y the storage
conditions stated on the label.
5.Study interventions should be stored in their original containers.
6.See the IP manual for storage conditions of the study intervention.
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Page 297.The investigator, institution, or the head of the medical institution (where applicable)
is responsible for stud y intervention accountability, reconciliation, and record
maintenance (ie, receipt, reconciliation, and final disposition records), such as the
IPAL or sponsor -approved equivalent. All stud y interventions will be accounted for
using a study intervention accountabilit y form/record.
8.Further guidance and information for the final disposition of unused study
interventions are provided in the I P manual. All destruction must be adequately
documented. If destruction is authorized to take place at the investigator site, the
investigator must ensure that the materials are destroy ed in compliance with
applicable environmental regulations, institutional policy , and any special instructions
provided b yPfizer.
Upon identification of a product complaint, notify the sponsor within 1 business day of
discovery as described in the I P manual.
6.2.1.Preparation and Dispensing
See the IP manual for instructions on how to prepare the stud y intervention for
administrat ion. Study intervention should be prepared and dispensed by an appropriatel y
qualified and experienced member of the stud y staff (eg, ph ysician, nurse, phy sician’s
assistant, nurse practitioner, pharmacy assistant/technician, or pharmacist) as allowed by
local, state, and institutional guidance. A second staff member will verify the preparation
and dispensing.
Study intervention will be prepared by qualified unblinded site personnel according to the IP
manual. The stud y intervention will be administered in such a way as to ensure the
participants remain blinded.
6.3.Measures to Minimize Bias: Randomization and Blinding
6.3.1.Allocation to Study Intervention
Allocation (randomization) of participants to vaccine groups will proceed through the use of
an IRT system (IWR). The site personnel (study coordinator or specified designee) will be
required to enter or select information including but not limited to the user’s I D and
password, the protocol number, and the participant number. The site personnel will then be
provided with a vaccine assignment and randomization number. The IRT sy stem will
provide a confirmation report containing the participant number, randomization number, and
study intervention allocation assigned. The confirmation report must be stored in th e site’s
files.
The study -specific IRT reference manual and I P manual will provide the contact information
and further details on the use of the IRT s ystem.
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Page 306.3.2. Blindingof Site Personnel
In this observer -blinded study , the study staff receiving, storing, dispensing, preparing, and
administering the stud y interventions will be unblinded. All other study and site personnel,
including the investigator, investigator staff, and participants, w ill be blinded to study
intervention assignments. I n particular, the individuals who evaluate participant safet y will
be blinded. Because there aredifferences in phy sical appearance of the BNT162b2
formulations, the study intervention will be administer ed in a manner that prevents the study
participants from identifying the stud y intervention group based on its appearance.
The PIwill assign the responsibility of the unblinded dispensers/administrators to persons
who will not participate in the evaluatio n of any study participant . To ensure adequate
coverage, at least 2 unblinded dispensers/administrators will be assigned per site. Members
of the study site staff or clinic pharmacy should fulfill these roles. Contact between the
unblinded dispensers and study participants should be kept to a minimum. The investigator,
study coordinator, and any site staff other than the unblinded dispensers/administrators must
not be allowed to know the study intervention assigned to an y study participant and must not
be allowed to see the study intervention container contents. In the event of a Quality
Assurance audit, the auditor(s) will be allowed access to unblinded study intervention records
at the site(s) to verify that randomization/dispensing has been done accu rately.
6.3.3.Blinding of the Sponsor
The majority of sponsor staff will be blinded to study intervention allocation. All laboratory
testing personnel performing serology assays will remain blinded to study intervention
assigned/received throughout the study . The following sponsor staff, who will have no part
in the blinded conduct of the study , will be unblinded (further details will be provided in a
data blinding plan):
Those study team members who are involved in ensuring that protocol
requirements for study intervention preparation, handling, allocation, and
administration are fulfilled at the site will be unblinded for the duration of the
study (eg, unblinded study manager, unblinded clinical research associate).
Unblinded clinician(s) who are not direct me mbers of the study team and will not
participate in an y other study -related activities will review unblinded protocol
deviations.
6.3.4. Breaking the Blind
All study participants will receive BNT162b2; blinding refers onl y to which vaccine
formulation the partici pant will receive. The IRT will be programmed with blind -breaking
instructions. I n case of an emergency , the investigator has the sole responsibility for
determining if unblinding of a participant’s study intervention assignment is warranted.
Participan t safety must alway s be the first consideration in making such a determination. If
the investigator decides that unblinding is warranted, the investigator should make every
effort to contact the sponsor prior to unblinding a participant’s vaccine assignme nt unless this
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Page 31could delay further management of the participant. If a participant’s vaccine assignment is
unblinded, the sponsor must be notified within 24 hours after breaking the blind. The date
and reason that the blind was broken must be recorded in the source documentation and CRF.
The study -specific IRT reference manual and I P manual will provide the contact information
and further details on the use of the IRT s ystem.
6.4. Study Intervention Compliance
When participants are dosed at the site, they willreceive stud y intervention directly from the
investigator or designee, under medical supervision. The date and time of each dose
administered in the clinic will be recorded in the source documents and recorded in the CRF.
The dose of stud y intervention and study participant identification will be confirmed at the
time of dosing b y a member of the stud y site staff other than the person administering the
study intervention.
6.5. Concomitant Therapy
The following concomitant medications and vaccinations will be recorded in the CRF:
All vaccinations received from 28 day s prior to study enrollment until the
1-month follow -up visit (Visit 3).
Prohibited medications listed in Section 6.5.1will be recorded, to include start
and stop dates, name of the medication, dose, unit, route, and frequency .
6.5.1.Prohibited During the Study
Receipt of the following vaccines and medications during the time periods listed below may
exclude a participant from the per-protocol anal ysis from that point onward and may require
vaccinations to be discontinued in that participant; however, it is anticipated that the
participant would not be withdrawn from the study (see Section 7). Medications should not
be withheld if required for a participant’s medical care.
Unless considered medically necessary , no vaccines other than study intervention
should be administered within 28 day s before and 28 day s after each study
vaccination. One exception to this is that se asonal and pandemic influenza vaccine
can be given at least 14 day s after, or at least 14 day s prior to, the administration of
study intervention.
Receipt of chronic s ystemic treatment with known immunosuppressant medications,
or radiotherap y, within 60 da ys before enrollment through conclusion of the study .
Receipt of s ystemic corticosteroids (≥ 20 mg/day of prednisone or equivalent) for
≥14days is prohibited from 28 day s prior to enrollment throughVisit 3.
Receipt of blood/plasma products or immunoglobul ins within 60 days before
enrollment through conclusion of the study .
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Page 32Receipt of an y other (nonstudy ) coronavirus vaccine at an y time prior to or during
study participation is prohibited.
Receipt of proph ylactic medications intended to preventsymptoms ass ociated with
COVID-19. However, if a participant is taking a medication for another condition,
even if it may have such properties, it should not be withheld prior to study
vaccination.
Prophylactic antipy retics and other pain medication to preventsymptoms associated
with study intervention administration are not permitted. However, if a participant is
taking a medication for another condition, even if it may have antipy retic or
pain-relieving properties, it should not be withheld prior to study vaccination.
6.5.2.Permitted During the Study
The use of antip yretics and other pain medication to treatsymptoms associated with study
intervention administration or ongoing conditions is permitted.
Medication other than that described as prohibited in Section 6.5.1required for treatment of
preexisting stable conditions is permitted.
Inhaled, topical, or localized in jections of corticosteroids (eg, intra -articular or intrabursal
administration) are permitted.
6.6. Dose Modification
Not applicable for this study .
6.7.Intervention After the End of the Study
No intervention will be provided to study participants at the end of th e study.
7.DISCONTINUATION OF S TUDY INTERVENTION AN D PARTICIPANT
DISCONTINUATION/WITH DRAWAL
7.1.Discontinuation of Study Intervention
In rare instances, it may be necessary for a participant to permanentl y discontinue study
intervention (definitive discontinuati on). Reasons for definitive discontinuation of study
intervention include the following: AEs; participant request; investigator request; pregnancy;
protocol deviation (including no longer meeting all the inclusion criteria, or meeting 1 or
more exclusion criteria*). In general, unless the investigator considers it unsafe to administer
the second dose, or the participant does not wish to receive it, it is preferred that the second
dose be administered.
*A positive SARS -CoV-2 NAAT result without sy mptoms or a COVID -19 diagnosis
(signs/symptomsonly or signs/symptoms and a positive SARS -CoV-2 NAAT result) should
not result in discontinuation of study intervention. If study intervention (Dose 2) has been
delayed per Section 5.5, because of febrile or other acute illness (I tem 1in the list in
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Page 33Section 5.5),and the investigator later diagnoses the signs and s ymptoms as COVID -19 (with
or without a positive SARS -CoV-2 NAAT result), the participant should not be discontinued
from any further doses of study intervention.
Note that discontinuation of study intervention does not represent withdrawal from the study .
Per the study estimands, if study intervention is definitively discontinued, the participant will
remain in the study to be evaluated for safet y and immunogenicit y. See the SoAfor data to
be collected at the time of discontinuation of study intervention and follow -up for any further
evaluations that need to be completed.
In the event of discontinuation of study intervention, it must be documented o n the
appropriate CRF/in the medical records whether the participant is discontinuing further
receipt of stud y intervention or also from study procedures, postvaccination study follow-up,
and/or future collection of additional information.
7.2.Participant Disc ontinuation/ Withdrawal F rom the Study
A participant may withdraw from the study at any time at his/her own request. Reasons for
discontinuation from the study include the following:
Refused further follow -up;
Lost to follow -up;
Death;
Study terminated by sponsor;
AEs;
Participant request;
Investigator request;
Protocol deviation.
If a participant does not return for a scheduled visit, every effort should be made to contact
the participant. All attempts to contact the participant and information received during
contact attempts must be documented in the participant’s source document. I n any
circumstance, every effort should be made to document participant outcome, if possible.
The investigator or his or her designee should capture the reason for withdrawa l in the CRF
for all participants.
If a participant withdraws from the study , he/she may request destruction of any remaining
samples taken and not tested, and the investigator must document any such requests in the
site study records and notify the sponso r accordingly .
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Page 34If the participant withdraws from the study and also withdraws consent (see Section 7.2.1)
for disclosure of future information, no further evaluations should be performed and no
additional data should be collected. The sponsor may retain and continue to use any data
collected before such withdrawal of consent.
Lack of completion of all or an y of the withdrawal/earl y termination procedures will not be
viewed as protocol deviations so long as the participant’s safet y was preserved.
7.2.1.Withdrawal of Consent
Participants who request to d iscontinue receipt of study intervention will remain in the study
and must continue to be followed for protocol -specified follow -up procedures. The onl y
exception to this is when a participant specificall y withdraws consent for any further contact
with him or her or persons previously authorized by the participant to provide this
information. Participants should notify the investigator in writing of the decision to
withdraw consent from future follow- up, whenever possible. The withdrawal of consent
should be explained in detail in the medical records by the investigator, as to whether the
withdrawal is only from further receipt of study intervention or also from study procedures
and/or postvaccination study follow-up, and entered on the appropriate CRF pa ge. In the
event that vital status (whether the participant is alive or dead) is being measured, publicl y
available information should be used to determine vital status only as appropriately directed
in accordance with local law.
7.3.Lost to Fol low-up
A participant will be considered lost to follow -up if he or she repeatedl y fails to return for
scheduled visits and is unable to be contacted b y the study site.
The following actions must be taken if a participant fails to attend a required study visit:
The site must attempt to contact the participant and reschedule the missed visit as
soon as possible and counsel the participant on the importance of maintaining the
assigned visit schedule and ascertain whether or not the participant wishes to
and/or should contin ue in the study ;
Before a participant is deemed lost to follow-up, the investigator or designee must
make every effort to regain contact with the participant (where possible, 3
telephone calls and, if necessary , a certified letter to the participant’s last known
mailing address or local equivalent methods). These contact attempts should be
documented in the participant’s medical record;
Should the participant continue to be unreachable, he/she will be considered to
have withdrawn from the study .
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Page 358.STUDY ASSE SSMENTS AND PROCEDURES
The investigator (or an appropriate delegate at the investigator site) must obtain a signed and
dated ICD before performing an y study-specific procedures.
The full date of birth will be collected to criticall y evaluate the immune res ponse and safet y
profile by age.
Study procedures and their timing are summarized in the SoA. Protocol waivers or
exemptions are not allowed.
Safety issues should be discussed with the sponsor immediately upon occurrence or
awareness to determine whether the participant should continue or discontinue study
intervention.
Adherence to the stud y design requirements, including those specified in the SoA, is essential
and required for stud y conduct.
All screening evaluations must be completed and reviewed to co nfirm that potential
participants meet all eligibility criteria. The investigator will maintain a screening log to
record details of all participants screened and to confirm eligibility or record reasons for
screening failure, as applicable.
Every effort should be made to ensure that protocol -required tests and procedures are
completed as described. However, it is anticipated that from time to time there may be
circumstances outside the control of the investigator that may make it unfeasible to perform
the test. In these cases, the investigator must take all steps necessary to ensure the safet y and
well-being of the participant. When a protocol- required test cannot be performed, the
investigator will document the reason for the missed test and an y corrective and preventive
actions that he or she has taken to ensure that required processes are adhered to as soon as
possible. The study team must be informed of these incidents in a timely manner.
For samples being collected and shipped, detailed collection, processing, storage, and
shipment instructions and contact information will be provided to the investigator site prior
to initiation of the study .
The total blood sampling volume for individual participants in this study is approximately
40mL. Additiona l blood samples may be taken for safet y assessments at times specified b y
Pfizer, provided the total volume taken during the study does not exceed 550 mL during an y
period of 60 consecutive day s.
8.1.Efficacy and/or Immunogenicity Assessments
Serum samples will be obtained for immunogenicity testing at the visits specified in the SoA.
The test to be performed will be the SARS -CoV-2 full-length S-binding IgG -level assay .
Note that all immunogenicity analyses will be based upon samples anal yzedat the central
laboratory .
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Page 36Nasal (midturbinate) swabs at the visits specified in the SoA will be obtained as one of the
determinations for participants to be included in the evaluable immunogenicity analysis.
These samples will be tested at the central l aboratory using an RT -PCR test (Cepheid, an
NAAT; FDA approved under EUA) to detect SARS -CoV-2. Another determination for
participants to be included in the evaluable immunogenicity analysis is the N -binding
antibody assay. Blood samples will be taken at visits specified in the SoA and anal yzed at
the central laboratory . A positive result on either test will result in the immunogenicity data
from that participant being excluded from the evaluable portion of the study population.
However, administration of study intervention is not dependent on these test results, which
will be available only after the study has ended.
8.1.1. Biological Samples
Blood and nasal swab samples will be used only for scientific research. Each sample will be
labeled with a code so tha t the laboratory personnel testing the samples will not know the
participant’s identity . Samples that remain after performing assay s outlined in the protocol
may be stored by Pfizer. Unless a time limitation is required by local regulations or ethical
requirements, the samples will be stored for up to 15 y ears after the end of the study and then
destroyed. If allowed by the ICD, stored samples may be used for additional testing to better
understand the immune responses to the vaccine(s) under stud y in this protocol, to inform the
development of other products, and/or for vaccine- related assay work supporting vaccine
programs. No testing of the participant’s genetic material will be performed.
The participant may request that his or her samples, if still identifiable, be destroyed at an y
time; however, an y data alread y collected from those samples will still be used for this
research. The biological samples may be shared with other researchers as long as
confidentiality is maintained and no testing of the participant’s genetic material is performed.
8.2.Safety Assessments
Planned time points for all safety assessments are provided in the SoA. Unscheduled clinical
laboratory measurements may be obtained at any time during the stud y to assess any
perceived safety issues.
A clinical assessment, including medical history , will be performed on all participants at their
first visit to establish a baseline. Significant medical history and observations from any
physical examination, if performe d, will be documented in the CRF.
AEs and SAEs are collected, recorded, and reported as defined in Section 8.3.
Acute reactions within the first 30 minutes after administration of the study intervention will
be assessed and documented in the AE CRF.
The safety parameters also include reactogenicit y e-diary reports of local reactions, sy stemic
events (including fever), and use of antip yretic medication that occur in the 7 day s after
administration of the study intervention. These prospectivel y self-collected occurrences of
local reactions and s ystemic events are graded as described in Section 8.2.2.
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Page 378.2.1. Clinical Safety Laboratory Assessments
Clinical safety laboratory assessments will not be collected in this study .
See Section 10.5, Appendix 5, for suggested actions and follow-up assessments in the event
of potential DILI.
8.2.2.Electronic Diary
Participants will be required to complete a reactogenicity e-diary through an a pplication
installed on a provisioned device or on the participant’s own personal device. All
participants will be asked to monitor and record local reactions, sy stemic events, and
antipyretic medication usage for 7 days from the day of administration of the study
intervention. The reactogenicity e-diary allows recording of these assessments only within a
fixed time window, thus providing the accurate representation of the participant’s experience
at that time. Data on local reactions and sy stemic events reported in the reactogenicit y
e-diary will be transferred electronically to a third- party vendor, where they will be available
for review b y investigators and the Pfizer clinicians at all times via an internet -based portal.
At intervals agreed to b y the vendor and Pfizer, these data will be transferred electronicall y
into Pfizer's database for anal ysis and reporting. These data do not need to be reported by the
investigator in the CRF as AEs.
Investigators (or designee) will be required to review the rea ctogenicity e-diary data online at
frequent intervals as part of the ongoing safet y review.
The investigator or designee must obtain stop dates from the participant for any ongoing
local reactions, sy stemic events, or use of antipy retic medication on the l ast day that the
reactogenicity e-diary was completed. The stop dates should be documented in the source
documents and the information entered in the CRF.
8.2.2.1.Grading Scales
The grading scales used in this study to assess local reactions and sy stemic events a s
described below are derived from the FDA CBER guidelines on toxicity grading scales for
healthy adult volunteers enrolled in preventive vaccine clinical trials.13
8.2.2.2.Local Reactions
During the reactogenicit y e-diary reporting period, participants will be asked to assess
redness, swelling, and pain at the injection site and to record the s ymptoms in the
reactogenicity e-diary. If a local reaction persists bey ond the end of the reactogenicity
e-diary period following vaccination, the participant will be requested to report that
information. The investigator will enter this additional information in the CRF.
Redness and swelling will be measured and recorded in measuring device units
(range:1to21) and then categorized during anal ysis as absent, mild, moderate, or severe
based on the grading scale in Table1. Measuring device units can be converted to
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Page 38centimeters according to the following formula: 1 measuring device unit = 0.5 cm. Pain at
the injection site will be assessed b y the participant as absen t, mild, moderate, or severe
according to the grading scale in Table1.
If a Grade 3 local reaction is reported in the reactogenicity e-diary, a telephone contact
should occur to ascertain further details and determine whether a site visit is clinically
indicated. Onl y an investigator or medicall y qualified person is able to classify a
participant’s local reaction as Grade 4. If a participant experien ces a confirmed Grade 4 local
reaction, the investigator must immediately notify the sponsor and, if it is determined to be
related to the administration of the study intervention, further vaccinations will be
discontinued in that participant.
Table1.Local Reaction Grading Scale
Mild
(Grade 1)Moderate
(Grade 2)Severe
(Grade 3)Potentially Life
Threatening
(Grade 4)
Pain at the
injection siteDoes not interfere
with activityInterferes with activity Prevents daily
activity Emergency room visit
or hospitalization for
severe pain
Redness >2.0cm to 5.0 cm
(5 to 10measuring
device units)>5.0cm to 10.0 cm
(11to 20measuring
device units)>10cm
(≥21measuring
device units)Necrosis or exfoliative
dermatitis
Swelling >2.0cm to 5.0 cm
(5 to 10 measuring
device units)>5.0cm to 10.0 cm
(11to 20measuring
device units)>10cm
(≥21measuring
device units)Necrosis
8.2.2.3.Systemic Events
During the reactogenicit y e-diary reporting period, participants will be asked to asses s
vomiting, diarrhea, headache, fatigue, chills, new or worsened muscle pain, and new or
worsened joint pain and to record the s ymptoms in the reactogenicit y e-diary. The symptoms
will be assessed b y the participant as absent, mild, moderate, or severe ac cording to the
grading scale in Table2.
If a Grade 3 s ystemic event is reported in the reactogenicity e-diary, a telephone contact
should occur to asc ertain further details and determine whether a site visit is clinically
indicated. Onl y an investigator or medicall y qualified person is able to classify a
participant’s s ystemic event as Grade4. If a participant experiences a confirmed Grade4
systemicevent, the investigator must immediately notify the sponsor and, if it is determined
to be related to the administration of the study intervention, further vaccinations will be
discontinued in that participant.
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Page 39Table2.Systemic Event Grading Scale
Mild
(Grade 1)Moderate
(Grade 2)Severe
(Grade 3)Potentially Life
Threatening
(Grade 4)
Vomiting 1-2 times in
24hours>2 times in
24hoursRequires IV hydration Emergency room visit
or hospitalization for
hypotensive shock
Diarrhea 2 to 3 loose stools
in 24 hours4 to 5 loose stools
in 24hours6 or more loose stools
in 24 hoursEmergency room visit
or hospitalization for
severe diarrhea
Headache Does not interfere
with activitySome interference
with activityPrevents dail y routine
activityEmergency room visit
or hospitalization for
severe headache
Fatigue/tiredness Does not interfere
with activitySome interference
with activityPrevents daily routine
activityEmergency room visit
or hospitalization for
severe fatigue
Chills Does not interfere
with activitySome interference
with activityPrevents daily routine
activityEmergency room visit
or hospitalization for
severe chills
New or worsened
muscle painDoes not interfere
with activitySome interference
with activityPrevents daily routine
activityEmergency room visit
or hospitalization for
severe ne w or worsened
muscle pain
New or worsened
joint painDoes not interfere
with activitySome interference
with activityPrevents daily routine
activityEmergency room visit
or hospitalization for
severe ne w or worsened
joint pain
Abbreviation: IV = intravenous.
During the 7 days following each vaccination, potential COVID -19 symptoms that overlap
with solicited sy stemic events (ie, fever, chills, new or increased muscle pain, diarrhea,
vomiting) should be assessed by the investigator.
If, in the investigator’s opinion, the sy mptoms are considered more likely to be vaccine
reactogenicity , but a participant is required to demonstrate that he or she is SARS-CoV-2–
negative, a local SARS -CoV-2 test may be performed: if positive, the sy mptoms should be
recorded as an AE rather than as sy stemic events in the reactogenicit y e-diary.
8.2.2.4.Fever
In order to record information on fever, a thermometer will be given to participants with
instructions on how to measure oral temperature at home. Temperature will be collected in
the reactogenicit y e-diary in the evening dail y during the reactogenicit y e-diary reporting
period. It will also be collected at an y time during the reactogenicit y e-diary data collection
periods when fever is suspected. Fever is defined as an oral temperature ≥38.0°C (100.4°F).
The highest temperature for each day will be recorded in the reactogenicit y e-diary.
Temperature will be measured and recorded to 1 decimal place. Temperatures recorded in
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Page 40degrees Fahrenheit will be programmatically converted to degrees Celsius and then
categorized according to the scale shown in Table3during anal ysis.
If a fever of ≥39.0°C (102.1°F) is reported in the reactogenicity e-diary, a telephone contact
should occur to ascertain further details and determine whether a site visit is clinically
indicated. Onl y an investigator or medicall y qualified person is able to confirm a
participant’s fever as >40.0°C (>104.0°F). If a participant experiences a confirmed fever
>40.0°C (>104.0°F), the investigator must immediately notify the sponsor and, if it is
determined to be related to the a dministration of the study intervention, further vaccinations
will be discontinued in that participant.
Table3.Scale for Fever
≥38.0-38.4°C (100.4 -101.1°F)
>38.4-38.9°C (101.2 -102.0°F)
>38.9-40.0°C (102.1 -104.0°F)
>40.0°C (>104.0°F)
8.2.2.5.Antipyretic Medication
The use of antip yretic medication to treat s ymptoms associated with study intervention
administration will be recorded in the reactogenicity e-diary daily during the reporting period
(Day 1 through Day 7).
8.2.3.Pregnancy Testin g
Pregnancy tests may be urine or serum tests, but must have a sensitivity of at least
25mIU/mL. Pregnancy tests will be performed in WOCBP at the times listed in the SoA ,
immediately before the administration of each vaccine dose. A negative pregnancy test result
will be required prior to the participant’s receiving the study intervention. Pregnancy tests
may also be repeated if requested by IRBs/ECs or if required b y local regulations. I n the
case of a positive confirmed pregna ncy, the participant will be withdrawn from
administration of study intervention but may remain in the study .
8.3. Adverse Events and Serious Adverse Events
The definitions of an AE and an SAE can be found in Appendix 3 .
AEs will be reported b y the participant (or, when appropriate, b y a caregiver, surrogate, or
the participant's legall y authorized representative).
The investigator and an y qualified designees are responsible for detecting, documenting, and
recording events that meet the definition of an AE or SAE and remain responsible to pursue
and obtain adequate information both to determine the outcome and to assess whether the
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Page 41event meets the criteria for classification as an SAE or caused the participant to discontinu e
the study intervention (see Section 7.1).
Each participant will be questioned about the occurrence of AEs in a nonl eading manner.
In addition, the investigator may be requested by Pfizer Safet y to obtain specific follow -up
information in an expedited fashion.
8.3.1. Time Period and Frequency for C ollecting AE and SAE Information
The time period for actively eliciting and coll ecting AEs and SAEs (“active collection
period”) for each participant begins from the time the participant provides informed consent,
which is obtained before the participant’s participation in the study (ie, before undergoing
any study-related procedure a nd/or receiving study intervention), through and including
Visit3 (1-month follow -up). In addition, an y AEs occurring up to 48 hours after the blood
draw and nasal swab collection at Visit 3 reported by the participant must be recorded in the
CRF.SAEs will be collected from the time the participant provides informed consent through
approximately 1month after the last dose of study intervention ( Visit 3).
Follow-up by the investigator continues throughout and after the active collection period and
until the AE or SAE or its sequelae resolve or stabilize at a level acceptable to the
investigator and Pfizer concurs with that assessment.
For participants who are screen failures, the active collection period ends when screen failure
status is determined.
If the participant withdraws from the study and also withdraws consent for the collection of
future information, the active collection period ends when consent is withdrawn.
If a participant definitively discontinues or temporarily discontinues study intervent ion
because of an AE or SAE, the AE or SAE must be recorded on the CRF and the SAE
reported using the Vaccine SAE Reporting Form.
Investigators are not obligated to activel y seek AEs or SAEs after the participant has
concluded stud y participation . However , if the investigator learns of any SAE, including a
death, at an y time after a participant has completed the study, and he/she considers the event
to be reasonably related to the study intervention, the investigator must promptly report the
SAE to Pfizer using the Vaccine SAE Reporting Form.
8.3.1.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a participant during the active collection period as described in
Section 8.3.1are reported to Pfizer Safety on the Vaccine SAE Reporting Form immediatel y
upon awareness and under no circumstance should this exceed 24 hours, as indicated in
Appendix 3. The investigator will submit any updated SAE data to the sponsor within
24 hours of it being available.
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Page 428.3.1.2. Recording Nonserious AEs and SAEs on the CRF
All nonserious AEs and SAEs occurring in a participant during the active collection period,
which begins after obtaining informed consent as described in Section 8.3.1,will be recorded
on the AE section of the CRF.
The investigator is to record on the CRF all directly observed and all spontaneously reported
AEs and SAEs reported by the participant.
8.3.2.Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AEs and SAEs and the
procedures for completing and transmitting SAE reports are provided in Section 10.3.
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open -ended and
nonleading verbal questioning of the participant is the preferred method to inquire about AE
occurrences.
8.3.3.Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactivel y follow each
participant at subsequent visits/contacts. For each event, the investigator must pursue and
obtain adequate information until resolut ion, stabilization, the event is otherwise explained,
or the participant is lost to follow- up (as defined in Section 7.3).
In general, follow -up information will include a description of the event in sufficient detail to
allow for a complete medical assessment of the case and independent determination of
possible causality . Any information relevant to the event, such as concomitant medications
and illnesses, must be provided. In the case of a participant death, a summary of available
autopsy findings must be submitted as soon as possible to Pfizer Safety .
Further information on follow -up procedures is given in Appendix 3 .
8.3.4. Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal
obligations and ethical responsibilities towards the safet y of participants and the safet y of a
study intervention under clinical investigation are met.
The sponsor has a legal responsibility to notify both the local regulatory authority and other
regulatory agencies about the safet y of a stud y intervention under clinical investig ation. The
sponsor will comply with country -specific regulatory requirements relating to safet y
reporting to the regulatory authority, IRBs/ECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory
requirements and sponsor policy and forwarded to investigators as necessary .
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Page 43An investigator who receives SUSARs or other specific safet y information (eg, summary or
listing of SAEs) from the sponsor will review and then file it along with the SRSD(s) for the
study and will notify the IRB/EC, if appropriate according to local requirements.
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational Exposure
Exposure to the study interventio nunder stud y during pregnancy or breastfeeding and
occupational exposur e are reportable to Pfizer Safety within 24 hours of investigator
awareness.
8.3.5.1.Exposure During Pregnancy
An EDP occurs if:
A female participant is found to be pregnant while receiving or after discontinuing
study intervention.
A male participant who is receiving or has discontinued study intervention exposes a
female partner prior to or around the time of conception.
A female is found to be pregnant while being exposed or having been exposed to
study intervention due to environmental exposure. Below are examples of
environmental exposure during pregnancy :
A female family member or healthcare provider reports that she is pregnant after
having been exposed to the study intervention by inhalation or skin contact.
A male famil y member or healthcare provide r who has been exposed to the study
intervention by inhalation or skin contact then exposes his female partner prior to
or around the time of conception.
The investigator must report EDP to Pfizer Safety within 24 hours of the investigator’s
awareness, irr espective of whether an SAE has occurred. The initial information submitted
should include the anticipated date of delivery (see below for information related to
termination of pregnancy).
If EDP occurs in a participant or a participant’s partner, the inv estigator must report
this information to Pfizer Safety on the Vaccine SAE Reporting Form and an EDP
Supplemental Form, regardless of whether an SAE has occurred. Details of the
pregnancy will be collected after the start of study intervention and until 1 month
after the last dose of study intervention.
If EDP occurs in the setting of environmental exposure, the investigator must report
information to Pfizer Safety using the Vaccine SAE Reporting Form and EDP
Supplemental Form. Since the exposure informat ion does not pertain to the
participant enrolled in the study , the information is not recorded on a CRF; however,
a copy of the completed Vaccine SAE Reporting Form is maintained in the I SF.
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Page 44Follow-up is conducted to obtain general information on the pregn ancy and its outcome for
all EDP reports with an unknown outcome. The investigator will follow the pregnancy until
completion (or until pregnancy termination) and notify Pfizer Safet y of the outcome as a
follow-up to the initial EDP Supplemental Form. In the case of a live birth, the structural
integrity of the neonate can be assessed at the time of birth. In the event of a termination, the
reason(s) for termination should be specified and, if clinically possible, the structural
integrity of the terminat ed fetus should be assessed by gross visual inspection (unless
preprocedure test findings are conclusive for a congenital anomal y and the findings are
reported).
Abnormal pregnancy outcomes are considered SAEs. If the outcome of the pregnancy meets
the criteria for an SAE (ie, ectopic pregnancy , spontaneous abortion, intrauterine fetal
demise, neonatal death, or congenital anomal y), the investigator should follow the procedures
for reporting SAEs. Additional information about pregnancy outcomes that are r eported to
Pfizer Safety as SAEs follows:
Spontaneous abortion including miscarriage and missed abortion;
Neonatal deaths that occur within 1 month of birth should be reported, without regard
to causality , as SAEs. In addition, infant deaths after 1 month should be reported as
SAEs when the investigator assesses the infant death as related or possibly related to
exposure to the study intervention.
Additional information regarding the EDP may be requested by the sponsor. Further
follow-up of birth outcome s will be handled on a case -by-case basis (eg, follow -up on
preterm infants to identify developmental delay s). In the case of paternal exposure, the
investigator will provide the participant with the Pregnant Partner Release of Information
Form to deliver to his partner. The investigator must document in the source documents that
the participant was given the Pregnant Partner Release of Information Form to provide to his
partner.
8.3.5.2.Exposure During Breastfeeding
An exposure during breastfeeding occurs if:
Afemale participant is found to be breastfeeding while receiving or after
discontinuing study intervention.
A female is found to be breastfeeding while being exposed or having been exposed to
study intervention (ie, environmental exposure). An example of environmental
exposure during breastfeeding is a female family member or healthcare provider who
reports that she is breastfeeding after having been exposed to the study intervention
by inhalation or skin contact.
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Page 45The investigator must report exposure duri ng breastfeeding to Pfizer Safety within 24 hours
of the investigator’s awareness, irrespective of whether an SAE has occurred. The
information must be reported using the Vaccine SAE Reporting Form. When exposure
during breastfeeding occurs in the setting of environmental exposure, the exposure
information does not pertain to the participant enrolled in the study , so the information is not
recorded on a CRF. However, a cop y of the completed Vaccine SAE Reporting Form is
maintained in the I SF.
An exposure during breastfeeding report is not created when a Pfizer drug specificall y
approved for use in breastfeeding women (eg, vitamins) is administered in accord with
authorized use. However, if the infant experiences an SAE associated with such a drug, the
SAE is reported together with the exposure during breastfeeding.
8.3.5.3.Occupational Exposure
An occupational exposure occurs when a person receives unplanned direct contact with the
study intervention, which may or may not lead to the occurrence of an AE. Such pe rsons
may include healthcare providers, famil y members, and other roles that are involved in the
trial participant’s care.
The investigator must report occupational exposure to Pfizer Safet y within 24 hours of the
investigator’s awareness, regardless of whether there is an associated SAE. The information
must be reported using the Vaccine SAE Reporting Form. Since the inform ation does not
pertain to a participant enrolled in the study, the information is not recorded on a CRF;
however, a cop y of the completed Vaccine SAE Reporting Form is maintained in the I SF.
8.3.6. Cardiovascular and Death Events
Not applicable.
8.3.7.Disease-Related Events and/or Disease -Related Outcomes Not Qualifying as AEs
or SAEs
Not applicable.
8.3.8.Adverse Events of Special Interest
This section provides information on AESI s that may be detected during the study :
Confirmed COVID -19 diagnosis (clinical signs/s ymptoms and positive SARS -CoV-2
NAAT test)
All AESIs must be reported as an AE or SAE following the procedures described in
Section 8.3.1through Section 8.3.4. An AESI is to be recorded as an AE or SAE on the
CRF. In addition, an AESI that is also an SAE must be reported using the Vaccine SAE
Reporting Form.
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Page 468.3.8.1.Lack of Efficacy
Lack of efficacy is reportable to Pfizer Safet y only if associated with an SAE.
8.3.9.Medical Device Deficiencies
Not applicable.
8.3.10.Medication Errors
Medication errors may result from the administration or consumption of the study
intervention by the wrong participant , or at the wrong time, or at the wrong dosage strength.
Exposures to the study intervention under stud y may occur in clinical trial settings, such as
medication errors.
Safety Event Recorded on the CRF Reported on the Vaccine SAE
Reporting Form to Pfizer Safety
Within 24 Hours of Awareness
Medication errors All (regardless of whether
associated with an AE)Only if associated with an SAE
Medication errors include:
Medication errors involving participant exposure to the study intervention;
Potential medication errors or uses outside of what is foreseen in the protocol that do
or do not involve the study participant;
The administration of expired study intervention;
The administration of an incorrect study intervention;
The administration of an incorrect dosage;
The administration of study intervention that has undergone temperature excursion
from the specified storage range, unless it is d etermined by the sponsor that the study
intervention under question is acceptable for use.
Such medication errors occurring to a study participant are to be captured on the medication
error page of the CRF, which is a specific version of the AE page.
In the event of a medication dosing error, the sponsor should be notified within 24 hours .
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Page 47Whether or not the medication error is accompanied by an AE, as determined by the
investigator, the medication error is recorded on the medication error page of the CRF and, if
applicable, an y associated AE(s), serious and nonserious, are recorded on theAE page of the
CRF.
Medication errors should be reported to Pfizer Safety within 24 hours on a VaccineSAE
ReportingForm only when associated with an SAE.
8.4.Treatment of Overdose
For this study , any dose of study intervention greater than 1 dose of study intervention within
a 24-hour time period will be considered an overdose.
Pfizer does not recommend specific treatment for an overdose.
In the event of an overdose, the investigator should:
1.Contact the medical monitor within 24 hours.
2.Closely monitor the participant for an y AEs/SAEs.
3.Document the quantit y of the excess dose as well as the duration of the overdose in
the CRF.
4.Overdose is reportable to Safety only when associated with an SAE.
Decisions regarding dose interruptions or modifications will be made by the investigator in
consultation with the medical monitor based on the clinical evaluation of the participant.
8.5.Pharmacokinetics
Pharmacokinetic parameters are not evaluated in this study .
8.6.Pharmacodynamics
Pharmacod ynamic parameters are not evaluated in this study .
8.7.Genetics
Genetics (specified anal yses) are not evaluated in this study .
8.8.Biomarkers
Biomarkers are not evaluated in this study .
8.9.Immunogenicity Assessments
Immunogenicit y assessments are described in Section 8.1.
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Page 488.10.Health Economics
Health economics/ medical resource utilization and health economics parameters are not
evaluated in this study .
8.11.Study Procedures
8.11.1. Visit 1 –Vaccination 1 (Day 1)
Before enrollment and before an y study-related procedures are performed, voluntary , written,
study-specific informed consent will be obtained from the participant. Each signature on the
ICD must be personall y dated by the signatory. The investigator or his or h er designee will
also sign the ICD. A copy of the signed and dated I CD must be given to the participant. The
source data must reflect that the informed consent was obtained before participation in the
study.
It is anticipated that the procedures below wi ll be conducted in a stepwise manner. The visit
may be conducted across 2 consecutive day s; if so, all steps from assessing the inclusion and
exclusion criteria onward must be conducted on the same day .
Assign a single participant number using the IRT sy stem.
Obtain the participant’s demograph y (including date of birth, sex, race, and ethnicity).
The full date of birth will be collected to criticall y evaluate the immune response and
safety profile b y age.
Obtain an y medical history of clinical significanc e.
Perform a clinical assessment. If the clinical assessment indicates that a phy sical
examination is necessary to comprehensivel y evaluate the participant, perform a
physical examination and record any findings in the source documents and, if
clinically significant, record on the medical history CRF.
Measure the participant’s height and weight.
Measure the participant’s body temperature.
Perform urine pregnancy test on WOCBP as described in Section 8.2.3.
Discuss contraceptive use as described in Section 5.3.1 .
Record nonstud y vaccinations as described in Section 6.5.
Ensureand document that all of the inclusion criteria and none of the exclusion
criteria are met.
Ensure that the participant meets none of the temporary delay criteria as described in
Section 5.5.
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Page 49Collect a blood sample of approximately 20 mL for immunogenicit y testing and to
test for prior COVID -19. Please refer to the ISF for further instructions.
Obtain a nasal (midturbinate) sw ab (collected by site staff) for determination of
current SARS -CoV-2 status. Please refer to the ISF for further instructions.
Obtain the participant’s randomization number and study intervention allocation
number using the IRT system. Only an unblinded site staff member may obtain this
information.
Unblinded site staff member(s) will dispense/administer 1 dose of study intervention
into the deltoid muscle of the ( preferably )nondominant arm. Please refer to the I P
manual for further instruction on this process.
Blinded site staff must observe the participant for at least 30 minutes after study
intervention administration for an y acute reactions. Record an y acute reactions
(including time of onset) in the participant’s source documents and on the AE page of
the CRF, and on an SAE form as applicable.
Explain the e -diary technologies available for this study (Section 8.2.2), and assist the
participant in downloading the stud y application onto the participant’s own device or
issue a provisioned device if required.
Provide instructions on reactogenicity e-diary completion and ask the participant
to complete the reactogenicity e-diary from Day1 through Day 7, with Day 1
being the day of vaccination.
Ask the participant to contact the site staff or investigator immediatel y if the
participant experiences any of the following from Day 1 through Day 7 after
vaccination (where Day 1 is the day of vaccination) to determine if an unscheduled
reactogenicity visit is required:
Fever ≥39.0°C (≥102.1°F).
Redness or swelling at the injection site measuring greater than 10 cm
(>20measuring device units).
Severe pain at the injection site.
Any severe systemic event.
Issue a measuring device to measure local reactions at the injection site and a
thermometer for recording daily temperatures and provide instructions on their use.
Record AEs/SAEs as described in Section 8.3.
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Page 50Ask the participant to contact the site staff or investigator if a medicall y attended
event (eg, doctor’s visit, emergency room visit) or hospitalization occurs.
Ask the participant to con tact the site staff or investigator if he/she develops
symptoms of a COVID -19 infection, as defined by the CDC,14including:
New or increased cough;
New or increased shortness of breath;
Chills;
New or increased muscle pain;
New loss of taste/smell;
Sore throat;
Diarrhea;
Vomiting.
Schedule an appointment for the participant to return for the next study visit.
Remind the participant to bring the reactogenicit y e-diary to the next visit.
Complete the source documents.
The investigator or an authorized design ee completes the CRFs and an unblinded
dispenser/administrator updates the study intervention accountability records.
The investigator or appropriately qualified designee reviews the reactogenicity e-diary data
online following vaccination to evaluate part icipant compliance and as part of the ongoing
safety review. Dail y review is optimal during the active diary period.
8.11.2. Visit 2 –Vaccination 2 (19 to 23 Days After Visit 1)
Record AEs/SAEs as described in Section 8.3.
Review the participant’s reactogenicity e-diary data. Collect stop dates of any
reactogenicity e-diary events ongoing on the last day that the reactogenicity e-diary
was completed and record stop dates in the CRF if required.
Perform urine pregnancy test on WOCBP as described in Section 8.2.3.
Discuss contraceptive use as described in Section 5.3.1.
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Page 51Record nonstud y vaccinations as described in Section 6.5.
Record details of an y of the prohibited medications specified in Section 6.5.1
received b y the participant if required for his or her clinical care.
Ensure and document that all of the inclusion criteria and none of the exclusion
criteria are met. If these eligibilit y criteria are not met, the participant may not
receive further study intervention but will remain in the study to be evaluated for
safety, immunogenicity, and efficacy (see Section 7).
Measure the participant’s body temperature.
Ensure that the participant meets none of the temporary delay criteria as described in
Section 5.5.
Unblinded site staff member(s) will dispense/administer 1 dose of study intervention
into the deltoid muscle of the ( preferably )nondominant arm. Please refer to the I P
manual for further instruction on this process.
Blinded site staff must observe the participant for at least 30 minutes after study
intervention administration for an y acute reactions. Record an y acute reactions
(including time of onset) in the participant’s source documents and on the AE page of
the CRF, and on an SAE form as applicable.
Ensure the participant has a measuring device to measure local reactions at the
injection site and a thermometer for recording d aily temperatures.
Ensure the participant remains comfortable with the chosen e- diary platform, confirm
instructions on e -diary completion, and ask the participant to complete the
reactogenicity e-diary from Day 1 through Day 7, with Day 1 being the day of
vaccination.
Ask the participant to contact the site staff or investigator immediatel y if the
participant experiences any of the following from Day 1 through Day 7 after
vaccination (where Day 1 is the day of vaccination) to determine if an unscheduled
reactogenicity visit is required:
Fever ≥39.0°C (≥102.1°F).
Redness or swelling at the injection site measuring greater than 10 cm
(>20measuring device units).
Severe pain at the injection site.
Any severe systemic event.
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Page 52Ask the participant to contact thesite staff or investigator if a medicall y attended
event (eg, doctor’s visit, emergency room visit) or hospitalization occurs.
Ask the participant to contact the site staff or investigator if he/she develops
symptoms of a COVID -19 infection, as defined by the CDC,14including:
New or increased cough;
New or increased shortness of breath;
Chills;
New or increased muscle pain;
New loss of taste/smell;
Sore throat;
Diarrhea;
Vomiting.
Schedule an appointment for the participant to return for the next study visit.
Remind the participant to bring the reactogenicit y e-diary to the next visit.
Complete the source documents.
The investigator or an authorized designee completes the CRFs and an unblinded
dispenser/administrator updates the study intervention accountability records.
The investigator or appropriately qualified designee reviews the reactogenicity e-diary data
online following vaccination to evaluate participant compliance and as part of the ongoing
safety review. Dail y review is optimal during the active diary period.
8.11.3. Visit 3 – 1-Month Follow -up (28 to 35 Days After Visit 2)
Record AEs/SAEs as described in Section 8.3.
Review the participant’s reactogenicity e-diary data. Collect stop dates of any
reactogenicity e-diary events ongoing on the last day that the reactogenicity e-diary
was completed and record stop dates in the CRF if required.
Record nonstud y vaccinations as described in Section 6.5.
Record details of an y of the prohibited medications specified in Section 6.5.1
received b y the participant if required for his or her clinical care.
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Page 53Discuss contraceptive use as described in Section 5.3.1.
Collect a blood sample of approximately 20 mL for immunogenicit y testing and to
test for prior COVID -19.
Obtain a nasal (midturbinate) swab (collected b y site staff) for determination of
current SARS -CoV-2 status.
Collect the participant’s reactogenicity e-diary or assist the participant to remove the
study application from his or her own personal device.
Complete the source documents.
The investigator or an authorized designee completes th e CRFs.
8.11.4. Unscheduled Visits for a Grade 3 or Suspected Grade 4 Reaction
If a Grade 3 local reaction ( Section 8.2.2.2),systemic event ( Section 8.2.2.3), or fever
(Section 8.2.2.4) is reported in the reactogenicit y e-diary, a telephone contact should occur to
ascertain further details and determine whether a site visi t is clinically indicated. If a
suspected Grade 4 local reaction ( Section 8.2.2.2), systemic event ( Section 8.2.2.3 ), or fever
(Section 8.2.2.4) is reported in the reactogenicit y e-diary, a telephone contact or site visit
should occur to confirm whether the event meets the criteria for Grade 4.
A site visit must be scheduled as soon as possible to assess the participant unless any of the
following is true:
The participant is unable to attend the unscheduled visit.
The local reaction/s ystemic event is no longer present at the time of the telephone
contact.
The participant recorded an incorrect value in the reactogenicity e-diary (confirmation
of a reactogenicity e-diary data entry error).
The PI or authorized designee determined it was not needed.
This telephone contact will be recorded in the participant’s source documentation and the
CRF.
If the participant is unable to attend the unscheduled visit, or the PI or authorized designee
determined it was not needed, an y ongoing local reactions/sy stemic events must be assessed
at the next study visit.
During the unscheduled visit, the reactions should be a ssessed by the investigator or a
medically qualified member of the study staff such as a study physician or a study nurse, as
applicable to the investigator’s local practice, who will:
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Page 54Measure bod y temperature (°F/°C).
Measure minimum and maximum diameters of redness (if present).
Measure minimum and maximum diameters of swelling (if present).
Assess injection site pain (if present) in accordance with the grades provided in
Section 8.2.2.2.
Assess sy stemic events (if present) in accordance with the grades provided in
Section 8.2.2.3 .
Assess for other findings associated with the reaction and record on the AE page of
the CRF, if appropriate.
The investigator or an authorized designee will complete the unscheduled visit assessment
page of the CRF.
9.STATISTICAL CONSIDERATIONS
Methodology for summary and statistical anal yses of the data collected in this study is
described here and further detailed in a SAP, which will be maintained by the sponsor. The
SAP may modify what is outlined in the protocol where appropriate; however, any major
modifications of the primary endpoint definitions or their anal yses will also be ref lected in a
protocol amendment.
9.1.Estimands and Statistical Hypotheses
9.1.1.Estimands
The estimands corresponding to each primary and secondary objective are described in the
table in Section 3.
The estimands to evaluate the immuno genicity objectives are based on the evaluable
immunogenicit y population ( Section 9.3). These estimands estimate the vaccine effect in the
hypothetical settings where participants follow the study schedules and protocol requirements
as directed. The estimands address the objective of estimating the maximum potential
difference between 2 groups, since the impact of noncompliance is likely to diminish the
observed difference between the 2 groups. Missing antibody results will not be imputed.
Immunogenicit y results that are below the LLOQ will be set to 0.5 × LLOQ in the anal ysis;
this maybe adjusted once additional data on the assay characteristics become available.
In the primary safety objective evaluations, missing reactogenicity e -diary data will not be
imputed. Missing AE startdates will be imputed according to Pfizer safet y rules. No other
missing information will be imputed in the safet y analysis.
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Page 559.1.2.Statistical Hypothesis
The 2primary immunogenicity objective sareto assess the noninferiorit y of the immune
response induced b y lyophilized SDV or MDV BNT162b2 compared to frozen- liquid MDV
BNT162b2. Taking the noninferiority assessment of ly ophilized SDV vs frozen- liquid MDV
BNT162b2 as the example,thenull hypothesis(H0) is
H0: ln(μ1) –ln(μ2) ≤ ln(0.67)vs H1: ln(μ1) –ln(μ2) > ln(0.67 )
where ln( 0.67) corresponds to a 1.5- fold margin for noninferiorit y and
ln(μ1) is the natural log of the geometric mean of full -length S-binding IgG levels
measured 1 month after Dose 2 from participants receiving l yophilized SDV
BNT162b2 ;
ln(μ2) is the natural log of the geometric mean of full-length S-binding IgG levels
measured 1 month after Dose 2 from participants receiving frozen -liquid MDV
BNT162b2 control for l yophilized SDV
Noninferiorit y will be declared if the lower bound of the 2 -sided 95% CIfor the GMR of
lyophilized SDV relat ive to the corresponding frozen-liquid MDV control is greater than
0.67 (1.5-fold criterion).
The statistical hy pothesis and testing will be similar for the noninferiorit y assessment of
lyophilized MDV vs frozen- liquid MDV BNT162b2.
9.1.3.Multiplicity Considerations
For theassessment of the noninferiority of the immune response induced by lyophilized SDV
or MDVBNT162b2 compared to frozen -liquid MDV BNT162b2 (ie, the primary
immunogenicit y objectives), each h ypothesis test will be carried out separatelyat a 1-sided
significan celevel of 0.025 . Each noninferiority analysis corresponds to a separate anal ysis
of the respective lyophilized formulation and its control, with a separate objective. The 2
lyophilized formulation groups and corresponding controlare included in the same stud y to
improve operational efficiency. There fore, there is no increase in the ty pe I error rate, and no
type I error adjustments are needed for the2noninferiorit y assessments.
9.2.Sample Size Determination
The study sample size is based on the noninferiority evaluation for the primary
immunogenicit y endpoint, full -length S-binding IgG levels 1 month after Dose 2, using a
1.5-fold noninferiorit y margin for the comparison between l yophilized SDV or MDV
BNT162b2 relative to fro zen-liquid MDV BNT162b2 .
Common assay standard deviations from each groupare assumed to be 0.6456based on
results from Phase 1 of Study C4591001 (BNT162b2 30 µg , 18-to 55-year age group). With
thisstandard deviation and the observed GMT difference assumed in the power analy sis
below, a sample size of 220evaluable participants per group will provide a power of 9 0.1%
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Page 56to declarenoninferiorit yof lyophilized BNT162b2 to frozen -liquid MDV for each primary
objective (Table4).
Assuming a nonevaluable rate of 20%, the stud y will randomize approximately 275
participants in each groupto achieve the required number of evaluable participants.
Table4. Power Analysis for Noninferiority Assessment
Criteria Standard
Deviation
(Log Value)aAssumed
Observed GMT
Difference
(LogScale)Number of
Evaluable
Participants per
GroupPowerb
Lower limit of 95%
CI for GMR
(lyophilized SDV
BNT162b2 /frozen-
liquid MDV
BNT162b2 ) >0.670.6456 -0.2 220 90.1%
Lower limit of 95%
CI for GMR
(lyophilized MDV
BNT162b2 /frozen-
liquid MDV
BNT162b2 ) >0.670.6456 -0.2 220 90.1%
Abbreviation s: GMR = geometric mean ratio ; GMT= geometric mean titer; MDV = multidose vial; SDV =
single-dose vial.
a.Reference: BNT162b2 (30 µg), 18-to 55-year age group ( C4591001 Phase 1, N=12). Calculation may be
updated if additional information becomes available to better estimate the standard deviation.
b.At the 0.05 alpha level (2 -sided).
9.3.Analysis Sets
For purposes of analy sis, the following anal ysis setsare defined:
Participant Analysis Set Description
Enrolled All participants who have a signed ICD .
Randomized All participants who are assigned a randomization number in
the IWR system.
Evaluable immunogenicity All eligible randomized participants who receive 2 doses of the
vaccine to which they are randomized with Dose 2 received
within the predefined window, have at least 1 valid and
determinate immunogenicity result from the blood sample
collected within an appropriate window at 1 month after the
Dose 2 visit, are negative for SARS- CoV-2 infection during
the study, and have no other important protocol deviations as
determined b y the clinician.
All-available All participants who receive at least 1 dose of the study
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Page 57Participant Analysis Set Description
immunogenicit y intervention and have at least 1 valid and determinate
immunogenicit y result after vaccination.
Safety All randomized participants who receive at least 1 dose of the
study intervention.
9.4.Statistical Analyses
The SAP will be developed and finalized before any analyses are performed and will
describe the anal yses and procedures for accounting for missing, unused, and spurious data.
This section is a summary of the planned statistical analys es of the primary and secondary
endpoints.
9.4.1.General C onsiderations
Lyophilized SDV and MDVBNT162b2 are 2independent parts of the study . Data from the
lyophilized SDV and MDV parts of the stud y will be anal yzed separatel y.
Unless stated otherwise, “vaccine group” in this section refers to participants receiving
lyophilized SDV , frozen-liquid MDV control for lyophilized SDV, ly ophilized MDV, or
frozen-liquid MDV control for ly ophilized MDV BNT162b2 . CIs for all endpoints in the
statistical analy sis will be presented as 2- sided at the 95% level unless specified otherwise.
For all the immunogenicity endpoints, the analy sis will be based on the evaluable
immunogenicit y population. An additional anal ysis will be performed based on the
all-available immunogenicity population if there is a large enough difference in sample size
between the all -available immunogenicit y population and the evaluable immunogenicit y
population. Participants will be summarized according to the vaccine group to which they
were randomized.
The safety analyses will be based on the safet y population. Participants will be summarized
by vaccine group according to the study intervention s they actually received.
9.4.1.1. Analysis for Binary Data
Descriptive statistics for categorical variables (eg, proportions) are the percentage (%), the
numerator (n) and the denominator (N) used in the percentage calculation, and the 95% CIs
where applicable.
The exact 95% CI for binaryendpoints for each group will be computed using the
Fdistribution (Clopper -Pearson).
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Page 589.4.1.2. Analysis for Continuous Data
Unless otherwise stated, descriptive statistics for continuous variables are n, mean, median,
standard deviation, minimum, and maximum.
9.4.1.2.1. Geometric Mean Ratios
The GMRs will be calculated as the mean of the difference of logarithmically transformed
assay results between 2 vaccine groups and exponentiating the mean. Two -sided CIs will be
obtained by calculating CI s using Student’s t -distribution for the mean difference of the
logarithmicall y transformed assay resultsand exponentiating the confidence limits.
9.4.1.2.2. Geometric Means
The geometric means will be calculated as the mean of the assay results after making the
logarithm ictransformation and then exponentiating the mean to express results on the
original scale. Two -sided 95% CI s will be obtained by taking log transforms of assay results,
calculating the 95% CI with reference to Student’s t-distribution, and then exponentiating the
confidence limits.
9.4.1.2.3. Geometric Mean Fold Rises
GMFRs are defined a s ratios of the results after vaccination to the results before vaccination.
GMFRs are limited to participants with nonmissing values at both time points.
GMFRs will be calculated as the mean of the difference of logarithmicall y transformed assay
results (later time point minus earlier time point) and exponentiating the mean. The
associated 2- sided 95% CI s will be obtained b y constructing CIs using Student’s
t-distribution for the mean difference on the logarithm scale and exponentiating the
confidence li mits.
9.4.1.2.4. Reverse Cumulative Distribution Curve
Empirical RCDCs will plot proportions of participants with values equal to or exceeding a
specified assay value versus the indicated assay value, for all observed assay values. Data
points will be joined by a step function with data points on the left side of the step.
9.4.2.Primary Endpoint(s)
Endpoint Statistical Analysis Methods
Immunogenicity GMR of full-length S-binding IgG levels in participants receiving lyophilized SDV
BNT162b2 compared to frozen -liquid MDV BNT162b2 control for lyophi lized
SDV
For full-length S-binding IgG levels, the GMR at 1 month after Dose 2 w ill be
provided along w ith associated 2 -sided 95% CIs (see Section 9.4.1.2.1).
Noninferiority will be declared if the lower limit of the 2-sided 95% CI for the GMR is
greater than 0.67 .
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Page 59Endpoint Statistical Analysis Methods
GMR of full-length S-binding IgG levels in participants receiving lyophilized
MDV BNT162b2 compared to frozen -liquid MDV BNT162b2 control for
lyophilized MDV
This endpoint will be analyzed the same way as above.Noninferi ority will be declared
if the low er limit of the 2 -sided 95% CI for the GMR is greater than 0.67 .
Safety Descriptive statistics will be provided for each reactogenicity endpoint for each dose
and vaccine group. Local reactions and systemic events from Day 1 through Day 7
after each vaccination (where Day 1 is the day of vaccination) will be presented by
severity and cumulatively across severity levels. Descriptive summary statistics will
include counts and percentages of participants with the indicated endpoint and the
associated Clopper -Pearson 95% CIs (see Section 9.4.1.1).
AEs and SAEs will be categorized according to MedDRA terms. Counts, percentages,
and the associated Clopper -Pearson 95% CIs of AEs and SAEs from Dose 1 through1
month after Dose 2 will be provided for each vaccine group .
9.4.3.Secondary Endpoint(s)
Endpoint Statistical Analysis Methods
Immunogenicity GMCs of full -length S-binding IgG levels
For full-length S-binding IgG levels, GMCs and 2 -sided 95% CIs will be provided for
each vaccine group at baseline (before Dose 1) and at 1 month after Dose 2.
Statistical methods are described in Section 9.4.1.2.2.
GMFRs of full-length S-binding IgG levels
For full-length S-binding IgG levels, the GMFRs and 2 -sided 95% CIs w ill be
provided for each vaccine group from baseline (before Dose 1) through 1 month after
Dose 2.
GMFRs will be limited to participants with nonmissing values prior to the first dose
and at the postvaccination time point. The statistical methods are described in
Section 9.4.1.2.3.
9.5.Interim Analyses
No formal interim anal ysis will be conducted for this study .
Thelyophilized SDV and MDV BNT162b2 are 2independent parts of the study . Data from
these 2parts of the stud y will be anal yzed separately . Statistical anal yses will be carried out
when the final data fora givenpart are available.
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Page 609.6.Data Monitoring Committee or Other Independent Oversight Committee
This study will use a DMC. The DMC is independ ent of the study team and includes
external members. The DMC charter describes the role of the DMC in more detail.
The DMC will be responsible for ongoing monitoring of the safety of participants in the
study according to the charter. This may include, b ut is not limited to:
Contemporaneous review of related AEs up to 1 month after completion of the
vaccination schedule,
Contemporaneous review of all SAEs up to 1 month after completion of the
vaccination schedule.
The recommendations made b y the DMC to al ter the conduct of the stud y will be forwarded
to the appropriate Pfizer personnel for final decision. Pfizer will forward such decisions,
which may include summaries of aggregate analy ses of safety data, to regulatory authorities,
as appropriate.
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Page 6110.SUPPORT ING DOCUMENTATION AND OPERATIONAL CONSID ERATIONS
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1.Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and with the following:
Consensus ethical principles derived from international guidelines including the
Declaration of Helsinki and CI OMS International Ethical Guidelines ;
Applicable ICHGCP guidelines;
Applicable laws and regulations , including applicable privacy laws.
The protocol, protocol amendments, I CD, SRSD(s), and other relevant documents
(eg,advertisements) must be reviewed and approved by the sponsor and submitted to an
IRB/EC by the investigator and reviewed and approved by the IRB/EC before the study is
initiated.
Any amendments to the protocol will require IRB/EC approval before implementation of
changes made to the study design, except for changes necessary to eliminate an immediate
hazard to study participants.
The investigator will be responsible for the following:
Providing written summaries of the status of the study to the IRB/EC annually or
more frequently in accordance with the requirements, policies, and procedures
established by the IRB/EC ;
Notifying the IRB/EC of SAEs or other significant safet y findings as required by
IRB/EC procedures;
Providing oversight of the conduct of the stud y at the site and adherence to
requirements of 21 CFR, ICH guidelines, the IRB/EC, European regulation 536/2014
for clinical studies (if applicable), and all other applicable loc al regulations.
10.1.1.1. Reporting of Safety Issues and Serious Brea ches of the Protocol or ICH GCP
In the event of an y prohibition or restriction imposed (ie , clinical hold) b y an applicable
regulatory authority in any area of the world, or if the investigator is aware of an y new
information that might influence the evaluation of the benefits and risks of the study
intervention , Pfizer should be informed immed iately.
In addition, the investigator will inform Pfizer immediately of any urgent safet y measures
taken by the investigator to protect the study participants against an y immediate hazard, and
of any serious breaches of this protocol or of ICH GCP that th e investigator becomes aware
of.
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Page 6210.1.2. Financial Disclosure
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial
information as requested to allow the sponsor to submit complete and accurate financial
certification or d isclosure statements to the appropriate regulatory authorities. I nvestigators
are responsible for providing information on financial interests during the course of the stud y
and for 1 year after completion of the study .
10.1.3.Informed Consent Process
The invest igator or his/her representative will explain the nature of the study to the
participant and answer all questions regarding the study . The participant should be given
sufficient time and opportunity to ask questions and to decide whether or not to participate in
the trial.
Participants must be informed that their participation is voluntary .Participants will be
required to sign a statement of informed consent that meets the requirements of 21 CFR 50,
local regulations, ICH guidelines, HIPAA requirements, where applicable, and the IRB/EC
or study center.
The investigator must ensure that each study participant is fully informed about the nature
and objectives of the study, the sharing of data related to the study ,and possible risks
associated with participation, including the risks associated with the processing of the
participant ’s personal data.
The participant must be informed that his/her personal study -related data will be used by the
sponsor in accordance with local data protection law. The level of disclosure must also be
explained to the participant.
The participant must be informed that his/her medical records may be examined by Clinical
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by
appropriate IRB/EC members, and b y inspectors from regulatory authorities.
The investigator further must ensure t hat each study participant is fully informed about his or
her right to access and correct his or her personal data and to withdraw consent for the
processing of his or her personal data.
The medical record must include a statement that written informed con sent was obtained
before the participant was enrolled in the study and the date the written consent was obtained.
The authorized person obtaining the informed consent must also sign the IC D.
Participants must be reconsented to the most current version of the ICD(s) during their
participation in the study .
A copy of the ICD(s) must be provided to the participant. Participants who are rescreened
are required to sign a new I CD.
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Page 63Unless prohibited by local requirements or IRB/EC decision, the I CD will contain a separate
section that addresses the use of samples for optional additional research. The optional
additional research does not require the collection of an y further samples. The investigator
or authorized designee will explain to each participant the o bjectives of the additional
research. Participants will be told that they are free to refuse to participate and may
withdraw their consent at any time and for any reason during the storage period.
10.1.4.Data Protection
All parties will comply with all applicab le laws, including laws regarding the implementation
of organizational and technical measures to ensure protection of participant data.
Participants’ personal data will be stored at the study site in encry pted electronic and/or paper
form and will be passw ord protected or secured in a locked room to ensure that only
authorized study staff have access. The study site will implement appropriate technical and
organizational measures to ensure that the personal data can be recovered in the event of
disaster. In the event of a potential personal data breach, the study site will be responsible
for determining whether a personal data breach has in fact occurred and, if so, providing
breach notifications as required by law.
To protect the rights and freedoms of participants with regard to the processing of personal
data, participants will be assigned a single, participant -specific numerical code. Any
participant records or data sets that are transferred to the sponsor will contain the numerical
code; participant n ames will not be transferred. All other identifiable data transferred to the
sponsor will be identified by this single, participant- specific code. The study site will
maintain a confidential list of participant s who participated in the study , linking eac h
participant ’s numerical code to his or her actual identity and medical record identification . In
case of data transfer, the sponsor will protect the confidentiality of participants’ personal data
consistent with the clinical study agreement and applicable privacy laws.
10.1.5.Dissemination of Clinical Study Data
Pfizer fulfills its commitment to publicly disclose clinical study results through posting the
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the EudraCT, and/or
www.pfizer.c om, and other public registries in accordance with applicable local
laws/regulations. In addition, Pfizer reports study results outside of the requirements of local
laws/regulations pursuant to its SOPs.
In all cases, stud y results are reported b y Pfizer in an objective, accurate, balanced, and
complete manner and are reported regardless of the outcome of the stud y or the country in
which the study was conducted.
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Page 64www.clinicaltrials.gov
Pfizer posts clinical trial results on www.clinicaltrials.gov for Pfizer-sponsored interventional
studies (conducted in patients) that evaluate the safety and/or efficacy of a product,
regardless of the geographical location in which the study is conducted. These r esults are
submitted for posting in accordance with the format and timelines set forth by US law.
EudraCT
Pfizer posts clinical trial r esults on EudraCT for Pfizer -sponsored interventional studies in
accordance with the format and timelines set forth by EU requirements.
www.pfizer.com
Pfizer posts public disclo sure synopses (CSR synopses in which an y data that could be used
to identify individual participants have been removed) on www.pfizer.com for
Pfizer-sponsored interventional studies at the same time the corresponding study results are
posted to www.clinica ltrials.gov .
Documents within marketing authorization packages/submissions
Pfizer complies with the European Union Policy 0070, the proactive publication of clinical
data to the EMA website. Clinical data, under Phase 1 of this policy , includes clinical
overviews, clinical summaries, CSRs, and appendices containing the protocol and protocol
amendments, sample CRFs, and statistical methods. Clinical data, under Phase 2 of this
policy, includes the publishing of individual participant data. Policy 0070 app lies to new
marketing authorization applications submitted via the centralized procedure since
01January2015 and applications for line extensions and for new indications submitted via
the centralized procedure since 01 July 2015.
Data Sharing
Pfizer provides researchers secure access to patient- level data or full CSRs for the purposes
of “bona-fide scientific research” that contribute sto the scientific understanding of the
disease, target, or compound class. Pfizer will make available data from thes e trials
24months after study completion. Patient -level data will be anon ymized in accordance with
applicable privacy laws and regulations. CSRs will have personall y identifiable information
redacted.
Data requests are considered from qualified research ers with the appropriate competencies to
perform the proposed analy ses.Research teams must include a biostatistician. Data will not
be provided to applicants with significant conflicts of interest, including individuals
requesting access for commercial/competitive or legal purposes.
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Page 6510.1.6. Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless
transmitted to the sponsor or designee electronically (eg, laboratory data). The investigator is
responsible for verify ing that data entries are accurate and correct by physically or
electronically signing the CRF.
The investigator must maintain accurate documentation (source data) that supports the
information entered in the CRF.
The investigator must ensure that the CRFs are securel y stored at the study site in encrypted
electronic and/or paper form and are password protected or secured in a locked room to
prevent access b y unauthorized third parties.
The investigator must permit study -related monitoring, au dits, IRB/EC review, and
regulatory agency inspections and provide direct access to source data documents. This
verification may also occur after study completion. I t is important that the investigator(s)
and their relevant personnel are available during the monitoring visits and possible audits or
inspections and that sufficient time is devoted to the process.
Monitoring details describing strategy (eg, risk- based initiatives in operations and quality
such as risk management and mitigation strategies and analytical risk-based monitoring),
methods, responsibilities ,and requirements, including handling of noncompliance issues and
monitoring techniques (central, remote, or on -site monitoring) ,are provided in the
monitoring plan.
The sponsor or designee is responsible for the data management of this study ,including
quality checking of the data.
Study monitors will perform ongoing source data verification to confirm that data entered
into the CRF by authorized site personnel are accurate, complete, and verif iable from source
documents; that the safety and rights of participants are being protected; and that the study is
being conducted in accordance with the currently approved protocol and any other study
agreements, I CH GCP, and all applicable regulatory requirements.
Records and documents, including signed IC Ds, pertaining to the conduct of this study must
be retained b y the investigator for 15years after study completion unless local regulations or
institutional policies require a longer retention period. No records may be destroy ed during
the retention period without the written approval of the sponsor. No records may be
transferred to another location or party without written notification to the sponsor. The
investigator must ensure that the records co ntinue to be stored securel y for aslong as they are
maintained.
When participant data are to be deleted, the investigator will ensure that all copies of such
data are promptly and irrevocabl y deleted from all systems.
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Page 66The investigator(s) will notify thesponsor or its agents immediately of any regulatory
inspection notification in relation to the study . Furthermore, the investigator will cooperate
with the sponsor or its agents to prepare the investigator site for the inspection and will allow
the sponsor or its agent, whenever feasible, to be present during the inspection. The
investigator site and investigator will promptly resolve any discrepancies that are identified
between the stud y data and the participant's medical records. The investigator wil l promptly
provide copies of the inspection findings to the sponsor or its agent. Before response
submission to the regulatory authorities, the investigator will provide the sponsor or its
agents with an opportunity to review and comment on responses to a ny such findings.
10.1.7.Source Documents
Source documents provide evidence for the existence of the participant and substantiate the
integrity of the data collected. Source document s are filed at the investigator site.
Data reported on the CRF or entered in the eCRF that are from source documents must be
consistent with the source documents or the discrepancies must be explained . The
investigator may need to request previous medical records or transfer records, depending on
the study. Also, current medical records must be available.
Definition of what constitutes source data can be found in the study monitoring plan .
Description of the use of computerized sy stem is documented in the data management plan.
10.1.8.Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment of
participants.
The first act of recruitment is the date of the first participant’s first visit and will be the study
start date.
The sponsor designee reserves the right to close the study site or terminate the study at any
time for an y reason at the sole discretion of the sponsor. Study sites will be closed upon
study completion. A study site is considered closed when all required documents and study
supplies have been c ollected and a study -site closure visit has been performed.
The investigator may initiate study -site closure at any timeupon notification to the sponsor
or designee if requested to do so by the responsible I RB/EC or if such termination is required
to protect the health of study participants .
Reasons for the earl y closure of a stud y site by the sponsor may include but are not limited
to:
Failure of the investigator to comply with the protocol, the requirements of the
IRB/EC or local health authorities, the sponsor's procedures, or GCP guidelines;
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Page 67Inadequate recruitment of participants by the investigator;
Discontinuation of further study intervention development .
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the
investigators, the ECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of
the reason for termination or suspension, as specified by the applicable regu latory
requirements. The investigator shall promptly inform the participant and should assure
appropriate participant therapy and/or follow -up.
Study termination is also provided for in the clinical study agreement. If there is any conflict
between the c ontract and this protocol ,the contract will control as to termination rights.
10.1.9.Publication Policy
The results of this study may be published or presented at scientific meetings b y the
investigator after publication of the overall study results or 1 y ear after the end of the study
(or study termination), whichever comes first.
The investigator agrees to refer to the primary publication in any subsequent publications
such as secondary manuscripts, and submits all manuscripts or abstracts to the sponsor
30 days before submission. This allows the sponsor to protect proprietary information and to
provide comments and the investigator will, on request, remove an y previously undisclosed
confidential information before disclosure, except for an y study-or Pfizer i ntervention-
related information necessary for the appropriate scientific presentation or understanding of
the study results.
For all publications relating to the stud y, the investigator will compl y with recognized ethical
standards concerning publications and authorship, including those established by the
International Committee of Medical Journal Editors.
The sponsor will comply with the requirements for publication of the overall study results
covering all investigator sites. I n accordance with standard editorial and ethical practice, the
sponsor will support publication of multicenter studies only in their entirety and not as
individual site data. I n this case, a coordinating investigator will be designated by mutual
agreement.
Authorship of publication s for the overall study results will be determined by mutual
agreement and in line with I nternational Committee of Medical Journal Editors authorship
requirements.
If publication is addressed in the clinical study agreement, the publication policy set outin
this section will not apply.
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Page 6810.1.10. S ponsor’s Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the
study is documented in the study contact list located in the supporting study documentation
or other electronic s ystem.
To facilitate access to appropriatel y qualified medical personnel on stud y-related medical
questions or problems, participant s are provided with a contact card at the time of informed
consent. The contact card contains, at a minimum, protocol and study intervention
identifiers, participant numbers, contact information for the investigator site, and contact
details for a contact center in the event that the investigator site staff cannot be reached to
provide advice on a medical question or problem originating from another healthcare
professional not involved in the participant ’s participation in the study . The contact number
can also be used b y investigator staff if they are seeking advice on medical questions or
problems; how ever, it should be used only in the event that the established communication
pathways between the investigator site and the study team are not available. I t is therefore
intended to augment, but not replace, the established communication pathway s between the
investigator site and the study team for advice on medical questions or problems that may
arise during the stud y. The contact number is not intended for use b y the participant directly,
and if a participant calls that number, he or she will be directe d back to the investigator site.
10.2.Appendix 2: Clinical Laboratory Tests
A pregnancy test will be performed at times defined in the SoA section of this protocol:
Visit 1 (Vaccination 1/Day 1) and Visit 2 (Vaccination 2/19 -23 days afte r Visit 1).
Pregnancy test (β-hCG): Local urine testing will be standard for the protocol unless
serum testing is required by local regulation or IRB/EC for female participants of
childbearing potential.
Unscheduled clinical laboratory measurements may beobtained at any time during the study
to assess an y perceived safet y issues. Investigators must document their review of each
laboratory safety report.
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Page 6910.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording,
Evaluating, Follow -up, and Reporting
10.3.1.Definition of AE
AE Definition
An AE is an y untoward medical occurrence in a patient or clinical study participant,
temporally associated with the use of study intervention, whether or not considered
related to the stud y intervention.
NOTE: An AE can therefore be an y unfavorable and unintended sign (including an
abnormal laboratory finding), s ymptom, or disease (new or exacerbated) temporally
associated with the use of study intervention.
Events Meeting the AE Definition
Any abnormal laborato ry test results (hematology , clinical chemistry , or urinaly sis) or
other safet y assessments (eg, ECG, radiological scans, vital sign measurements),
including those that worsen from baseline, considered clinicall y significant in the
medical and scientific judgment of the investigator Any abnormal laboratory test
results that meet an y of the conditions below must be recorded as an AE:
Is associated with accompany ing symptoms.
Requires additional diagnostic testing or medical/surgical intervention .
Leads to a change in study dosing (outside of any protocol-specified dose
adjustments) or discontinuation from the study , significant additional concomitant
drug treatment, or other therap y.
Exacerbation of a chronic or intermittent preexisting condition including e ither an
increase in frequency and/or intensity of the condition.
New conditions detected or diagnosed after stud y intervention administration even
though it may have been present before the start of the study .
Signs, symptoms, or the clinical sequelae of a suspected drug- drug interaction.
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study
intervention or a concomitant medication. Overdose per se will not be reported as an
AE/SAE unless it is an intentional overdose taken wit h possible suicidal/self -harming
intent. Such overdoses should be reported regardless of sequelae.
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Page 70Events NOT Meeting the AE Definition
Any clinically significant abnormal laboratory findings or other abnormal safet y
assessments which are associated with the underl ying disease, unless judged by the
investigator to be more severe than expected for the participant’s condition.
The disease/disorder being studied or expected progression, signs, or s ymptoms of the
disease/disorder being studied, unless more severe than expected for the participant’s
condition.
Medical or surgical procedure (eg, endoscop y, appendectom y): the condition that
leads to the procedure is the AE.
Situations in which an untoward medical occurrence did not occur (social and/or
convenience admission to a hospital).
Anticipated day -to-day fluctuations of preexisting disease(s) or condition(s) present
or detected at the start of the study that do not worsen.
10.3.2.Definition of SAE
If an event is not an AE per definition above, then it canno t be an SAE even if serious
conditions are met (eg, hospitalization for signs/symptoms of the disease under study , death
due to progression of disease).
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Page 71An SAE is defined as any untoward medical occurrence that, at any dose:
a.Results in death
b.Is life-threatening
The term “life-threatening ”in the definition of “serious”refers to an event in which the
participant was at risk of death at the time of the event. It does not refer to an event that
hypothetically might have caused death if it were more sev ere.
c.Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually involving
at least an overnight stay) at the hospital or emergency ward for observation and/or treatment
that would not have been appropriate in the ph ysician’s office or outpatient setting.
Complications that occur during hospitalization are AEs. If a complication prolongs
hospitalization or fulfills any other serious criteria, the event is serious. When in doubt as to
whether “hospitalization” occurred or was necessary , the AE should be considered serious.
Hospitalization for elective treatment of a preexisting condition that did not worsen from
baseline is not considered an A E.
d.Results in persistent disability/incapacity
The term disability means a substantial disruption of a person’s ability to conduct
normal life functions.
This definition is not intended to include experiences of relativel y minor medical
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza,
and accidental trauma (eg, sprained ankle) which may interfere with or prevent
everyday life functions but do not constitute a substantial disruption.
e.Is a congenital anomaly/birth defect
f.Other situations:
Medical or scientific judgment should be exercised in deciding whether SAE
reporting is appropriate in other situations such as important medical events that may
not be immediately life-threatening or result in death or hospitalization bu t may
jeopardize the participant or may require medical or surgical intervention to prevent
one of the other outcomes listed in the above definition. These events should usually
be considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment in
an emergency room or at home for allergic bronchospasm, blood dy scrasias or
convulsions that do not result in hospitalization, or development of drug dependency
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Page 72or drug abuse.
Suspected transmission via a Pfizer product of an infectious agent, pathogenic or non-
pathogenic, is considered serious. The event may be suspected from clinical
symptoms or laboratory findings indicating an infection in a patient exposed to a
Pfizer product. The terms “suspected transmission” and “tr ansmission” are
considered s ynonymous. These cases are considered unexpected and handled as
serious expedited cases by pharmacovigilance personnel. Such cases are also
considered for reporting as product defects, if appropriate.
10.3.3.Recording/Reporting and Follow-up of AEsand/or SAE s
AE and SAE Recording /Reporting
The table below summarizes the requirements for recording adverse events on the CRF and
for reporting serious adverse events on the VaccineSAE Report ingForm to Pfizer Safety .
These requirements are delineated for 3 ty pes of events: (1) SAEs; (2) nonserious adverse
events (AEs); and (3) exposure to the study intervention under study during pregnancy or
breastfeeding, and occupational exposure.
It should be noted that the VaccineSAE Report ingForm for reporting of SAE information is
not the same as the AE page of the CRF. When the same data are collected, the forms must
be completed in a consistent manner. AEs should be recorded using concise medical
terminology and the same AE term should be used on both the CRF and the VaccineSAE
ReportingForm for reporting of SAE information.
Safety Event Recorded on the CRF Reported on the Vaccine
SAE Report ingForm to
Pfizer Safety Within 24
Hours of Awareness
SAE All All
Nonserious AE All None
Exposure to the study
intervention under stud y
during pregnancy or
breastfeeding, and
occupational exposureAll AEs/SAEs associated
with exposure during
pregnancy or breastfeeding
Occupational exposure is not
recorded.All (and EDP supplemental
form for EDP)
Note: Include all SAEs
associated with exposure
during pregnancy or
breastfeeding. Include all
AEs/SAEs associated with
occupational exposure.
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Page 73When an AE/SAE occurs, it is the responsibility of the investigator to review all
documentation (eg, hospital progress notes, laboratory reports, and diagnostic reports)
related to the event.
The investigator will then record all relevant AE/SAE information in the CRF.
It is notacceptable for the investigator to send pho tocopies of the participant’s
medical records to Pfizer Safety in lieu of completion of the Vaccine SAE Report ing
Form/AE/SAE CRF page.
There may be instances when copies of medical records for certain cases are
requested b y Pfizer Safety . In this case, all participant identifiers, with the exception
of the participant number, will be redacted on the copies of the medical records
before submission to Pfizer Safet y.
The investigator will attempt to establish a diagnosis of the event based on signs,
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not
the individual signs/sy mptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported during
the study and assign it to 1 of the following categories:
GRADE If required on the AE page of the CRF, the investigator will use the adjectives
MILD, MODERATE, SEVERE, or LIFE -THREATENING to describe the
maximum intensity of the AE. For purposes of consistency , these intensity
grades are defined as follows:
1 MILD Does not interfere with participant 's usual function.
2 MODERATE Interferes to some extent with participant 's usual
function.
3 SEVERE Interferes significantl y with participant 's usual
function.
4 LIFE-THREATENING Life-threatening consequences; urgent intervention
indicated.
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Page 74Assessment of Causality
The investigator is obligated to assess the relationship between stud y intervention and
each occurrence of each AE/SAE.
A “reasonable possibility” of a relationship convey s that there are facts, evidence,
and/or arguments to suggest a causal relationship, rather than a relationship cannot be
ruled out.
The investigator will use clinical judgment to determine the relationship.
Alternative causes, such as underl ying disease(s), concomitant therap y, and other risk
factors, as well as the temporal relationship of the event to study intervention
administration, will be considered and investigated.
The investigator will also consult the IB and/or product information, for marketed
products, in his/her assessment.
For each AE/SAE, the investigator mustdocument in the medical notes that he/she
has reviewed the AE/SAE and has provided an assessment of causality .
There may be situations in which an SAE has occurred and the investigator has
minimal information to include in the initial report to the sponsor. However, it is
very important that the investigator always make an assessment of causality for
every event before the initial transm ission of the SAE data to the sponsor .
The investigator may change his/her opinion of causality in light of follow -up
information and send a nSAE follow -up report with the updated causality assessment.
The causality assessment is one of the criteria used when determining regulatory
reporting requirements.
If the investigator does not know whether or not the study intervention caused the
event, then the event will be handled as “related to study intervention ” for reporting
purposes, as defined b y the sponsor. In addition, if the investigator determines that an
SAE is associated with study procedures, the investigator must record this causal
relationship in the source documents and CRF, and report such an assessment in the
dedicated section of the VaccineSAE ReportingForm and in accordance with the
SAE reporting requirements.
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Page 75Follow-up of AEs and SAEs
The investigator is obligated to perform or arrange for the conduct of supplemental
measurements and/or evaluations as medically indicated or as requested by the
sponsorto elucidate the nature and/or causalit y of the AE or SAE as fully as possible.
This may include additional laboratory tests or investigations, histopathological
examinations, or consultation with other healthcare providers .
If a participant dies during participation in the study or during a recognized follow -up
period, the investigator will provide Pfizer Safety with a cop y of any postmortem
findings including histopathology .
New or updated information will be recorded in the originally completed CRF.
The investigator will submit any updated SAE data to the sponsor within 24 hours of
receipt of the information.
10.3.4.Reporting of SAEs
SAE Reporting to Pfizer Safety via VaccineSAE Report ingForm
Facsimile transmission of the Vaccine SAE Report ingFormis the preferred method
to transmit this information to Pfizer Safety .
In circumstances when the facsimile is not working , notification by telephone is
acceptable with a cop y of the VaccineSAE Report ingForm sent b y overnight mail or
courier service.
Initial notification via telephone does not replace the need for the investigator to
complete and sign the Vaccine SAE Report ingForm pages within the designated
reporting time frames.
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CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (15 May 2020)
Page 7610.4.Appendix 4: Contraceptive Guidance
10.4.1.Male Participant Reproductive Inclusion Criteria
Male participants are eligible to participate if they agree to the following requirements during
the intervention period and for at least 28days/weeksafter the last dose of study intervention ,
which corresponds to the time needed to eliminate reproductive safet y risk of the study
intervention(s) :
Refrain from donating sperm.
PLUS either :
Be abstinent from heterosexual intercourse with a female of childbearing potential as
their preferred and usual lifesty le (abstinent on a long -term and persistent basis) and
agree to remain abstinent .
OR
Must agree to use a male condom when engaging in any activity that allows for
passage of ejaculate to another person .
In addition to male condom use, a highl y effective method of contraception may be
considere d in WOCBP partners of male participants (refer to the list of highly
effective methods below in Section 10.4.4).
10.4.2.Female Participant Reproductive Inclusion Criteria
A female participant is eligible to participate if she is not pregnant or breastfeeding, and at
least 1of the following conditions applies:
Is not a WOCBP (see definitions belowin Section 10.4.3 ).
OR
Is a WOCBP and using an acceptable contraceptive method as described below
during the intervention period (for a minimum of 28 days after the last dose of study
intervention) . The investigator should evaluate the effectiveness of the contraceptive
method in relationship to the first dose of stud y intervention.
The investigator is responsible for review of medical history , menstrual history, and recent
sexual activity to decrease the risk for inclusion of a woman with an earl y undetected
pregnancy .
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PF-07302048 (BNT162b2 RNA -Based COVID -19 Vaccine)
Protocol C4591020
Protocol, 18January2021
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CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (15 May 2020)
Page 7710.4.3.Woman of Childbearing Potential
A woman is considered fertile following menarche and until becoming postmenopausal
unless permanentl y sterile (see below).
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cy cle cannot
be confirmed before the first dose of study intervention, additional evaluation should be
considered.
Women in the following categories are notconsidered WOCBP:
1.Premenopausal female with 1 of the following:
Documented h ysterectomy ;
Documented bilateral salpingectomy ;
Documented bilateral oophorectom y.
For individuals with permanent infertility due to an alternate medical cause other than the
above,(eg, mullerian agenesis, androgen insensitivity ), investigator discretion should be
applied to determining study entry.
Note: Documentation for any of the above categories can come from the site personnel’s
review of the participant’s medical record s, medical examination, or medical history
interview. The method of documentation should be recorded in the participant’s medical
record for the stud y.
2.Postmenopausal female :
A postmenopausal state is defined as no menses for 12 months without an alternative
medical cause. In addition, a
high FSH level in the postmenopausal range must be used to confirm a
postmenopausal state in women under 60 years of age and not using hormonal
contraception or HRT.
Female on HRT and whose menopausal status is in doubt will be required to use
one of the nonestrogen hormonal highl y effective contraception methods if they
wish to continue their HRT during the stud y. Otherwise, they must discontinue
HRT to allow confirmation of postmenopausal status before study enrollment .
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Protocol C4591020
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CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (15 May 2020)
Page 7810.4.4.Contracepti onMethods
Contraceptive use b y men or women should be consistent with local availability /regulations
regarding the use of contraceptive methods for those participating in clinical trials.
1.Implantable progestogen -only hormone contraception associated with inhibition of
ovulation.
2.Intrauterine device .
3.Intrauterine hormone -releasing s ystem.
4.Bilateral tubal occlusion .
5.Vasectomized partner :
Vasectomized partner is a highl y effective contraceptive method provided that the
partner is the sole sexu al partner of the woman of childbearing potential and the
absence of sperm has been confirmed. If not, an additional highly effective method
of contraception should be used. The spermatogenesis cy cle is approximately 90
days.
6.Combined (estrogen- and progestogen-containing) hormonal contraception associated
with inhibition of ovulation :
Oral;
Intravaginal;
Transdermal ;
Injectable.
7.Progestogen -only hormone contraception associated with inhibition of ovulation :
Oral;
Injectable.
8.Sexual abstinence :
Sexual abstinence is considered a highl y effective method only if defined as
refraining from heterosexual intercourse during the entire period of risk associated
with the study intervention. The reliability of sexual abstinence needs to be evaluated
in relation to the duration of the study and the preferred and usual lifest yle of the
participant.
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PF-07302048 (BNT162b2 RNA -Based COVID -19 Vaccine)
Protocol C4591020
Protocol, 18January2021
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CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (15 May 2020)
Page 799.Progestogen -only oral hormonal contraception where inhibition of ovulation is not the
primary mode of action.
10. Male or female condom with or without spermicide.
11.Cervical cap, diaphragm, or sponge with spermicide .
12. A combination of male condom with either cervical cap, diaphragm, or sponge with
spermicide (double -barrier methods) .
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Protocol, 18January2021
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CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (15 May 2020)
Page 8010.5.Appendix 5: Liver Safety: Suggested Actions and Follow -up Assessments
Potential Cases of Drug- Induced Liver Injury
Humans exposed to a drug who show no si
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