Pfizer-BioNTech COVID-19 Vaccine Emergency Use Authorization Review Memorandum
- Date
- 2021-09-16
Summary
Exhibit 4, filed September 16, 2021 as Document 24-4 in Case 2:21-cv-00702-CLM in the U.S. District Court, N.D. of Alabama, is the FDA's Pfizer-BioNTech COVID-19 Vaccine Emergency Use Authorization Review Memorandum dated December 11, 2020. The memorandum reviews the EUA request submitted November 20, 2020 by Pfizer, on behalf of Pfizer and BioNTech, for the BNT162b2 vaccine for individuals 16 years of age and older. Its executive summary reports efficacy of 95.0% in the per-protocol analysis, with 8 cases in the vaccine group and 162 in the placebo group, and lists the most common solicited adverse reactions. It records a VRBPAC vote of 17-4 on December 10, 2020, and the review team recommends issuance of an EUA. The 58-page exhibit includes a table of contents, glossary, references and an appendix on the Charlson Comorbidity Index.
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Case 2:21-cv-00702-CLM Document 24-4 Filed 09/16/21 Page 1 of 58 FILED
2021 Sep-16 AM 11:09
U.S. DISTRICT COURT
N.D. OF ALABAMA
Exhibit 4
Pfizer-BioNTech: COVID-19 Vaccine
Emergency Use Authorization Review
Memorandum (Dec. 11, 2020)
Case 2:21-cv-00702-CLM Document 24-4 Filed 09/16/21 Page 2 of 58
Emergency Use Authorization (EUA) for an Unapproved Product
Review Memorandum
Identifying Information
Application Type EUA (Event-driven EUA request)
Application Number 27034
Sponsor Pfizer, Inc., on behalf of Pfizer and BioNTech
Submission Date November 20, 2020
Receipt Date November 20, 2020
Signatory Authority Marion F. Gruber, Ph.D., Director, CBER/OVRR
Review Team Ramachandra Naik, Ph.D., Chair, OVRR/DVRPA;
CAPT Michael Smith, Ph.D., Regulatory Project Manager,
OVRR/DVRPA;
Susan Wollersheim, M.D., Clinical reviewer, OVRR/DVRPA;
Nabil Al-Humadi, Ph.D., Toxicology reviewer, OVRR/DVRPA;
Lei Huang, Ph.D., Biostatistics reviewer, OBE/DB;
Haruhiko Murata, Ph.D., CMC/Product reviewer, OVRR/DVP;
Xiao Wang, Ph.D., CMC/Product reviewer, OVRR/DVP;
Laura Fontan, Ph.D., CMC/Facility reviewer; OCBQ/DMPQ;
Kathleen Jones, Ph.D., CMC/Facility reviewer, OCBQ/DMPQ;
Kerry Welsh, M.D., Pharmacovigilance reviewer, OBE/DE;
Narayan Nair, M.D., Pharmacovigilance reviewer, OBE/DE;
Brenda Baldwin, Ph.D., Data Integrity reviewer, OVRR/DVRPA;
Bhanumathi Kannan, Ph.D., BIMO reviewer, OCBQ/DIS/BMB;
Oluchi Elekwachi, Ph.D., Labeling reviewer, OCBQ/DCM/APLB
Review Completion Date December 11, 2020
Established Name/Other names Pfizer-BioNTech COVID-19 Vaccine/ BNT162b2
used during development
Dosage Forms/Strengths and A 0.3 mL Suspension for intramuscular injection
Route of Administration
Intended Use for EUA Active immunization to prevent coronavirus disease 2019
(COVID-19) caused by Severe Acute Respiratory Syndrome
Coronavirus 2 (SARS-CoV-2)
Intended Population Individuals 16 years of age and older
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Pfizer-BioNTech COVID-19 Vaccine Emergency Use Authorization Review Memorandum
Table of Contents
List of Tables ............................................................................................................................. 3
List of Figures ............................................................................................................................ 4
Glossary..................................................................................................................................... 5
1. Executive Summary .............................................................................................................. 6
2. Background........................................................................................................................... 8
2.1. SARS-CoV-2 Pandemic ................................................................................................ 8
2.2. Available Therapies for COVID-19................................................................................. 8
2.3. EUA Request for the Pfizer-BioNTech COVID-19 Vaccine (BNT162b2)........................ 9
2.4. U.S. Requirements to Support Issuance of an EUA for a Biological
Product................................................................................................................................. 9
2.5. Applicable Guidance for Industry..................................................................................10
3. Pfizer-BioNTech COVID-19 Vaccine (BNT162b2)................................................................11
3.1. Vaccine Composition, Dosing Regimen........................................................................11
3.2. Proposed Use Under EUA............................................................................................12
4. FDA Review of Clinical Safety and Effectiveness Data ........................................................12
4.1. Overview of Clinical Studies .........................................................................................12
4.2. Study C4591001...........................................................................................................12
4.2.1. Design...................................................................................................................12
4.2.2. FDA Assessment of Phase 2/3 Follow-Up Duration...............................................17
4.2.3. Subject Disposition and Inclusion in Analysis Populations.....................................17
4.2.4. Demographics and Other Baseline Characteristics................................................19
4.2.5. Vaccine Efficacy ....................................................................................................23
4.2.6. Safety....................................................................................................................32
4.3. Study BNT162-01.........................................................................................................43
5. FDA Review of Other Information Submitted in Support of the EUA.....................................44
5.1. Sponsor’s Plans for Continuing Blinded, Placebo-Controlled Follow-Up.......................44
5.2. Pharmacovigilance Activities ........................................................................................44
5.3. Non-Clinical Studies .....................................................................................................46
5.4. Chemistry, Manufacturing, and Control (CMC) Information ..........................................47
5.5. Clinical Assay Information ............................................................................................48
5.6. Inspections of Clinical Study Sites................................................................................49
5.7. EUA Prescribing Information and Fact Sheets..............................................................49
6. Benefit/Risk Assessment in the Context of Proposed Indication and Use
Under EUA................................................................................................................................49
6.1. Known Benefits ............................................................................................................49
6.2. Unknown Benefits/Data Gaps.......................................................................................49
2
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Pfizer-BioNTech COVID-19 Vaccine Emergency Use Authorization Review Memorandum
6.3. Known Risks ................................................................................................................51
6.4. Unknown Risks/Data Gaps...........................................................................................52
7. VRBPAC Meeting Summary ................................................................................................52
8. Overall Summary and Recommendation..............................................................................54
9. References ..........................................................................................................................56
10. Appendix A. Charlson Comorbidity Index.............................................................................57
List of Tables
Table 1: Clinical Trials Submitted in Support of Efficacy and Safety Determinations of the
Pfizer-BioNTech COVID-19 Vaccine .................................................................................12
Table 2. Efficacy Populations, Treatment Groups as Randomized ............................................18
Table 3. Disposition of All Randomized Participants, Phase 2/3 Safety Population ...................19
Table 4. Demographic Characteristics, Participants With or Without Evidence of Infection Prior
to 7 Days After Dose 2, Evaluable Efficacy (7 Days) Population .......................................20
Table 5. Demographics and Other Baseline Characteristics, Phase 2/3 Safety Population .......21
Table 6. Final Analysis of Efficacy of BNT162b2 Against Confirmed COVID-19 From 7 Days
After Dose 2 in Participants Without Evidence of Prior SARS-CoV-2 Infection, Evaluable
Efficacy Population ...........................................................................................................23
Table 7. Efficacy of BNT162b2 Against Confirmed COVID-19 From 7 Days After Dose 2 in
Participants With and Without Evidence of Prior SARS-CoV-2 Infection, Evaluable Efficacy
Population.........................................................................................................................24
Table 8: Subgroup Analyses of Second Primary Endpoint: First COVID-19 Occurrence From 7
Days After Dose 2, by Subgroup, Participants With and Without Evidence of Infection Prior
to 7 Days After Dose 2, Evaluable Efficacy (7 Days) Population .......................................25
Table 9. Demographic Characteristics, Participants With Protocol Defined Case (Without
Evidence of Infection Prior to 7 Days After Dose 2)...........................................................27
Table 10. Vaccine Efficacy: First COVID-19 Occurrence From 7 Days After Dose 2, by
Comorbidity Status, Among Participants Without Evidence of Infection Prior to 7 Days After
Dose 2, Evaluable Efficacy (7 Days) Population ...............................................................28
Table 11. First Severe COVID-19 Occurrence from 7 Days after Dose 2, Evaluable Efficacy
Population.........................................................................................................................30
Table 12. First Severe COVID-19 Occurrence After Dose 1, Dose 1 All-Available Efficacy
Population.........................................................................................................................30
Table 13. Primary Efficacy Endpoint, All-Available Efficacy Population .....................................31
Table 14. Study C4591001 Safety Overview, Ages 16 Years and Older ...................................32
Table 15. Frequency of Solicited Local Reactions Within 7 Days After Each Vaccination,
Reactogenicity Subset of the Phase 2/3 Safety Population, 18 to 55 Years of Age*..........33
Table 16. Frequency of Solicited Local Reactions Within 7 Days After Each Vaccination,
Reactogenicity Subset of the Phase 2/3 Safety Population, >55 Years of Age and Older..34
Table 17. Frequency of Solicited Systemic Adverse Events Within 7 Days After Each
Vaccination- Reactogenicity Subset of the Phase 2/3 Safety Population, 18 to 55 Years of
Age*..................................................................................................................................34
3
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Pfizer-BioNTech COVID-19 Vaccine Emergency Use Authorization Review Memorandum
Table 18. Frequency of Solicited Systemic Adverse Events Within 7 Days After Each
Vaccination- Reactogenicity Subset of the Phase 2/3 Safety Population, >55 Years of Age
r.] a6 ©) (6 (-] ee eee 36
Table 19. Frequency of Unsolicited AEs with Occurrence in 21% of Participants in any
Treatment Group from Dose 1 to 1-month After Dose 2, Phase 2/3 Safety Population, 16
Years of Age and OIdEN.......... cc cece cee eeeeeeeeneeeeeeeeeeeeeeceaeeeeeeeeeeeseecccaaeeeeeeeeeeeeeseeeenueeeeeeees 37
Table 20. Frequency of Unsolicited Local Reactions and Systemic Adverse Events Reported
Within 7 Days After Each Dose, Phase 2/3 Safety Population, 16 and 17 Years of Age ...38
Table 21. Frequency of Unsolicited AEs with Occurrence in 21% of Participants in any
Treatment Group from Dose 1 to 1 Month After Dose 2, Phase 2/3 Safety Population*, 65
a Z=y- Teee- 1010 ©) (0 =) eee 38
List of Figures
Figure 1. Safety Monitoring Plan, Study C4591001 00.0.2... eeeceeeee eee e eee eeeeeneeeaaeeeeeeeeeeeeeeeeaaees 15
Figure 2. Cumulative Incidence Curves for the First COVID-19 Occurrence After Dose 1, Dose 1
All-Available Efficacy Population ............::ccccceccieeeceeeeeeeeeeeeeeeceecnieeeeeeeeeeeeeeeiieeeeeeeeeteeneeee 29
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Pfizer-BioNTech COVID-19 Vaccine Emergency Use Authorization Review Memorandum
Glossary
AE adverse event
AESI adverse event of special interest
AIDS acquired immunodeficiency syndrome
ARDS acute respiratory distress syndrome
BNT162b2 Pfizer-BioNTech COVID-19 Vaccine
CBRN chemical, biological, radiological, or nuclear
CDC Centers for Disease Control and Prevention
CMC chemistry, manufacturing, and controls
EUA Emergency Use Authorization
FDA Food and Drug Administration
hACE2 human angiotensin converting enzyme 2
HHS Health and Human Services
HIV human immunodeficiency virus
IM intramuscular
LNP lipid nanoparticle
MERS-CoV Middle Eastern respiratory syndrome
modRNA nucleoside-modified messenger RNA
NAAT nucleic acid amplification-based test
PVP Pharmacovigilance Plan
RBD receptor binding domain
RT-PCR reverse transcription-polymerase chain reaction
SAE serious adverse event
SARS-CoV-2 severe acute respiratory syndrome coronavirus 2
VE vaccine efficacy
VRBPAC Vaccines and Related Biological Products Advisory Committee
5
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Pfizer-BioNTech COVID-19 Vaccine Emergency Use Authorization Review Memorandum
1. Executive Summary
The SARS-CoV-2 pandemic presents an extraordinary challenge to global health and, as of
November 30, 2020, has caused more than 60 million cases of COVID-19 and claimed the lives
of 1.5 million people worldwide. In the United States, over 13 million cases have been reported
to the Centers for Disease Control and Prevention (CDC), with over 260,000 deaths. Based on
a declaration by the Secretary of Health and Human Services (HHS) that the COVID-19
pandemic constitutes a public health emergency with a significant potential to affect national
security or the health and security of United States citizens living abroad, FDA may issue an
EVA for a COVID-19 vaccine after determining that certain statutory requirements are met.
On November 20, 2020, the Sponsor (Pfizer, on behalf of Pfizer and BioNTech) submitted an
Emergency Use Authorization (EUA) request to FDA for an investigational COVID-19 vaccine
(BNT162b2) intended to prevent COVID-19 caused by severe acute respiratory syndrome
coronavirus 2 (SARS-CoV-2). The vaccine is based on the SARS-CoV-2 spike glycoprotein (S)
antigen encoded by RNA and formulated in lipid nanoparticles (LNPs). The proposed use under
an EUA is “for active immunization for the prevention of COVID-19 caused by SARS-CoV-2 in
individuals 16 years of age and older.” The proposed dosing regimen is 2 doses, 30 ug each,
administered 21 days apart.
The EVA request includes safety and efficacy data from an ongoing Phase 3 randomized,
double-blinded and placebo-controlled trial of BNT162b2 in approximately 44,000 participants.
The primary efficacy endpoint is incidence of COVID-19 among participants without evidence of
SARS-CoV-2 infection before or during the 2-dose vaccination regimen. In a mid-November
analysis 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 prior to 7 days after completion of the vaccination regimen, efficacy in preventing
confirmed COVID-19 occurring at least 7 days after the second dose of vaccine was 95.0%,
with 8 COVID-19 cases in the vaccine group and 162 COVID-19 cases in the placebo group.
Subgroup analyses of the primary efficacy endpoint showed similar efficacy point estimates
across age groups, genders, 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 and in preventing COVID-19
following the first dose, although available data for these outcomes did not allow for firm
conclusions.
Safety data from approximately 38,000 participants 216 years 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, with no specific safety concerns identified that would preclude issuance of an
EUA. Available safety data from all participants enrolled through the November 14, 2020, data
cut-off (N=43,252, which includes late enrollment of additional adolescent and adult
participants), was consistent with the safety profile for the approximately 38,000 participants
with median follow-up of 2 months and also did not raise specific safety concerns. 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%), 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 generally less frequent in participants 255 years of age (<
2.8%) as compared to younger participants (<4.6%). The frequency of serious adverse events
was low (<0.5%), without meaningful imbalances between study arms. Among non-serious
unsolicited adverse events, there was a numerical imbalance of four cases of Bell’s palsy in the
6
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vaccine group compared with no cases in the placebo group, though the four cases in the
vaccine group do not represent a frequency above that expected in the general population.
Otherwise, there were no notable patterns or numerical imbalances between treatment groups
for specific categories of non-serious adverse events (including other neurologic, neuro-
inflammatory, and thrombotic events) that would suggest a causal relationship to BNT162b2
vaccine. With the exception of more frequent, generally mild to moderate reactogenicity in
participants <55 years of age, the safety profile of BNT162b2 was generally similar across age
groups, genders, ethnic and racial groups, participants with or without medical comorbidities,
and participants with or without evidence of prior SARS-CoV-2 infection at enrollment.
While not observed in the clinical trials, two anaphylactic reactions in the immediate post-
vaccination period have occurred with use of the vaccine in the United Kingdom, in individuals
reported to have prior history of anaphylactic reaction. The component(s) of the vaccine that
may have triggered these anaphylactic reactions are unknown at this time, and the two
individuals were not reported to have known history of allergy to specific components of the
vaccine. Risk of allergic reactions, including the potential for severe allergic reactions and the
need for vaccine providers to be able to manage them should they occur and a contraindication
for use in individuals with known allergy to any component of the vaccine, are described in the
vaccine Fact Sheets and Prescribing Information. Additionally, risk of anaphylaxis will be further
evaluated as part of the pharmacovigilance plan for the vaccine.
Non-clinical toxicology studies with BNT162b did not raise specific safety concerns, and other
non-clinical studies support the vaccine’s immunogenicity, reduction of SARS-CoV-2 pulmonary
viral load in animal challenge models, and absence of findings suggesting risk of vaccine-
enhanced disease.
FDA has reviewed the CMC data submitted to date for this vaccine and has determined that the
CMC information is consistent with the recommendations set forth in FDA’s Guidance on
Emergency Use Authorization for Vaccines to Prevent COVID-19. FDA has determined that the
Sponsor has provided adequate information to ensure the vaccine’s quality and consistency for
authorization of the product under an EUA.
A meeting of the Vaccines and Related Biological Products Advisory Committee (VRBPAC) was
convened on December 10, 2020. Following a discussion of the data presented, the VRBPAC
voted 17-4 (with one abstention) in favor of the determination that based on the totality of
scientific evidence available, the benefits of the Pfizer-BioNTech COVID-19 Vaccine outweigh
its risks for use in individuals 16 years of age and older.
Following review of information submitted in support of the EUA request and considering
VRBPAC recommendations from the December 10, 2020, meeting, the review team concludes
that:
x The chemical, biological, radiological, or nuclear (CBRN) agent referred to in the
March 27, 2020, EUA declaration by the Secretary of HHS (SARS-CoV-2) can cause a
serious or life-threatening disease or condition.
x Based on the totality of scientific evidence available, including data from adequate and well-
controlled trials, it is reasonable to believe that the Pfizer-BioNTech COVID-19 vaccine
(BNT162b) may be effective to prevent such serious or life-threatening disease or condition
that can be caused by SARS-CoV-2.
7
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Pfizer-BioNTech COVID-19 Vaccine Emergency Use Authorization Review Memorandum
x The known and potential benefits of the vaccine outweigh the known and potential risks of
the vaccine when used for active immunization to prevent COVID-19 caused by SARS-CoV-
2 in individuals 16 years of age and older.
x There is no adequate, approved, and available alternative to the product for preventing
COVID-19 caused by SARS-CoV-2.
The review team therefore recommends issuance of an EUA for use of the Pfizer-BioNTech
COVID-19 Vaccine for active immunization to prevent COVID-19 caused by SARS-CoV-2 in
individuals 16 years of age and older.
2. Background
2.1. SARS-CoV-2 Pandemic
The SARS-CoV-2 pandemic presents an extraordinary challenge to global health and, as of
November 30, 2020, has caused more than 60 million cases of COVID-19 and claimed the lives
of 1.5 million people worldwide. In the United States, over 13 million cases have been reported
to the Centers for Disease Control and Prevention (CDC), with over 260,000 deaths. Confirmed
cases and mortality continue to rise globally. On January 31, 2020, the U.S. Secretary of HHS
declared a public health emergency related to COVID-19 and mobilized the Operating Divisions
of HHS. Following the World Health Organization’s declaration of the novel coronavirus
pandemic on March 11, 2020, the U.S. President declared a national emergency in response to
COVID-19 on March 13, 2020. Vaccines to protect against COVID-19 are critical to mitigate the
current SARS-CoV-2 pandemic and to prevent future disease outbreaks.
SARS-CoV-2 is a novel, zoonotic coronavirus that emerged in late 2019 in patients with
pneumonia of unknown cause.1 The virus was named SARS-CoV-2 because of its similarity to
the coronavirus responsible for severe acute respiratory syndrome (SARS-CoV, a lineage B
betacoronavirus).2 SARS-CoV-2 is an enveloped, positive sense, single stranded RNA virus
sharing more than 70% of its sequence with SARS-CoV, and ~50% with the coronavirus
responsible for Middle Eastern respiratory syndrome (MERS-CoV).3 The SARS-CoV-2 spike
glycoprotein (S), which is a main target for neutralizing antibody, binds to its receptor human
angiotensin converting enzyme 2 (hACE2) to initiate infection.4 SARS-CoV-2 is the cause of
COVID-19, an infectious disease with respiratory and systemic manifestations. Disease
symptoms vary, with many persons presenting with asymptomatic or mild disease and some
progressing to severe respiratory tract disease including pneumonia and acute respiratory
distress syndrome (ARDS), leading to multiorgan failure and death.
In an attempt to prevent the spread of disease and to control the pandemic, numerous COVID-
19 vaccine candidates are in development. These vaccines are based on different platforms
including mRNA and DNA technologies and include viral vectored, subunit, inactivated, and live
attenuated vaccines. Most COVID-19 candidate vaccines express the spike protein or parts of
the spike protein, i.e., the receptor binding domain (RBD), as the immunogenic determinant.
2.2. Available Therapies for COVID-19
No vaccine or other medical product is FDA approved for prevention of COVID-19. On October
22, 2020, FDA approved remdesivir for use in adult and pediatric patients 12 years of age and
older and weighing at least 40 kilograms (about 88 pounds) for the treatment of COVID-19
requiring hospitalization. Several other therapies are currently available under emergency use
8
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authorization, but not FDA approved, for treatment of COVID-19. Thus, there is currently no
adequate, approved, and available alternative for prevention of COVID-19.
2.3. EUA Request for the Pfizer-BioNTech COVID-19 Vaccine (BNT162b2)
Pfizer, in partnership with BioNTech Manufacturing GmbH, is developing a vaccine to prevent
COVID-19 which is based on the SARS-CoV-2 spike glycoprotein (S) antigen encoded by RNA
and formulated in lipid nanoparticles (LNP). The Pfizer-BioNTech COVID-19 Vaccine (also
referred to as BNT162b2) is administered intramuscularly as a 2-dose series spaced 21 days
apart at a dose of 30 μg each. The vaccine is supplied as a multi-dose vial (5 doses) containing
a frozen suspension (-80qC to -60qC) of BNT162b2 that must be thawed and diluted with 1.8 mL
of sterile 0.9% sodium chloride, allowing for five 0.3 mL doses. The vaccine is preservative free.
A Phase 3 randomized and placebo-controlled trial using BNT162b2 in approximately 44,000
participants is currently ongoing to evaluate the vaccine’s safety and efficacy. Vaccine efficacy
for the primary endpoint against confirmed COVID-19 occurring at least 7 days after the second
dose was 95.0% with 8 COVID-19 cases in the vaccine group compared to 162 COVID-19
cases in the placebo group. Data from about 38,000 participants randomized 1:1 with a median
of 2 months of follow-up after the second dose of vaccine showed a favorable safety profile at a
dose of 30 Pg in participants 16 years of age and older. On November 20, 2020, Pfizer and
BioNTech submitted an EUA request to FDA for its investigational COVID-19 vaccine
(BNT162b2) intended to prevent COVID-19 caused by SARS-CoV-2.
2.4. U.S. Requirements to Support Issuance of an EUA for a Biological Product
Based on the declaration by the Secretary of HHS that the COVID-19 pandemic constitutes a
public health emergency with a significant potential to affect national security or the health and
security of United States citizens living abroad, FDA may issue an EUA after determining that
certain statutory requirements are met (section 564 of the Federal Food, Drug, and Cosmetic
Act (the FD&C Act) (21 U.S.C. 360bbb-3)).5
x The chemical, biological, radiological, or nuclear (CBRN) agent referred to in the March 27,
2020, EUA declaration by the Secretary of HHS (SARS-CoV-2) can cause a serious or life-
threatening disease or condition.
x Based on the totality of scientific evidence available, including data from adequate and well-
controlled trials, if available, it is reasonable to believe that the product may be effective in
preventing, diagnosing, or treating such serious or life-threatening disease or condition that
can be caused by SARS-CoV-2.
x The known and potential benefits of the product, when used to diagnose, prevent, or treat
the identified serious or life-threatening disease or condition, outweigh the known and
potential risks of the product.
x There is no adequate, approved, and available alternative to the product for diagnosing,
preventing, or treating the disease or condition.
If these criteria are met, under an EUA, FDA can allow unapproved medical products (or
unapproved uses of approved medical products) to be used in an emergency to diagnose, treat,
or prevent serious or life-threatening diseases or conditions caused by threat agents. FDA has
been providing regulatory advice to COVID-19 vaccine manufacturers regarding the data
needed to determine that a vaccine’s benefit outweigh its risks. This includes demonstrating that
manufacturing information ensures product quality and consistency along with data from at least
9
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one Phase 3 clinical trial demonstrating a vaccine’s safety and efficacy in a clear and compelling
manner.
2.5. Applicable Guidance for Industry
Risk and benefit considerations are unique for COVID-19 vaccines, given that an EUA may be
requested to allow for a vaccine’s rapid and widespread deployment for administration to
millions of individuals, including healthy people. FDA published in October 2020 guidance for
industry entitled “Emergency Use Authorization for Vaccines to Prevent COVID-19” describing
FDA’s current recommendations regarding the manufacturing, nonclinical, and clinical data and
information needed under section 564 of the FD&C Act to support the issuance of an EUA for
an investigational vaccine to prevent COVID-19, including a discussion of FDA’s current thinking
regarding the circumstances under which an EUA for a COVID-19 vaccine would be
appropriate.6 These considerations are summarized below.
Safety and Effectiveness Information Needed to Support an EUA
Effectiveness data
Issuance of an EUA requires a determination that the known and potential benefits of the
vaccine outweigh the known and potential risks. For a preventive COVID-19 vaccine to be
potentially administered to millions of individuals, including healthy individuals, data adequate to
inform an assessment of the vaccine’s benefits and risks and support issuance of an EUA would
include meeting the prespecified success criteria for the study’s primary efficacy endpoint, as
described in the guidance for industry entitled “Development and Licensure of Vaccines to
Prevent COVID-19” (i.e., a point estimate for a placebo-controlled efficacy trial of at least 50%,
with a lower bound of the appropriately alpha-adjusted confidence interval around the primary
efficacy endpoint point estimate of >30%).7
Safety data
An EUA request for a COVID-19 vaccine should include all safety data accumulated from
studies conducted with the vaccine, with data from Phase 1 and 2 focused on serious adverse
events, adverse events of special interest, and cases of severe COVID-19 among study
participants. Phase 3 safety data should include characterization of reactogenicity (common and
expected adverse reactions shortly following vaccination) in a sufficient number of participants
from relevant age groups and should include a high proportion of enrolled participants
(numbering well over 3,000) followed for serious adverse events and adverse events of special
interest for at least one month after completion of the full vaccination regimen. The Phase 1 and
2 safety data likely will be of a longer duration than the available safety data from the Phase 3
trial at the time of submission of an EUA request and thus, are intended to complement the
available data from safety follow-up from ongoing Phase 3 studies.
Phase 3 follow-up
Data from Phase 3 studies should include a median follow-up duration of at least 2 months after
completion of the full vaccination regimen to help provide adequate information to assess a
vaccine’s benefit-risk profile. From a safety perspective, a 2-month median follow-up following
completion of the full vaccination regimen will allow identification of potential adverse events
that were not apparent in the immediate postvaccination period. Adverse events considered
plausibly linked to vaccination generally start within 6 weeks of vaccine receipt.8 Therefore, a 2-
month follow-up period may allow for identification of potential immune-mediated adverse
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events that began within 6 weeks of vaccination. From the perspective of vaccine efficacy, it is
important to assess whether protection mediated by early responses has not started to wane. A
2-month median follow-up is the shortest follow-up period to achieve some confidence that any
protection against COVID-19 is likely to be more than short-lived. The EUA request should
include a plan for active follow-up for safety (including deaths, hospitalizations, and other
serious or clinically significant adverse events) among individuals administered the vaccine
under an EUA in order to inform ongoing benefit-risk review and assessment to support
continuation of the EUA.
Continuation of Clinical Trials Following Issuance of an EUA for a COVID-19 Vaccine
FDA does not consider availability of a COVID-19 vaccine under EUA, in and of itself, as
grounds for immediately stopping blinded follow-up in an ongoing clinical trial or grounds for
offering vaccine to all placebo recipients. To minimize the risk that use of an unapproved
vaccine under EUA will interfere with long-term assessment of safety and efficacy in ongoing
trials, it is critical to continue to gather data about the vaccine even after it is made available
under EUA. An EUA request should therefore include strategies that will be implemented to
ensure that ongoing clinical trials of the vaccine are able to assess long-term safety and efficacy
(including evaluating for vaccine-associated enhanced respiratory disease and decreased
effectiveness as immunity wanes over time) in sufficient numbers of participants to support
vaccine licensure. These strategies should address how ongoing trial(s) will handle loss of
follow-up information for study participants who choose to withdraw from the study in order to
receive the vaccine under an EUA.
FDA is aware that some COVID-19 vaccine developers may wish to immediately unblind their
trials upon issuance of an EUA in order to rapidly provide vaccine to trial participants who
received placebo. Some developers have proposed maintaining blinding in a crossover design
that provides vaccine to previous placebo recipients and placebo to previous vaccine recipients.
Such strategies would impact collection of longer-term placebo-controlled safety data and
evaluation of the duration of vaccine efficacy. Ethical and scientific issues associated with
offering vaccination to placebo recipients have been discussed in recent statements and
articles.9-11
3. Pfizer-BioNTech COVID-19 Vaccine (BNT162b2)
3.1. Vaccine Composition, Dosing Regimen
The Pfizer-BioNTech COVID-19 Vaccine is a white to off-white, sterile, preservative-free, frozen
suspension for intramuscular injection. The vaccine contains a nucleoside-modified messenger
RNA (modRNA) encoding the viral spike glycoprotein (S) of SARS-CoV-2. The vaccine also
includes the following ingredients: lipids ((4-hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)bis(2-
hexyldecanoate), 2-[(polyethylene glycol)-2000]-N,N-ditetradecylacetamide, 1,2-distearoyl-sn-
glycero-3-phosphocholine, and cholesterol), potassium chloride, monobasic potassium
phosphate, sodium chloride, dibasic sodium phosphate dihydrate, and sucrose.
The Pfizer-BioNTech COVID-19 Vaccine is supplied as a frozen [between -80qC to -60qC (-
112qF to -76qF)] multi-dose (5-dose) vial. The vaccine must be thawed and diluted in its original
vial with 1.8 mL of sterile 0.9% Sodium Chloride Injection, USP prior to administration. After
dilution, the vial contains 5 doses of 0.3 mL per dose. After dilution, the multiple-dose vials must
be stored between 2°C to 25°C (35°F to 77°F) and used within 6 hours from the time of dilution.
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The Pfizer-BioNTech COVID-19 Vaccine, BNT162b2 (30 ug), is administered intramuscularly
(IM) as a series of two 30 ug doses (0.3 mL each) 21 days apart.
3.2. Proposed Use Under EUA
The proposed indication and use of the vaccine under an EUA is “for active immunization for the
prevention of COVID-19 caused by SARS-CoV-2 in individuals 16 years of age and older.”
4. FDA Review of Clinical Safety and Effectiveness Data
4.1. Overview of Clinical Studies
Data from two ongoing clinical studies were included in the EUA request, which are summarized
in Table 1 below. Study C4591001 is a multi-center, multi-national Phase 1,2,3 randomized,
blinded, placebo-controlled safety, immunogenicity, and efficacy study that is the focus of the
EUA review. Study BNT162-01 is a Phase 1 study that explored various vaccine candidates and
dose levels and will not be discussed in detail.
Table 1: Clinical Trials Submitted in Support of Efficacy and Safety Determinations of the
Pfizer-BioNTech COVID-19 Vaccine
BNT162b2 (30 yg)* Placebo
Study Number/ participants participants Study
Country Description (N) (N) Status
C4591001 Phase 1,2,3 randomized,
USA, Argentina, placebo-controlled, observer- Phase 1:24 Phase 1:6
Brazil, Germany, blind; to evaluate safety, Phase 2/3: 21823 Phase 2/3: 21828 Ongoing
S. Africa, Turkey immunogenicity and efficacy of ‘ ‘
COVID-19 vaccine
BNT162-01 Phase 1/2 randomized, open-
Germany label; to evaluate safety and 12 0 Ongoing
immunogenicity, dose escalation
N= total number of randomized participants as of November 14, 2020. Placebo: saline.
*Phase 1 studies included additional participants vaccinated with other dose levels and other mRNA vaccine candidates.
Studies C4591001 and BNT162-01 started in April 2020 (first participant, first visit).
4.2. Study C4591001
4.2.1. Design
Study C4591001 is an ongoing, randomized, placebo-controlled, Phase 1/2/3 study being
conducted in the US, Argentina, Brazil, Germany, South Africa and Turkey. Initially the study
was designed as a Phase 1/2 study in healthy adults in the US for vaccine candidate and
dosage selection, immunogenicity and preliminary efficacy, but the protocol was revised to
expand the study design for inclusion of a Phase 2/3 portion to evaluate clinical disease
endpoint efficacy in individuals 12 years of age and older in the US and additional sites outside
of the US.
In Phase 1, two age groups were evaluated in separate cohorts, younger participants 18
through 55 years of age (N=45) and older participants 65 through 85 years of age (N=45). The
study population included healthy men and women and excluded participants at high risk of
SARS-CoV-2 infection or with serological evidence of prior or current SARS-CoV-2 infection.
Two different vaccine candidates were evaluated, and younger participants received escalating
dose levels with progression to subsequent dose levels and evaluation of escalating dose levels
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in the older age group (65 through 85 years), based on recommendations from an internal
review committee that reviewed safety and immunogenicity data. For each vaccine candidate
and dose level, participants were randomized 4:1, such that 12 participants received the vaccine
candidate and 3 participants received placebo. Review of the safety and immunogenicity from
Phase 1, in combination with data from Study BNT 162-01 (See Section 10), supported the final
vaccine candidate and dose level (BNT162b2 at 30 ug, given 21 days apart) to proceed into
Phase 2/3.
In Phase 2/3, participants were enrolled with stratification by age (younger adults: 18 through 55
years of age; older adults: over 55 years of age) and a goal of 40% enrollment in the older adult
age group. Adolescents were added to the protocol, based on review of safety data in younger
adults enrolled in the ongoing study, so the age strata were revised as follows: 12 through 15
years of age, 16 through 54 years of age, and 55 years of age and older. The study population
for Phase 2/3 includes participants at higher risk for acquiring COVID-19 and at higher risk of
severe COVID-19 disease, such as participants working in the healthcare field, participants with
autoimmune disease, and participants with chronic but stable medical conditions such as
hypertension, asthma, diabetes, and infection with HIV, hepatitis B or hepatitis C. Participants
were randomized 1:1 to receive 2 doses of either BNT162b2 or placebo, 21 days apart. The
Phase 2 portion of the study evaluated reactogenicity and immunogenicity for 360 participants
enrolled early-on, and these participants also contribute to the overall efficacy and safety data in
the Phase 3 portion. The ongoing Phase 3 portion of the study is evaluating the safety and
efficacy of BNT162b2 for the prevention of COVID-19 disease occurring at least 7 days after the
second dose of vaccine. Efficacy is being assessed throughout a participant’s follow-up in the
study through surveillance for potential cases of COVID-19. If, at any time, a participant
develops acute respiratory illness, an illness visit occurs. Assessments for illness visits include a
nasal (midturbinate) swab, which is tested at a central laboratory using a reverse transcription-
polymerase chain reaction (RT-PCR) test (e.g., Cepheid; FDA authorized under EUA), or other
sufficiently validated nucleic acid amplification-based test (NAAT), to detect SARS-CoV-2. The
central laboratory NAAT result is used for the case definition, unless it is not possible to test the
sample at the central laboratory. In that case, the following NAAT results are acceptable:
Cepheid Xpert Xpress SARS-CoV-2, Roche cobas SARS-CoV-2 real-time RT-PCR test
(EUA200009/A001), and Abbott Molecular/RealTime SARS-CoV-2 assay (EUA200023/A001).
The study design includes planned interim analyses of the first primary efficacy endpoint at pre-
specified numbers of COVID-19 cases (at least 62, 92, and 120 cases), and all primary and
secondary efficacy endpoints were analyzed in the final efficacy analysis after at least 164
COVID-19 cases were accrued (see Statistical Analysis section, below). Participants are
expected to participate for a maximum of approximately 26 months.
Primary efficacy endpoints
Study C4591001 has two primary endpoints:
First primary endpoint: COVID-19 incidence per 1000 person-years of follow-up in participants
without serological or virological evidence of past SARS-CoV-2 infection before and during
vaccination regimen — cases confirmed 27 days after Dose 2
Second primary endpoint: COVID-19 incidence per 1000 person-years of follow-up in
participants with and without evidence of past SARS-CoV-2 infection before and during
vaccination regimen — cases confirmed 27 days after Dose 2
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Secondary Efficacy Endpoints
Study C4591001 has secondary endpoints based on different approaches to COVID-19 case
evaluation criteria as follows:
COVID-19 confirmed at least 14 days after Dose 2: COVID-19 incidence per 1000 person-
years of follow up in participants either (1) without or (2) with and without serological or
virological evidence of past SARS-CoV-2 infection before and during vaccination regimen —
cases confirmed 214 days after Dose 2
Severe COVID-19: incidence per 1000 person-years of follow-up in participants either
(1) without or (2) with and without evidence of past SARS-CoV-2 infection before and during
vaccination regimen — cases confirmed either (1) 27 days after Dose 2 or (2) 214 days after
Dose 2
CDC-defined COVID-19: incidence per 1000 person-years of follow-up in participants either (1)
without or (2) with and without evidence of past SARS-CoV-2 infection before and during
vaccination regimen — cases confirmed either (1) 27 days after Dose 2 or (2) 214 days after
Dose 2.
For the primary efficacy endpoint, the case definition for a confirmed COVID-19 case was the
presence of at least one of the following symptoms and a positive SARS-CoV-2 NAAT within 4
days of the symptomatic period:
Fever;
New or increased cough;
New or increased shortness of breath;
Chills;
New or increased muscle pain;
New loss of taste or smell;
Sore throat;
Diarrhea;
Vomiting.
For a secondary efficacy endpoint, a second definition, which may be updated as more is
learned about COVID-19, included the following additional symptoms defined by CDC (listed at
https://www.cdc.gov/coronavirus/2019-ncov/symptoms-testing/symptoms.html):
e Fatigue;
e Headache;
e Nasal congestion or runny nose;
e Nausea.
For another secondary endpoint, the case definition for a severe COVID-19 case was a
confirmed COVID-19 case with at least one of the following:
e Clinical signs at rest indicative of severe systemic illness (RR 230 breaths per minute,
HR 2125 beats per minute, SpoO2 <93% on room air at sea level, or PaO2/FiO2 <300
mm Hg);
e Respiratory failure (defined as needing high-flow oxygen, noninvasive ventilation,
mechanical ventilation, or ECMO);
e Evidence of shock (SBP <90 mm Hg, DBP <60 mm Hg, or requiring vasopressors)
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x Significant acute renal, hepatic, or neurologic dysfunction;
x Admission to an ICU;
x Death.
Evaluation of safety
The primary safety objective for all phases was to describe the safety of BNT162 vaccine(s) in
healthy adults after 1 or 2 doses. All Phase 1 participants (n=30), and then 6653 U.S.
participants (360 Phase 2, 6293 Phase 3) and the first ~500 Phase 3 participants/per country
with enrollment through October 9, 2020 (Argentina, Brazil and South Africa) recorded local
reactions, systemic events, and antipyretic/pain medication usage from Day 1 through Day 7
after each dose. For all participants, unsolicited adverse events (AEs) were collected from Dose
1 to 1 month after the last dose and serious AEs (SAEs) from Dose 1 to 6 months after the last
dose. Figure 1 below shows the study safety monitoring plan.
Figure 1. Safety Monitoring Plan, Study C4591001
Reactogenicity assessments included solicited injection site reactions (pain, redness, swelling)
and systemic AEs (fever, fatigue, headache, chills, vomiting, diarrhea, new or worsened muscle
pain, and new or worsened joint pain), and antipyretic/pain medication use were recorded in an
e-diary. As of the data cutoff date, reactogenicity assessed as solicited reactions and events are
available from a limited number of adolescents 16 and 17 years of age, since enrollment for this
age group began with implementation of Protocol Amendment 6 (finalized September 8, 2020)
and the Phase 2/3 safety population only participants 16 and 17 years of age enrolled by
October 9, 2020. Adolescents enrolled after implementation of Protocol Amendment 9 (finalized
29 October 2020) were included in the reactogenicity subset. For any Phase 3 participants who
were not in the reactogenicity subset, local reactions and systemic events consistent with
reactogenicity were detected and reported as unsolicited AEs. HIV-positive participants and
adolescents 12 through 15 years of age were included in the reactogenicity subset with
implementation of protocol amendment 6 (finalized on September 8, 2020) and amendment 7
(finalized on October 6, 2020), respectively. Solicited reactogenicity data in adolescents 16-17
years of age are not available for the reporting period. Reactogenicity data from a total of 100
adolescents 12 through 15 years of age enrolled in C4591001 Phase 2/3 were provided in the
EUA submission. However, the Sponsor did not request inclusion of this age group in the EUA
because the available data, including number of participants and follow-up duration, were
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insufficient to support favorable a benefit-risk determination at this time. Therefore, the
reactogenicity data for participants 12 through 15 years of age are not presented in this
document.
Clinical laboratory tests were assessed in Phase 1 at 1-week postvaccination. The planned
safety follow-up for currently enrolled adolescents and adults is through 24 months after
vaccination #2.
Potential COVID-19 illnesses and their sequelae were not to be reported as AEs, with the
exception of illnesses that met regulatory criteria for seriousness and were not confirmed to be
COVID-19. These illnesses were evaluated and reported as SAEs.
In Phase 2/3, monitoring for risk of vaccine-enhanced disease was performed by an unblinded
team supporting the Data Monitoring Committee that reviewed cases of severe COVID-19 as
they were received and reviewed AEs at least weekly for additional potential cases of severe
COVID-19. The stopping rule was triggered when the 1-sided probability of observing the same
or a more extreme case split was 5% or less when the true incidence of severe disease was the
same for vaccine and placebo participants, and alert criteria were triggered when this probability
was less than 11%.
Analysis populations
For the purposes of analysis, the following populations are defined:
Population Description
Enrolled All participants who have a signed informed consent document.
Randomized All participants who are assigned a randomization number.
Evaluable efficacy All eligible randomized participants who receive all vaccination(s) as
randomized within the predefined window and have no other important
protocol deviations as determined by the clinician.
All-available efficacy 1. All randomized participants who receive at least 1 vaccination.
2. All randomized participants who complete 2 vaccination doses.
Phase 2/3 safety analysis populations were as follows:
x Phase 2/3 all-enrolled population: composed of a total of 43,448 (21720 vaccine, 21728
placebo) participants >16 years of age, regardless of duration of follow-up, for whom
written informed consent was obtained. Initial enrollment included individuals 18 years
and older, then included individuals as young as 16 years of age and individuals with
known HIV (protocol amendment 6; finalized on September 8, 2020). As of November
14, 2020, 43.9% and 79.5% of vaccine recipients completed at least 2 months (>8
weeks) and at least 1 month (>4 weeks), respectively, of safety follow-up after Dose 2.
The percentages of placebo recipients completing at least 2 months (>8 weeks) and at
least 1 month (>4 weeks) were similar to the vaccine group.
x Phase 2/3 safety population (median follow-up time of 2 months after vaccination #2):
comprised of a total of 37586 (18801 vaccine,18785 placebo) participants >16 years of
age enrolled by October 9, 2020 and received at least 1 dose of study vaccine or
placebo; overall, 98.1% of participants completed the 2-dose series. As of November 14,
2020, 50.6% and 91.6% of vaccine recipients completed at least 2 months (>8 weeks)
and at least 1 month (>4 weeks), respectively, of safety follow-up after Dose 2. The
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percentages of placebo recipients completing at least 2 months (>8 weeks) and at least
1 month (>4 weeks) were similar to the vaccine group. A total of 283 (138 vaccine,145
placebo) individuals were 16 to <18 years of age. HIV-positive individuals were included
in the all-enrolled population, but not the Phase 2/3 safety population because the
number of participants enrolled by October 9, 2020 was small (n=120) and the median
duration of safety follow-up was short.
4.2.2. FDA Assessment of Phase 2/3 Follow-Up Duration
Study C4591001 initially enrolled approximately 30,000 participants and then several months
later began enrollment of approximately 14,000 additional participants, including adolescents
and participants with chronic, stable HIV, hepatitis B, or hepatitis C infections. Because of the
gap in enrollment, the entire enrolled study population had a median follow-up of less than 2
months as of the EUA submission data cut-off date of November 14, 2020. However, the
analyses submitted to support this EUA request meet the expectation for median duration of
follow-up time, as follows:
x Submitted safety analyses for participants enrolled through October 9, 2020, and
followed through November 14, 2020 (referred to by Pfizer and in this document as the
Phase 2/3 safety population and including a total of 37,586 participants), represent a
median follow-up of 2 months. Additionally, this safety database is larger than for the
initial planned enrollment of approximately 30,000 participants.
x The date for data cut-off for the first interim analysis for efficacy was November 4, 2020,
when a total of 94 confirmed COVID-19 cases were accrued. All of the participants
included in the first interim efficacy analysis had at least 7 days of follow-up after Dose 2,
and thus were enrolled no later than October 7, 2020. All participants in the first interim
efficacy analysis were therefore included in the Phase 2/3 safety population defined
above. Although the median follow-up duration for participants included in the first
interim efficacy analysis was slightly less than 2 months as of November 4, 2020, these
participants were also included in the final efficacy analyses with data cut-off of
November 14, 2020, which extended the median follow-up for these participants to
greater than 2 months. The results of the final efficacy analysis on data to November 14,
2020, indicate that the conclusions from the first interim efficacy analysis would not
change when including additional follow-up to November 14, 2020.
The date for data cut-off for the final efficacy analysis was November 14, 2020, when a total of
170 confirmed COVID-19 cases were accrued. As noted above, the median follow-up duration
after completion of the full vaccination regimen for all participants enrolled at that time was less
than 2 months for both safety and efficacy populations, due to a gap in enrollment. Because the
data for the final efficacy analysis could be submitted in support of the EUA request and could
provide data from a greater number of participants than from the interim analysis, FDA has
focused its review on the efficacy data from the final efficacy analyses. Additional safety
analyses from this larger database of all enrolled participants were also reviewed to evaluate for
differences compared with the smaller Phase 2/3 safety population.
4.2.3. Subject Disposition and Inclusion in Analysis Populations
Disposition tables are presented below in Table 2 (efficacy analysis populations) and Table 3
(Phase 2/3 safety population). Overall, few participants were discontinued or lost to follow-up,
and these and other analysis population exclusions were generally balanced between treatment
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groups. Of 43,448 participants in the Phase 2/3 all-enrolled population, 94.2% of vaccine
recipients and 94.1% of placebo recipients completed 2 doses (data not shown).
Table 2. Efficacy Populations, Treatment Groups as Randomized
BNT162b2
(30 ȝJ Placebo Total
Population na (%) na (%) na (%)
Randomizedb 21823 (100.0) 21828 (100.0) 43651 (100.0)
Dose 1 all-available efficacy population 21768 (99.7) 21783 (99.8) 43551 (99.8)
Participants without evidence of infection before Dose 1 20314 (93.1) 20296 (93.0) 40610 (93.0)
Participants excluded from Dose 1 all-available efficacy 55 (0.3) 45 (0.2) 100 (0.2)
population
Reason for exclusionc
Did not receive at least 1 vaccination 54 (0.2) 45 (0.2) 99 (0.2)
Did not provide informed consent 1 (0.0) 0 1 (0.0)
Dose 2 all-available efficacy population 20566 (94.2) 20536 (94.1) 41102 (94.2)
Participants without evidence of infection prior to 7 days 18701 (85.7) 18627 (85.3) 37328 (85.5)
after Dose 2
Participants without evidence of infection prior to 14 18678 (85.6) 18563 (85.0) 37241 (85.3)
days after Dose 2
Participants excluded from Dose 2 all-available efficacy 1257 (5.8) 1292 (5.9) 2549 (5.8)
population
Reason for exclusionc
Did not receive 2 vaccinations 1256 (5.8) 1292 (5.9) 2548 (5.8)
Did not provide informed consent 1 (0.0) 0 1 (0.0)
Evaluable efficacy (7 days) population 20033 (91.8) 20244 (92.7) 40277 (92.3)
Evaluable efficacy (14 days) population 20033 (91.8) 20243 (92.7) 40276 (92.3)
Participants excluded from evaluable efficacy (7 days) 1790 (8.2) 1584 (7.3) 3374 (7.7)
population
Participants excluded from evaluable efficacy (14 days) 1790 (8.2) 1585 (7.3) 3375 (7.7)
population
Reason for exclusionc
Randomized but did not meet all eligibility criteria 36 (0.2) 26 (0.1) 62 (0.1)
Did not provide informed consent 1 (0.0) 0 1 (0.0)
Did not receive all vaccinations as randomized or did 1550 (7.1) 1561 (7.2) 3111 (7.1)
not receive Dose 2 within the predefined window (19-42
days after Dose 1)
Had other important protocol deviations on or prior to 311 (1.4) 60 (0.3) 371 (0.8)
7 days after Dose 2
Had other important protocol deviations on or prior to 311 (1.4) 61 (0.3) 372 (0.9)
14 days after Dose 2
a
n = Number of participants with the specified characteristic.
b
These values are the denominators for the percentage calculations.
c
Participants may have been excluded for more than 1 reason.
Note: 100 participants 12 through 15 years of age with limited follow-up are included in the randomized population (49 in the vaccine
group and 51 in the placebo group). Some of these subjects were included in the denominators of efficacy analyses, depending on
the population analyzed, but did not contribute primary endpoint cases and do not affect efficacy conclusions for ages 16 years and
above.
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Table 3. Disposition of All Randomized Participants, Phase 2/3 Safety Population
BNT162b2 Placebo Total
N=18904 N=18892) N=37796
Population n (%) n (%) n (%)
Randomized 18904 (100.0) 18892 (100.0) 37796 (100.0)
Vaccinated
Completed 1 dose 18858 (99.8) 18849 (99.8) 37707 (99.8)
Completed 2 doses 18555 (98.2) 18533 (98.1) 37088 (98.1)
Withdrawn from Study 180 (1.0) 259 (1.4) 439 (1.2)
Reason for Withdrawal ௗ ௗ ௗ
Adverse Event 8 (0.0) 5 (0.0) 13 (0.0)
Death 2 (0.0) 4 (0.0) 6 (0.0)
Withdrawal by Subject 84 (0.4) 157 (0.8) 241 (0.6)
Lost to Follow-up 80 (0.4) 86 (0.5) 166 (0.4)
No longer meets eligibility criteria 1 (0.0) 2 (0.0) 3 (0.0)
Refused further study procedures 0 1 (0.0) 1 (0.0)
Source: EUA 27036, amendment 3, Table 2; c4591001-safety-tables-cos-reacto.pdf, page 43.
Note: One participant was randomized but did not sign informed consent and therefore not included in any analysis population.
Note: 120 HIV-positive participants included in this table. HIV population analyses were summarized separately from analyses
based on the Phase 2/3 safety population, but included in the all-enrolled poplation analyses presented in this briefing document.
%:n/N. n = number of subjects with the specified characteristic. N = number of participants >16 years of age enrolled by October 9,
2020, including 120 HIV-positive participants, and received at least 1 dose of study vaccine or placebo. N is the denominator used
for the percentage calculations.
Data analysis cutoff date: November 14, 2020
The numbers of randomized participants contributing to efficacy analyses presented in this
document include 100 participants 12 through 15 years of age (49 in the vaccine group and 51
in the placebo group) who had limited follow-up at the time of the November 14, 2020, data cut-
off. However, the sponsor did not include this age group in the EUA request. The numbers of
participants presented and used as denominators for efficacy calculations were not adjusted to
remove participants 12 through 15 years of age. Because the number of participants 12 through
15 years of age is very small relative to the overall efficacy analysis populations, and no primary
endpoint COVID-19 cases occurred in this age group, the vaccine efficacy conclusions are not
impacted. No participants 12 through 15 years of age are included in the safety analyses.
However, the safety disposition table includes 120 HIV-positive participants who were not
included in the Phase 2/3 safety population analyses.
4.2.4. Demographics and Other Baseline Characteristics
Overall, the Phase 2/3 evaluable efficacy population included 49.4% females, 81.9% White,
9.8% African American, 4.4% Asian participants, and <3% from other racial groups; 26.2% of
participants were Hispanic/Latino; 21.4% of participants were >65 years of age. The median
age was 51 years. The most frequently reported comorbidities were obesity (35.1%), diabetes
(with and without chronic complications, 8.4%) and pulmonary disease (7.8%). Geographically,
76.7% of participants were from the US, 15.3% from Argentina, 6.1% from Brazil, and 2% from
South Africa.
The population for the analysis of the primary efficacy endpoint (evaluable efficacy population)
included, 36,621 participants 12 years of age and older (18,242 in the Pfizer BioNTech COVID-
19 Vaccine group and 18,379 in the placebo group) who did not have evidence of prior infection
with SARS-CoV-2 through 7 days after the second dose. The demographic characteristics
among vaccine and placebo participants in the each of the efficacy populations were similar.
The demographics of the evaluable efficacy population used for the second primary endpoint is
displayed in Table 4.
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Table 4. Demographic Characteristics, Participants With or Without Evidence of Infection Prior to
7 Days After Dose 2, Evaluable Efficacy (7 Days) Population
BNT162b2 Placebo Total
N?=20033 N?=20244 N=40277
Characteristic n° (%) n° (%) n° (%)
Sex: Female 9794 (48.9) 10107 (49.9) 19901 (49.4)
Sex: Male 10239 (51.1) 10137 (50.1) 20376 (50.6)
Age at Vaccination: Mean years (SD) 50.3 Ce. = 50.1 ee) 50.2 ee
Age at Vaccination: Median (years) 1.0 1.0 1.0
Age at Vaccination: Min, max (years) a 59) (12, 3 (12, 3
Age Group: 16 to <18 years 77 (0.4) 76 (0.4) 153 (0.4)
Age Group: 16 to 55 years 11589 (57.8) 11743 (58.0) 23332 (57.9)
Age Group: >55 years 8396 (41.9) 8454 (41.8) 16850 (41.8)
Age Group: 265 years 4294 (21.4) 4319 (21.3) 8613 (21.38)
Age Group: 275 years 860 (4.3) 852 (4.2) 1712 (4.3)
Race: American Indian or Alaska Native 131 (0.7) 122 (0.6) 253 (0.6)
Race: Asian 880 (4.4) 883 (4.4) 1763 (4.4)
Race: Black or African American eet (9.8) we (9.7) 2e (9.8)
Race: Native Hawaiian or Other Pacific 54 (0.3) 9 (0.1) 83 (0.2)
Islander
Race: White 16387 (81.8) 16619 (82.1) 33006 (81.9)
Race: Multiracial 523 (2.6) 493 (2.4) 1016 (2.5)
Race: Not reported 101 (0.5) 126 (0.6) 227 (0.6)
Ethnicity: Hispanic or Latino 5272 (26.3) 5281 (26.1) 10553 (26.2)
Ethnicity: Not Hispanic or Latino 14652 (73.1) 14847 (73.3) 29499 (73.2)
Ethnicity: Not reported 109 (0.5) 116 (0.6) 225 (0.6)
Comorbidities*: Yes 9278 (46.3) 9314 (46.0) 18592 (46.2)
Comorbidities: No 10755 (53.7) 10930 (54.0) 21685 (53.8)
Comorbidity: Obesity 6934 (34.6) 7093 (35.0) 14027 (34.8)
* N = number of participants in the specified group, or the total sample. This value is the denominator for the percentage
calculations.
> n = number of participants with the specified characteristic.
° Number of participants who have 1 or more comorbidities that increase the risk of severe COVID-19 disease: defined as patients
who had at least one of the Charlson comorbidity index (Appendix A, page 57) category or obesity only (BMI 230 kg/m?).
Overall, the Phase 2/3 safety population included 83.1% White, 9.1% African American, 4.3%
Asian participants, and <3% from other racial groups; 28.0% of participants were
Hispanic/Latino; 21.6% of participants were >65 years of age. The median age was 52 years,
and safety data from a total of 103 participants 16 and 17 years of age were included in this
submission. The most frequently reported comorbidities were obesity (35.1%), diabetes (without
chronic complications, 7.8%) and chronic pulmonary disease (7.8%). Geographically, 76.7% of
participants were from the US, 15.3% from Argentina, 6.1% from Brazil, and 2.0% from South
Africa.
The demographic characteristics among vaccine and placebo participants in the all-enrolled
population were similar and were also enrolled from sites in Germany (1%) and Turkey (1%).
There were no significant imbalances in demographic and other baseline characteristics
between the all-enrolled population and Phase 2/3 safety population with median 2-month
follow-up.
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Table 5. Demographics and Other Baseline Characteristics, Phase 2/3 Safety Population
BNT162b2 Placebo Total
N=18801 BNT162b2 BNT162b2 BNT162b2 N=18785 Placebo Placebo Placebo N=37586
Characteristic n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%)
Age (years) 16 to <18 18 to <65 65 to <75 >75 16 to <18 18 to <65 65 to <75 >75
Age (years)
Mean 16.40 44.99 68.84 78.07 16.36 44.78 68.84 78.10 50.38
[SD] [0.49] [12.66] [2.80] [2.78] [0.48] [12.72] [2.78] [2.81] [15.70]
Median 16 46 68 77 16 46 69 77 52
Min, max 16-17 18-64 65-74 75-89 16-17 18-64 65-74 75-91 16-91
Sex
Male 33 (0.2) 7385 (39.3) 1714 (9.1) 470 (2.5) 24 (0.1) 7153 (38.1) 1724 (9.2) 498 (2.7) 19001 (50.6)
Female 20 (0.1) 7305 (38.9) 1513 (8.0) 361 (1.9) 26 (0.1) 7539 (40.1) 1511 (8.0) 310 (1.7) 18585 (49.4)
Race
White 37 (0.2) 11895 (63.3) 2908 (15.5) 775 (4.1) 38 (0.2) 11891 (63.3) 2930 (15.6) 756 (4.0) 31230 (83.1)
African 11 (0.1) 1477 (7.9) 186 (1.0) 20 (0.1) 7 (0.0) 1505 (8.0) 189 (1.0) 21 (0.1) 3416 (9.1)
American
Asian 0 (0.0) 693 (3.7) 81 (0.4) 26 (0.1) 0 (0.0) 715 (3.8) 72 (0.4) 19 (0.1) 1606 (4.3)
Multiracial 3 (0.0) 417 (2.2) 21 (0.1) 7 (0.0) 3 (0.0) 379 (2.0) 18 (0.1) 5 (0.0) 853 (2.3)
Not reported 0 (0.0) 82 (0.4) 11 (0.1) 0 (0.0) 1 (0.0) 98 (0.5) 10 (0.1) 5 (0.0) 207 (0.6)
American 0 (0.0) 84 (0.4) 15 (0.1) 2 (0.0) 1 (0.0) 83 (0.4) 11 (0.1) 2 (0.0) 198 (0.5)
Indian or
Alaska native
Nat. HI or 2 (0.0) 42 (0.2) 5 (0.0) 1 (0.0) 0 (0.0) 21 (0.1) 5 (0.0) 0 (0.0) 76 (0.2)
Other Pac. Isl.
Ethnicity
Hispanic or 6 (0.0) 4595 (24.4) 549 (2.9) 103 (0.5) 5 (0.0) 4616 (24.6) 558 (3.0) 90 (0.5) 10522 (28.0)
Latino
Non- 47 (0.2) 10009 (53.2) 2658 (14.1) 722 (3.8) 44 (0.2) 10004 (53.3) 2652 (14.1) 707 (3.8) 26843 (71.4)
Hispanic/non-
Latino
Not reported 0 (0.0) 86 (0.5) 20 (0.1) 6 (0.0) 1 (0.0) 72 (0.4) 25 (0.1) 11 (0.1) 221 (0.6)
Baseline Body
Mass Index (BMI)
Obese 3 (0.0) 5200 (27.7) 1079 (5.7) 248 (1.3) 14 (0.1) 5242 (27.9) 1147 (6.1) 235 (1.3) 13168 (35.0)
Overweight 14 (0.1) 4901 (26.1) 1278 (6.8) 368 (2.0) 9 (0.0) 4857 (25.9) 1255 (6.7) 340 (1.8) 13022 (34.6)
Baseline
Evidence of Prior
SARS-CoV-2
Infection
Case 2:21-cv-00702-CLM Document 24-4 Filed 09/16/21 Page 22 of 58
Negative 48 (0.3) 13879 3109 (16.5) 805 (4.3) 47 (0.3%) 13858 3115 (16.6%) 788 (4.2%) 35649 (94.8%)
(73.8%) (73.8%)
Positive 3 (0.0) 473 (2.5%) 53 (0.3) 16 (0.1) 3 (0.0%) 520 (2.8%) 52 (0.3%) 5 (0.0%) 1125 (3.0%)
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BNT162b2 Placebo Total
N=18801 BNT162b2 BNT162b2 BNT162b2 N=18785 Placebo Placebo Placebo N=37586
Characteristic n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%)
Age (years) 16 to <18 18 to <65 65 to <75 >75 16 to <18 18 to <65 65 to <75 >75
Missing 2 (0.0) 338 (1.8%) 65 (0.3) 10 (0.1) 0 (0.0%) 314 (1.7%) 68 (0.4%) 15 (0.1%) 812 (2.2%)
Comorbidities
No 48 (0.3) 12353 2081 (11.1) 444 (2.4) 37 (0.2%) 12412 2118 (11.3%) 470 (2.5%) 29963 (79.7%)
(65.7%) (66.1%)
Yes 5 (0.0) 2337 (12.4%) 1146 (6.1) 387 (2.1) 13 (0.1%) 2280 (12.1%) 1117 (5.9%) 338 (1.8%) 7623 (20.3%)
Diabetes 0 (0.0) 814 (4.3%) 497 (2.6) 156 (0.8) 1 (0.0%) 849 (4.5%) 491 (2.6%) 132 (0.7%) 2940 (7.8%)
Without
Chronic
Complication
Chronic 5 (0.0) 1093 (5.8%) 286 (1.5) 89 (0.5) 12 (0.1%) 1060 (5.6%) 309 (1.6%) 66 (0.4%) 2920 (7.8%)
Pulmonary
Disease
Myocardial 0 (0.0) 82 (0.4%) 71 (0.4) 41 (0.2) 0 (0.0%) 73 (0.4%) 83 (0.4%) 31 (0.2%) 381 (1.0%)
Infarction
Peripheral 0 (0.0) 26 (0.1%) 67 (0.4) 31 (0.2) 0 (0.0%) 29 (0.2%) 52 (0.3%) 33 (0.2%) 238 (0.6%)
Vascular
Disease
Liver Disease 0 (0.0) 83 (0.4%) 34 (0.2) 7 (0.0) 0 (0.0%) 67 (0.4%) 17 (0.1%) 6 (0.0%) 214 (0.6%)
(mild,
moderate or
severe)
Diabetes With 0 (0.0) 47 (0.2%) 36 (0.2) 15 (0.1) 0 (0.0%) 47 (0.3%) 47 (0.3%) 18 (0.1%) 210 (0.6%)
Chronic
Complication
Congestive 0 (0.0) 44 (0.2%) 26 (0.1) 17 (0.1) 0 (0.0%) 36 (0.2%) 30 (0.2%) 16 (0.1%) 169 (0.4%)
Heart Failure
AIDS/HIV 0 (0.0) 0 (0.0%) 0 (0.0) 0 (0.0) 0 (0.0%) 1 (0.0%) 0 (0.0%) 0 (0.0%) 1 (0.0%)
Hypertension 0 (0.0) 2569 (13.7%) 1528 (8.1) 488 (2.6) 1 (0.0%) 2621 (14.0%) 1569 (8.4%) 432 (2.3%) 9208 (24.5%)
only
Source: FDA-generated table.
Abbreviations: n = number of participants with the specified characteristic; N = number of participants >16 years of age enrolled by October 9, 2020 and received at least 1 dose of
vaccine or placebo, N is denominator for the percentage calculations; SD = standard deviation; min, max = minimum, maximum; Nat. HI = Native Hawaiian; Pac. Isl. = Pacific Islander
Data analysis cutoff date: November 14, 2020.
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4.2.5. Vaccine Efficacy
Primary efficacy analyses
Efficacy Results – Primary Endpoint (Evaluable Efficacy Population)
For the first primary efficacy endpoint, vaccine efficacy (VE) for BNT162b2 against confirmed
COVID-19 was evaluated in participants without evidence of prior SARS-CoV-2 infection prior to
7 days after Dose 2. For the second primary efficacy endpoint, VE for BNT162b2 against
confirmed COVID-19 was evaluated in participants with and without evidence of prior SARS-
CoV-2 infection prior to 7 days after Dose 2. Cases were counted from 7 days after Dose 2 for
both endpoints. The criterion for success was met if the posterior probability that true vaccine
efficacy >30% conditioning on the available data was >99.5% at the final analysis.
The population in the primary efficacy analysis included all participants 12 years of age and
older who had been enrolled from July 27, 2020, and followed for the development of COVID-19
through November 14, 2020. Participants 18 to 55 years of age and 56 years of age and older
began enrollment from July 27, 2020, 16 to 17 years of age began enrollment from September
16, 2020 and 12 to 15 years of age began enrollment from October 15, 2020.
For participants without evidence of SARS-CoV-2 infection prior to 7 days after Dose 2, VE
against confirmed COVID-19 occurring at least 7 days after Dose 2 was 95.0%. The case split
was 8 COVID-19 cases in the BNT162b2 group compared to 162 COVID-19 cases in the
placebo group (Table 6). The 95% credible interval for the vaccine efficacy was 90.3% to
97.6%, indicating that the true VE is at least 90.3% with a 97.5% probability, which met the pre-
specified success criterion.
Table 6. Final Analysis of Efficacy of BNT162b2 Against Confirmed COVID-19 From 7 Days After
Dose 2 in Participants Without Evidence of Prior SARS-CoV-2 Infection, Evaluable Efficacy
Population
BNT162b2 Placebo
Na = 18198 Na =18325
Cases Cases Met
n1b n1b Vaccine Predefined
Surveillance Surveillance Efficacy % Success
Pre-specified Age Group Timec (n2d) Timec (n2d) (95% CI) Criterion*
All participants 8 162 95.0 Yes
2.214 (17411) 2.222 (17511) (90.3, 97.6)e
16 to 55 years 5 114 95.6 NA
1.234 (9897) 1.239 (9955) (89.4, 98.6)f
>55 years 3 48 93.7 NA
0.980 (7500) 0.983 (7543) (80.6, 98.8)f
*Success criterion: the posterior probability that true vaccine efficacy > 30% conditioning on the available data is >99.5% at the final
analysis
a
N = number of participants in the specified group.
b
n1 = Number of participants meeting the endpoint definition.
c
Total surveillance time in 1000 person-years for the given endpoint across all participants within each group at risk for the
endpoint. Time period for COVID-19 case accrual is from 7 days after Dose 2 to the end of the surveillance period.
d
n2 = Number of participants at risk for the endpoint.
e
Credible interval for VE was calculated using a beta-binomial model with prior beta (0.700102, 1) adjusted for surveillance time.
f
Confidence interval (CI) for VE is derived based on the Clopper and Pearson method adjusted to the surveillance time.
For participants with and without evidence of SARS-CoV-2 infection before and during
vaccination regimen, VE against confirmed COVID-19 occurring at least 7 days after Dose 2
was 94.6%, with 9 and 169 cases in the BNT162b2 and placebo groups respectively (Table 7).
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The posterior probability was >99.99% for the true VE being greater than 30%. The 95%
credible interval for the vaccine efficacy was 89.9% to 97.3%, indicating that the true VE is at
least 89.9% with a 97.5% probability given the available data.
Table 7. Efficacy of BNT162b2 Against Confirmed COVID-19 From 7 Days After Dose 2 in
Participants With and Without Evidence of Prior SARS-CoV-2 Infection, Evaluable Efficacy
Population
BNT162b2 Placebo
Na = 19965 Na =20172 Met
Cases n1b Cases n1b Vaccine Predefined
Surveillance Surveillance Efficacy % Success
Pre-specified Age Group Timec (n2d) Timec (n2d) (95% CI) Criterion*
All participants 9 169 94.6 Yes
2.332 (18559) 2.345 (18708) (89.9, 97.3)e
16 to 55 years 6 120 95.0 NA
1.309 (10653) 1.317 (10738) (88.7, 98.2)f
>55 years 3 49 93.8 NA
1.022 (7892) 1.028 (7956) (80.9, 98.8)f
*Success criterion: the posterior probability that true vaccine efficacy >30% conditioning on the available data is >99.5% at the final
analysis
a
N = number of participants in the specified group.
b
n1 = Number of participants meeting the endpoint definition.
c
Total surveillance time in 1000 person-years for the given endpoint across all participants within each group at risk for the
endpoint. Time period for COVID-19 case accrual is from 7 days after Dose 2 to the end of the surveillance period.
d
n2 = Number of participants at risk for the endpoint.
e
Credible interval for VE was calculated using a beta-binomial model with prior beta (0.700102, 1) adjusted for surveillance time.
f
Confidence interval (CI) for VE is derived based on the Clopper and Pearson method adjusted to the surveillance time.
Subgroup analyses of vaccine efficacy
Subgroup analyses of the second primary efficacy endpoint provide additional information about
the VE for participants with and without evidence of infection prior to vaccination in specific
populations enrolled, which is the endpoint considered to represent the general population who
may receive the vaccine, as baseline evidence of prior infection may not be known by all people
who might receive the vaccine. The results are displayed below in Table 8. The VE point
estimates for the subgroup analyses were comparable to results for the first primary efficacy
endpoint.
VE point estimates were uniformly high across the subgroups examined with the exception of
participants identifying as multiracial and participants with evidence of prior SARS-CoV-2
infection at enrollment, for which too few COVID-19 cases occurred to interpret efficacy data for
these subgroups. Additionally, the numbers of participants and cases in some other specific
subgroups, such as the adolescent age group and racial subgroups, limits the interpretability of
the VE results because of the wide credible intervals, but are displayed for completeness.
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Table 8: Subgroup Analyses of Second Primary Endpoint: First COVID-19 Occurrence From 7
Days After Dose 2, by Subgroup, Participants With and Without Evidence of Infection Prior to 7
Days After Dose 2, Evaluable Efficacy (7 Days) Population
Efficacy Endpoint
Subgroup
BNT162b2
N?=19965
Cases n1>
Surveillance Time*
(n2°)
Placebo
N?=20172
Cases n1°
Surveillance Time*
(n2°)
Vaccine Efficacy %
(95% Cl)®
Overall
9
2.332 (18559)
169
2.345 (18708)
94.6 (89.6, 97.6)
Age group (years)
16 to 17 0 1 100.0 (-3969.9,
0.003 (58) 0.003 (61) 100.0)
18 to 64 8 149 94.6 (89.1, 97.7)
1.799 (14443) 1.811 (14566)
65 to 74 1 14 92.9 (53.2, 99.8)
0.424 (3239) 0.423 (3255)
275 0 5 100.0 (-12.1, 100.0)
0.106 (805) 0.109 (812)
At risk?
Yes 4 87 95.4 (87.8, 98.8)
1.083 (8584) 1.084 (8609)
No 5 82 93.8 (85.0, 98.1)
1.250 (9975)
1.261 (10099)
Age group (years) and at risk
16-64 and not at risk 5 15 93.3 (83.6, 97.9)
1.012 (8172) 1.019 (8239)
16-64 and at risk 3 15 96.0 (87.8, 99.2)
0.790 (6329) 0.794 (6388)
265 and not at risk 0 7 100.0 (29.5, 100.0)
0.238 (1794) 0.241 (1849)
265 and at risk 1 12 91.7 (44.2, 99.8)
0.293 (2250)
0.290 (2218)
Obeseg
Yes 3 68 95.5 (86.2, 99.1)
0.810 (6445) 0.832 (6582)
No 6 101 94.1 (86.7, 97.9)
1.522 (12108
—
1.513 (12120)
Age group (years) and obese
16-64 and not obese 5 89 94.4 (86.4, 98.2)
1.163 (9380) 1.162 (9422)
16-64 and obese 3 61 95.0 (84.6, 99.0)
0.637 (5116) 0.651 (5199)
265 and not obese 1 12 91.8 (44.7, 99.8)
0.358 (2715) 0.351 (2685)
265 and obese 0 7 100.0 (27.4, 100.0)
0.172 (1328)
0.180 (1382)
Sex
Female 5 84 93.9 (85.2, 98.1)
1.149 (9102) 1.176 (9366)
Male 4 85 95.3 (87.6, 98.8)
1.183 (9457) 1.170 (9342)
Ethnicity
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Efficacy Endpoint
BNT162b2
N#=19965
Cases n1°
Surveillance Time*
Placebo
N?=20172
Cases n1°
Surveillance Time*
Vaccine Efficacy %
Subgroup (n2°) (n2°) (95% Cl)®
Hispanic or Latino 3 55 94.5 (83.2, 98.9)
0.637 (5074) 0.638 (5090)
Not Hispanic or Latino 6 114 94.7 (88.1, 98.1)
1.681 (13380) 1.693 (13509)
Race
American Indian or Alaska native 0 1 100.0 (-3511.0,
0.011 (104) 0.010 (104) 100.0)
Asian 1 4 74.4 (-158.7, 99.5)
0.095 (796) 0.097 (808)
Black or African American 0 7 100.0 (30.4, 100.0)
0.187 (1758) 0.188 (1758)
Native Hawaiian or Other Pacific 0 1 100.0 (-2112.1,
Islander 0.006 (50) 0.003 (29) 100.0)
White 7 153 95.4 (90.3, 98.2)
1.975 (15294) 1.990 (15473)
Multiracial 1 1 10.4 (-6934.9, 98.9)
0.047 (467) 0.042 (424)
Not reported 0 2 100.0 (-581.6, 100.0)
0.010 (90) 0.013 (112)
Baseline SARS-CoV-2 Status
Positive" 1 1 -7.1 (-8309.9, 98.6)
0.056 (526) 0.060 (567)
Negative' 8 164 95.1 (90.1, 97.9)
2.237 (17637) 2.242 (17720)
Unknown 0 4 100.0 (-68.9, 100.0)
0.039 (396) 0.043 (421)
* N = number of participants in the specified group.
> n1 = Number of participants meeting the endpoint definition.
° Total surveillance time in 1000 person-years for the given endpoint across all participants within each group at risk for the
endpoint. Time period for COVID-19 case accrual is from 7 days after Dose 2 to the end of the surveillance period.
4 n2 = Number of participants at risk for the endpoint.
© Confidence interval (Cl) for VE is derived based on the Clopper and Pearson method adjusted to the surveillance time.
' At risk is defined as having at least one of the Charlson comorbidity index (Appendix A, page 57) category or obesity (BMI 230
kg/m?).
3 Obese is defined as BMI 230 kg/m?.
" Positive N-binding antibody result at Visit 1, positive NAAT result at Visit 1, or medical history of COVID-19.
' Negative N-binding antibody result at Visit 1, negative NAAT result at Visit 1, and no medical history of COVID-19.
The demographics of the participants with confirmed COVID-19 cases contributing to the
primary efficacy analysis are displayed below in Table 9.
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Table 9. Demographic Characteristics, Participants With Protocol Defined Case (Without Evidence
of Infection Prior to 7 Days After Dose 2)
BNT162b2 Placebo Total
N?=8 N?=162 N?=170
Characteristic n? (%) n? (%) n? (%)
Sex: Female 5 (62.5) 81 (50.0) 86 (50.6)
Sex: Male 3 (37.5) 81 (50.0) 84 (49.4)
Age at Vaccination: Mean years (SD) 51.4 (12.47) 47.4 (15.21) 47.6 (15.09)
Age at Vaccination: Median (years) 51 48 48
Age at Vaccination: Min, max (years) (30, 69) (18, 79) (18, 79)
Age Group: 16 to < 18 years 0 0 0
Age Group: 18 to < 65 years 7 (87.5) 143 (88.3) 150 (88.2)
Age Group: 2 65 to < 75 years 1 (12.5) 14 (8.6) 15 (8.8)
Age Group: 2 75 years 0 5 (3.1) 5 (2.9)
Race: American Indian or Alaska Native 0 1 (0.6) 1 (0.6)
Race: Asian 1 (12.5) 4 (2.5) 5 (2.9)
Race: Black or African American 0 T (4.3) 7 (4.1)
Race: Native Hawaiian or Other Pacific Islander 0 1 (0.6) 1 (0.6)
Race: White 7 (87.5) 146 (90.1) 153 (90.0)
Race: Multiracial 0 1 (0.6) 1 (0.6)
Race: Not reported 0 2 (1.2) 2 (1.2)
Ethnicity: Hispanic or Latino 3 (37.5) 53 (32.7) 56 (32.9)
Ethnicity: Not Hispanic or Latino 5 (62.5) 109 (67.3) 114 (67.1)
Ethnicity: Not reported 0 0 0
Comorbidities*: Yes 4 (50.0) 86 (53.1) 90 (52.9)
Comorbidities: No 4 (50.0) 76 (46.9) 80 (47.1)
Comorbidity: Obesity 3 (37.5) 67 (41.4) 70 (41.2)
* N = number of participants in the specified group, or the total sample. This value is the denominator for the percentage
calculations.
> n = Number of participants with the specified characteristic.
° Number of participants who have 1 or more comorbidities that increase the risk of severe COVID-19 disease: defined as patients
who had at least one of the Charlson comorbidity index (Appendix A, page 57) category or obesity only (BMI 230 kg/m?).
Only 3% of participants had evidence of prior infection at study enrollment, and additional
analyses showed that very few COVID-19 cases occurred in these participants over the course
of the entire study (9 in the placebo group and 10 in the BNT162b2 group, only 1 of which
occurred 7 days or more after completion of the vaccination regimen — data not shown). The
placebo group attack rate from enrollment to the November 14, 2020, data cut-off date was
1.3% both for participants without evidence of prior infection at enrollment (259 cases in 19,818
participants) and for participants with evidence of prior infection at enrollment (9 cases in 670
participants). While limited, these data do suggest that previously infected individuals can be at
risk of COVID-19 (i.e., reinfection). However, available data are insufficient to determine
whether such individuals could benefit from vaccination.
Additional analyses of the first primary efficacy endpoint were conducted to evaluate the vaccine
efficacy, by comorbidity status. VE point estimates were uniformly high across the comorbidities
examined, though for some interpretation of the results is limited by small numbers of
participants and/or cases.
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Table 10. Vaccine Efficacy: First COVID-19 Occurrence From 7 Days After Dose 2, by Comorbidity
Status, Among Participants Without Evidence of Infection Prior to 7 Days After Dose 2, Evaluable
Efficacy (7 Days) Population
BNT162b2 Placebo
N?=18198 N?=18325
Cases n1° Cases n1°
Efficacy Endpoint Surveillance Time* Surveillance Time* Vaccine Efficacy %
Subgroup (n29) (n29) (95% Cl®)
Overall 8 162 95.0
2.214 (17411) 2.222 (17511) (90.0, 97.9)
Comorbidity
No comorbidity 4 76 94.7
1.189 (9381) 1.197 (9482) (85.9, 98.6)
Any comorbidity‘ 4 86 95.3
1.025 (8030) 1.025 (8029) (87.7, 98.8)
Any malignancy 1 4 75.7
0.092 (704) 0.090 (681) (-145.8, 99.5)
Cardiovascular 0 5 100.0
0.067 (534) 0.062 (492) (-0.8, 100.0)
Chronic pulmonary 1 14 93.0
disease 0.175 (1374) 0.171 (1358) (54.1, 99.8)
Diabetes 1 19 94.7
0.176 (1372) 0.176 (1374) (66.8, 99.9)
Obese (BMI230.0 kg/m?) 3 67 95.4
0.763 (6000) 0.782 (6103) (86.0, 99.1)
Hypertension 2 44 95.4
0.567 (4413) 0.567 (4437) (82.6, 99.5)
Diabetes (including 1 20 95.0
gestational diabetes) 0.177 (1381) 0.178 (1384) (68.7, 99.9)
Abbreviations: N-binding = SARS-CoV-2 nucleoprotein—binding; NAAT = nucleic acid amplification test; SARS-CoV-2 = severe
acute respiratory syndrome coronavirus 2; VE = vaccine efficacy.
Note: Participants who had no serological or virological evidence (prior to 7 days after receipt of the last dose) of past SARS-CoV-2
infection (i.e., N-binding antibody [serum] negative at Visit 1 and SARS-CoV-2 not detected by NAAT [nasal swab] at Visits 1 and 2),
and had negative NAAT (nasal swab) at any unscheduled visit prior to 7 days after Dose 2 were included in the analysis.
*N = number of participants in the specified group.
’n1 = Number of participants meeting the endpoint definition.
° Total surveillance time in 1000 person-years for the given endpoint across all participants within each group at risk for the endpoint.
Time period for COVID-19 case accrual is from 7 days after Dose 2 to the end of the surveillance period.
4 n2 = Number of participants at risk for the endpoint.
© Confidence interval (Cl) for VE is derived based on the Clopper and Pearson method adjusted for surveillance time.
Subject who had 1 or more comorbidities that increase the risk of severe COVID-19 disease: defined as participants who had at
least one of the Charlson comorbidity index (Appendix A, page 57) category or BMI 230 kg/m2.
Cumulative incidence curves
Based on the cumulative incidence curve for the all-available efficacy population after Dose 1,
(Figure 2), COVID-19 disease onset appears to occur similarly for both BNT162b2 and placebo
groups until approximately 14 days after Dose 1, at which time point, the curves diverge, with
more cases accumulating in the placebo group than in the BNT162b2 group, and there does not
appear to be evidence of waning protection during the follow-up time of approximately 2 months
following the second dose that is being evaluated at this point in time.
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Figure 2. Cumulative Incidence Curves for the First COVID-19 Occurrence After Dose 1, Dose 1
All-Available Efficacy Population
Secondary efficacy analyses
The secondary efficacy endpoints evaluate the VE of BNT162b2 for the prevention of COVID-19
disease from 14 days after Dose 2 and based on the CDC’s definition of COVID-19 disease
from 7 and 14 days after Dose 2. The case splits and VE for each of these secondary efficacy
endpoints were each similar to the primary efficacy endpoints described above.
Severe COVID-19 Cases
In the final analysis of the evaluable efficacy population (7 days), four participants had severe
COVID-19 disease at least 7 days after Dose 2 (one subject who received BNT162b2 and three
participants who received placebo). The vaccine recipient who had severe COVID-19 disease
met the severe case definition because oxygen saturation at the COVID-19 illness visit was
93% on room air. The subject was not hospitalized, did not seek further medical care, and did
not have risk factors for severe disease. The three placebo recipients who had severe COVID-
19 disease met the severe case definition for the following reasons: one subject had an oxygen
saturation of 92% on room air without other severe disease criteria, one subject was
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hospitalized for noninvasive positive pressure ventilation with bilateral pneumonia, and one
subject had an oxygen saturation of 92% and ICU admission for heart block. One of these
placebo recipients with severe disease also had a body mass index > 30 kg/m? as a risk factor,
while the other two participants did not have any risk factors for severe disease. The vaccine
efficacy of this secondary efficacy endpoint is shown in Table 11.
Table 11. First Severe COVID-19 Occurrence from 7 Days after Dose 2, Evaluable Efficacy
Population
BNT162b2 Placebo
N2=18198 N?=18325 Met
Cases n1° Cases n1° Vaccine Predefined
Secondary Efficacy Surveillance Time® Surveillance Time‘ Efficacy % Success
Endpoint (n24) (n24) (95% Cl) Criterion*
First_severe COVID-19 1 3 66.4 No
occurrence from 7 days after 2.215 (17411) 2.232 (17511) (-124.8,
Dose 2 in participants 96.3)¢
without evidence of prior
SARS-CoV-2 infection
*Success criterion: the posterior probability that true vaccine efficacy > 30% conditioning on the available data is >98.6% at the final
analysis.
@ N = number of participants in the specified group.
>. n1 = Number of participants meeting the endpoint definition.
° Total surveillance time in 1000 person-years for the given endpoint across all participants within each group at risk for the endpoint.
Time period for COVID-19 case accrual is from 7 or 14 days after Dose 2 to the end of the surveillance period depending on
specified endpoint.
4 n2 = Number of participants at risk for the endpoint.
© Credible interval for VE was calculated using a beta-binomial model with prior beta (0.700102, 1) adjusted for surveillance time.
Confidence interval (Cl) for VE is derived based on the Clopper and Pearson method adjusted to the surveillance time.
In the all-available efficacy population, ten participants had severe COVID-19 disease after
Dose 1 (one subject who received BNT162b2 and nine participants who received placebo). Five
of the remaining six placebo recipients who had severe COVID-19 disease were hospitalized,
two of whom were admitted to an intensive care unit. Five of these remaining six placebo
recipients who had severe disease had at least one risk factor for severe disease. The total
number of severe cases is small, which limits the overall conclusions that can be drawn;
however, the case split does suggest protection from severe COVID-19 disease.
Table 12. First Severe COVID-19 Occurrence After Dose 1, Dose 1 All-Available Efficacy
Population
BNT162b2 Placebo
N?=21669 N?=21686
Cases n1° Cases n1°
Surveillance Time*® Surveillance Time* Vaccine Efficacy %
Secondary Efficacy Endpoint (n2°) (n2°) (95% Cl)
First severe case occurrence after 1 9 88.9
Dose 1 4.021 (21314) 4.006 (21259) (20.1, 99.7)f
After Dose 1 to before Dose 2 100.0 (-51.5, 100.0)
Dose 2 to 6 days after Dose 2
-|O;O
4
1 100.0 (-3800.0, 100.0
4
)
2/7 Days after Dose 2 75.0 (-152.6, 99.5)
*N = number of participants in the specified group.
> n1 = Number of participants meeting the endpoint definition.
° Total surveillance time in 1000 person-years for the given endpoint across all participants within each group at risk for the endpoint.
Time period for COVID-19 case accrual is from 7 or 14 days after Dose 2 to the end of the surveillance period depending on
specified endpoint.
4 n2 = Number of participants at risk for the endpoint.
* Credible interval for VE was calculated using a beta-binomial model with prior beta (0.700102, 1) adjusted for surveillance time.
‘ Confidence interval (Cl) for VE is derived based on the Clopper and Pearson method adjusted to the surveillance time.
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Additional efficacy analyses
Additional analyses of the first primary efficacy endpoint were conducted to evaluate the all-
available efficacy population, for all participants regardless of evidence of prior infection through
7 days after Dose 2 (Table 13).
Table 13. Primary Efficacy Endpoint, All-Available Efficacy Population
BNT162b2 Placebo
N*=21669 N?=21686
Cases n1° Cases n1°
Surveillance Time*® Surveillance Time‘ Vaccine Efficacy %
Efficacy Endpoint (n2°) (n2°) (95% Cl)
First COVID-19 occurrence after 50 275 82.0
Dose 1 — Dose 1 4.015 (21314) 3.982 (21258) (75.6, 86.9)
After Dose 1 to before Dose 2 39 82 52.4 (29.5, 68.4)
Dose 2 to 6 days after Dose 2 2 21 90.5 (61, 98.9)
2/7 Days after Dose 2 9 172 94.8 (89.8, 97.6)
*N = number of participants in the specified group.
> n1 = Number of participants meeting the endpoint definition.
° Total surveillance time in 1000 person-years for the given endpoint across all participants within each group at risk for the endpoint.
Time period for COVID-19 case accrual is from 7 or 14 days after Dose 2 to the end of the surveillance period depending on
specified endpoint.
4 n2 = Number of participants at risk for the endpoint.
° Credible interval for VE was calculated using a beta-binomial model with prior beta (0.700102, 1) adjusted for surveillance time.
‘ Confidence interval (Cl) for VE is derived based on the Clopper and Pearson method adjusted to the surveillance time.
VE in participants in the all-available efficacy population was similar to results in the evaluable
efficacy population. The VE for the prevention of COVID-19 disease after Dose 1 is 82%, in the
all-available efficacy population. Based on the number of cases accumulated after Dose 1 and
before Dose 2, there does seem to be some protection against COVID-19 disease following one
dose; however, these data do not provide information about longer term protection beyond 21
days after a single dose.
Efficacy summary
The data submitted in this EUA request were consistent with the recommendations set forth in
the FDA Guidance on Emergency Use Authorization for Vaccines to Prevent COVID-19 and met
the prespecified success criteria established in the protocol. In the planned final primary efficacy
analysis, vaccine efficacy after 7 days post Dose 2 was 95%, (95% Cl 90.3; 97.6) in participants
without prior evidence of SARS-CoV-2 infection and >94% in the group of participants with or
without prior infection. Efficacy outcomes were consistently robust (293%) across demographic
subgroups.
Efficacy against severe COVID-19 occurring after the first dose was 88.9% (95% Cl 20.1, 99.7),
with an estimated VE of 75.0% (95% Cl -152.6, 99.5) (1 case in BNT162b2 group and 4 cases
in placebo group) against severe COVID-19 occurring at least 7 days after Dose 2.
Among all participants (regardless of evidence of infection before or during the vaccination
regimen), 50 cases of COVID-19 occurred after Dose 1 in the BNT162b2 group compared with
275 cases in the placebo group, indicating an estimated VE of 82% (95% Cl: 75.6%, 86.9%)
against confirmed COVID-19 occurring after Dose 1, with VE of 52.4% (95% Cl: 29.5%, 68.4%)
between Dose 1 and Dose 2. The efficacy observed after Dose 1 and before Dose 2, from a
post-hoc analysis, cannot support a conclusion on the efficacy of a single dose of the vaccine,
because the time of observation is limited by the fact that most of the participants received a
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second dose after three weeks. The trial did not have a single-dose arm to make an adequate
comparison.
4.2.6. Safety
Overview of adverse events
Table 14 below presents an overview of all adverse events in the Phase 2/3 safety population. A
higher proportion of vaccine recipients reported adverse events compared with placebo
recipients, and this imbalance was driven by reactogenicity (solicited adverse events) reported
in the 7 days following vaccination and unsolicited adverse events corresponding to
reactogenicity symptoms among participants not in the reactogenicity subset (see presentation
of unsolicited adverse events in a later section). Proportions of participants with serious adverse
events, deaths, and withdrawals due to adverse events were balanced between treatment
groups.
Table 14. Study C4591001 Safety Overview, Ages 16 Years and Older
BNT162b2 Placebo
Participants Experiencing at Least One: n/N (%) n/N (%)
Immediate unsolicited AE Within 30 minutes after
vaccinationa
Dose #1 78/18801 (0.4) 66/18785 (0.4)
Dose #2 52/18494 (0.3) 39/18470 (0.2)
Solicited injection site reaction within 7 daysb
Dose #1 3216/4093 (78.6) 525/4090 (12.8)
Dose #2 2748/3758 (73.1) 396/3749 (10.6)
Solicited systemic AE within 7 daysb
Dose #1 2421/4093 (59.1) 1922/4090 (47.0)
Dose #2 2627/3758 (69.9) 1267/3749 (33.8)
From Dose 1 through 1 month after Dose 2a
Unsolicited non-serious AE 5071/18801 (27.0) 2356/18785 (12.5)
SAE 103/18801 (0.5) 81/18785 (0.4)
From Dose 1 through cutoff date (safety population)
SAE 124/18801 (0.7) 101/18785 (0.5)
From Dose 1 through cutoff date (all-enrolled)c
Withdrawal due AEs 37/21621 (0.6) 30/21631 (0.5)
SAE 126/21621 (0.6) 111/21631 (0.5)
Deaths 2/21621 (0.0) 4/21631 (0.0)
Source: c4591001-safety-tables-ae3.pdf pages 216,446,459,463; c4591001-safety-tables-cos-reacto.pdf, pages 113-114.
n= number of participants with the specified reaction or AE.
a
N: number of participants in the Phase 2/3 safety population.
b
N: number of participants in the reactogenicity subset of the Phase 2/3 safety population.
b
N: number of participants in the all-enrolled population.
Data analysis cutoff date: November 14, 2020.
Solicited local reactions and systemic adverse events
As of the cutoff date, solicited reactogenicity data in participants 16 and 17 years of age were
not collected by e-diary and are not available. Symptoms consistent with solicited reactogenicity
that were reported by these participants were collected and analyzed as unsolicited adverse
events and are discussed with review of those data.
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Solicited Local Reactions
For each age group in the reactogenicity subset (younger: 18 to 55 years, older: >55 years) and
overall (18 years and older), the median onset of local reactions in the vaccine group was 0 (day
of vaccination) to 2 days after either dose and lasted a median duration between 1 and 2 days.
For both age groups, injection site pain was the most frequent solicited local adverse reaction.
After dose 2, the younger age group reported any pain more frequently than the older age group
(77.8% vs 66.1%) and pain characterized as moderate (27.1% vs. 18.0%); a similar pattern was
observed after Dose 1. Injection site redness and swelling after each dose were generally
similar for both age groups.
Subgroup analyses by age
Table 15. Frequency of Solicited Local Reactions Within 7 Days After Each Vaccination,
Reactogenicity Subset of the Phase 2/3 Safety Population, 18 to 55 Years of Age*
BNT162b2 Placebo BNT162b2 Placebo
Dose 1 Dose 1 Dose 2 Dose 2
N=2291 N=2298 N=2098 N=2103
Local Reaction n (%) n (%) n (%) n (%)
Paina
Any 1904 (83.1) 322 (14.0) 1632 (77.8) 245 (11.7)
Mild 1170 (51.1) 308 (13.4) 1039 (49.5) 225 (10.7)
Moderate 710 (31.0) 12 (0.5) 568 (27.1) 20 (1.0)
Severe 24 (1.0) 2 (0.1) 25 (1.2) 0 (0.0)
Rednessb
Any 104 (4.5) 26 (1.1) 123 (5.9) 14 (0.7)
Mild 70 (3.1) 16 (0.7) 73 (3.5) 8 (0.4)
Moderate 28 (1.2) 6 (0.3) 40 (1.9) 6 (0.3)
Severe 6 (0.3) 4 (0.2) 10 (0.5) 0 (0.0)
Swellingb
Any 132 (5.8) 11 (0.5) 132 (6.3) 5 (0.2)
Mild 88 (3.8) 3 (0.1) 80 (3.8) 3 (0.1)
Moderate 39 (1.7) 5 (0.2) 45 (2.1) 2 (0.1)
Severe 5 (0.2) 3 (0.1) 7 (0.3) 0 (0.0)
Source: adapted from EUA 27034, amendment 3, Table 17.
n = number of participants with the specified reaction.
N = number of participants reporting at least 1 yes or no response for the specified reaction after the specified dose.
a
Mild: does not interfere with activity; moderate: interferes with activity; severe: prevents daily activity.
b
Mild: 2.0 to <5.0 cm; moderate: 5.0 to <10.0 cm; severe: >10.0 cm.
*Includes <10 participants 16 and 17 years of age.
Data analysis cutoff date: November 14, 2020.
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Table 16. Frequency of Solicited Local Reactions Within 7 Days After Each Vaccination,
Reactogenicity Subset of the Phase 2/3 Safety Population, >55 Years of Age and Older
Local Reaction
BNT162b2
Dose 1
Placebo
Dose 1
N=1792
n (%)
BNT162b2
Dose 2
N=1660
n (%)
Placebo
Dose 2
N=1646
n (%)
Pain@
Any
Mild
Moderate
Severe
1098 (
792 (
298 (
8
Redness?
Any
Mild
Moderate
Severe
=a
NO ONn ©
—_~ ~~
oOo =—
Ne a SS
Swelling?
Any
Mild
Moderate
Severe
1
7
4
— — PO
ono
—_~ ~~
eoo°o>
OD ® NM
Wa a aS
Source: EUA 27036, amendment 3, Table 21.
n = number of participants with the specified reaction.
N = number of participants reporting at least 1 yes or no response for the specified reaction after the specified dose.
* Mild: does not interfere with activity; moderate: interferes with activity; severe: prevents daily activity.
> Mild: 2.0 to <5.0 cm; moderate: 5.0 to <10.0 cm; severe: >10.0 cm.
Data analysis cutoff date: November 14, 2020.
Solicited Systemic AEs
For each age group in the reactogenicity subset (younger: 18 to 55 years, older: >55 years) and
overall (18 years and older), the median onset of systemic AEs in the vaccine group in general
was 1 to 2 days after either dose and lasted a median duration of 1 day.
The frequency and severity of systemic AEs were higher in the younger than the older age
groups. Within each age group, the frequency and severity of systemic AEs was higher after
Dose 2 than Dose 1, except for vomiting and diarrhea, which was generally similar regardless of
dose. For both age groups, fatigue, headache and new/worsened muscle pain were most
common.
Subgroup analyses by age
Table 17. Frequency of Solicited Systemic Adverse Events Within 7 Days After Each Vaccination-
Reactogenicity Subset of the Phase 2/3 Safety Population, 18 to 55 Years of Age*
BNT162b2 Placebo BNT162b2 Placebo
Dose 1 Dose 1 Dose 2 Dose 2
N=2291 N=2298 N=2098 N=2103
Adverse Event n (%) n (%) n (%) n (%)
Fever
238.0°C 85 (3.7) 20 (0.9) 331 (15.8) 10 (0.5)
>38.0°C to <38.4°C 64 (2.8) 10 (0.4) 194 (9.2) 5 (0.2)
>38.4°C to <38.9°C 15 (0.7) 5 (0.2) oy (5.2) 3 (0.1)
>38.9°C to <40.0°C 6 (0.3) 3 (0.1) 26 (1.2) 2 (0.1)
>40.0°C 0 (0.0) 2 (0.1) 1 (0.0) 0 (0.0)
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BNT162b2 Placebo BNT162b2 Placebo
Dose 1 Dose 1 Dose 2 Dose 2
N=2291 N=2298 N=2098 N=2103
Adverse Event n (%) n (%) n (%) n (%)
Fatiguea
Any 1085 (47.4) 767 (33.4) 1247 (59.4) 479 (22.8)
Mild 597 (26.1) 46 (20.3) 442 (21.1) 248 (11.8)
Moderate 455 (19.9) 289 (12.6) 708 (33.7) 217 (10.3)
Severe 33 (1.4) 11 (0.5) 97 (4.6) 14 (0.7)
Headachea
Any 959 (41.9) 775 (33.7) 1085 (51.7) 506 (24.1)
Mild 628 (27.4) 505 (22.0) 538 (25.6) 321 (15.3)
Moderate 308 (13.4) 251 (10.9) 480 (22.9) 170 (8.1)
Severe 23 (1.0) 19 (0.8) 67 (3.2) 15 (0.7)
Chillsa
Any 321 (14.0) 146 (6.4) 737 (35.1) 79 (3.8)
Mild 230 (10.0) 111 (4.8) 359 (17.1) 65 (3.1)
Moderate 82 (3.6) 33 (1.4) 333 (15.9) 14 (0.7)
Severe 9 (0.4) 2 (0.1) 45 (2.1) 0 (0.0)
Vomitingb
Any 28 (1.2) 28 (1.2) 40 (1.9) 25 (1.2)
Mild 24 (1.0) 22 (1.0) 28 (1.3) 16 (0.8)
Moderate 4 (0.2) 5 (0.2) 8 (0.4) 9 (0.4)
Severe 0 (0.0) 1 (0.0) 4 (0.2) 0 (0.0)
Diarrheac
Any 255 (11.1) 270 (11.7) 219 (10.4) 177 (8.4)
Mild 206 (9.0) 217 (9.4) 179 (8.5) 144 (6.8)
Moderate 46 (2.0) 52 (2.3) 36 (1.7) 32 (1.5)
Severe 3 (0.1) 1 (0.0) 4 (0.2) 1 (0.0)
New or worsened
muscle paina
Any 487 (21.3) 249 (10.8) 783 (37.3) 173 (8.2)
Mild 256 (11.2) 175 (7.6) 326 (15.5) 111 (5.3)
Moderate 218 (9.5) 72 (3.1) 410 (19.5) 59 (2.8)
Severe 13 (0.6) 2 (0.1) 47 (2.2) 3 (0.1)
New or worsened joint
paina
Any 251 (11.0) 138 (6.0) 459 (21.9) 109 (5.2)
Mild 147 (6.4) 95 (4.1) 205 (9.8) 54 (2.6)
Moderate 99 (4.3) 43 (1.9) 234 (11.2) 51 (2.4)
Severe 5 (0.2) 0 (0.0) 20 (1.0) 4 (0.2)
Use of antipyretic or 638 (27.8) 332 (14.4) 945 (45.0) 266 (12.6)
pain medication
Source: adapted from EUA 27036, amendment 3, Table 19.
n = number of participants with the specified reaction.
N = number of participants in the reactogenicity subset reporting at least 1 yes or no response for the specified reaction after the
specified dose.
a
Mild: does not interfere with activity; moderate: some interference with activity; severe: prevents daily activity.
b
Mild: 1 to 2 times in 24 hours; moderate: >2 times in 24 hours; severe: requires intravenous hydration.
c
Mild: 2 to 3 loose stools in 24 hours; moderate: 4 to 5 loose stools in 24 hours; severe: 6 or more loose stools in 24 hours.
*Includes <10 participants 16 and 17 years of age.
Data analysis cutoff date: November 14, 2020.
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Table 18. Frequency of Solicited Systemic Adverse Events Within 7 Days After Each Vaccination-
Reactogenicity Subset of the Phase 2/3 Safety Population, >55 Years of Age and Older
BNT162b2 Placebo BNT162b2 Placebo
Dose 1 Dose 1 Dose 2 Dose 2
N=1802 N=1792 N=1660 N=1646
Adverse Event n (%) n (%) n (%) n (%)
Fever
238.0°C 26 (1.4) 7 (0.4) 181 (10.9) 4 (0.2)
>38.0°C to <38.4°C 23 (1.3) 2 (0.1) 131 (7.9) 2 (0.1)
>38.4°C to <38.9°C 1 (0.1) 3 (0.2) 45 (2.7) 1 (0.1)
>38.9°C to <40.0°C 1 (0.1) 2 (0.1) 5 (0.3) 1 (0.1)
>40.0°C 1 (0.1) 0 (0.0) 0 (0.0) 0 (0.0)
Fatigue?
Any 615 (34.1) 405 (22.6) 839 (50.5) 277 (16.8)
Mild 373 (20.7) 252 (14.1) 351 (21.1) 161 (9.8)
Moderate 240 (13.3) 150 (8.4) 442 (26.6) 114 (6.9)
Severe 2 (0.1) 3 (0.2) 46 (2.8) 2 (0.1)
Headache#
Any 454 (“0 2) 325 (18.1) 647 (39.0) 229 (13.9)
Mild 348 (19.3) 242 (13.5) 422 (25.4) 165 (10.0)
Moderate 104 (5.8) 80 (4.5) 216 (13.0) 60 (3.6)
Severe 2 (0.1) 3 (0.2) 9 (0.5) 4 (0.2)
Chills?
Any 113 (6.3) 57 (3.2) 377 (22.7) 46 (2.8)
Mild 87 (4.8) 40 (2.2) 199 (12.0) 35 (2.1)
Moderate 26 (1.4) 16 (0.9) 161 (9.7) 11 (0.7)
Severe 0 (0.0) 1 (0.1) 17 (1.0) 0 (0.0)
Vomiting®
Any 9 (0.5) 9 (0.5) 11 (0.7) 5 (0.3)
Mild 8 (0.4) 9 (0.5) 9 (0.5) 5 (0.3)
Moderate 1 (0.1) 0 (0.0) 1 (0.1) 0 (0.0)
Severe 0 (0.0) 0 (0.0) 1 (0.1) 0 (0.0)
Diarrhea‘
Any 147 (8.2) 118 (6.6) 137 (8.3) 99 (6.0)
Mild 118 (6.5) 100 (5.6) 114 (6.9) 73 (4.4)
Moderate 26 (1.4) 17 (0.9) 21 (1.3) 22 (1.3)
Severe 3 (0.2) 1 (0.1) 2 (0.1) 4 (0.2)
New or worsened
muscle pain?
Any 251 (13.9) 149 (8.3) 47T (28.7) 87 (5.3)
Mild 168 (9.3) 100 (5.6) 202 (12.2) 57 (3.5)
Moderate 82 (4.6) 46 (2.6) 259 (15.6) 29 (1.8)
Severe 1 (0.1) 3 (0.2) 16 (1.0) 1 (0.1)
New or worsened joint
pain?
Any 155 (8.6) 109 (6.1) 313 (18.9) 61 (3.7)
Mild 101 (5.6) 68 (3.8) 161 (9.7) 35 (2.1)
Moderate 52 (2.9) AO (2.2) 145 (8.7) 25 (1.5)
Severe 2 (0.1) 1 (0.1) 7 (0.4) 1 (0.1)
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BNT162b2 Placebo BNT162b2 Placebo
Dose 1 Dose 1 Dose 2 Dose 2
N=1802 N=1792 N=1660 N=1646
Adverse Event n (%) n (%) n (%) n (%)
Use of antipyretic or 358 (19.9) 213 (11.9) 625 (37.7) 161 (9.8)
pain medication
Source: EUA 27036, amendment 3, Table 23.
n = number of participants with the specified reaction.
N = number of participants in the reactogenicity subset reporting at least 1 yes or no response for the specified reaction after the
specified dose.
4 Mild: does not interfere with activity; moderate: some interference with activity; severe: prevents daily activity.
> Mild: 1 to 2 times in 24 hours; moderate: >2 times in 24 hours; severe: requires intravenous hydration.
°Mild: 2 to 3 loose stools in 24 hours; moderate: 4 to 5 loose stools in 24 hours; severe: 6 or more loose stools in 24 hours.
Data analysis cutoff date: November 14, 2020.
Unsolicited (non-serious) AEs
A higher frequency of unsolicited, non-serious adverse events was reported in the vaccine
group compared to placebo group and was primarily attributed to local reactions and systemic
adverse events in subjects not in the reactogenicity subset and are consistent with solicited
reactions/events reported by reactogenicity subset participants during the first 7 days following
vaccination. Table 19 below presents unsolicited adverse events reported by at least 1% of
participants in any treatment group for the Phase 2/3 safety population.
Reports of lymphadenopathy were imbalanced with notably more cases in the vaccine group
(64) vs. the placebo group (6), which is plausibly related to vaccination. Bell’s palsy was
reported by four vaccine participants and none in the placebo group. These cases occurred at 3,
9, 37, and 48 days after vaccination. One case (onset at 3 days postvaccination) was reported
as resolved with sequelae within three days after onset, and the other three were reported as
continuing or resolving as of the November 14, 2020, data cut-off with ongoing durations of 10,
15, and 21 days, respectively. The observed frequency of reported Bell’s palsy in the vaccine
group is consistent with the expected background rate in the general population, and there is no
clear basis upon which to conclude a causal relationship at this time, but FDA will recommend
surveillance for cases of Bell’s palsy with deployment of the vaccine into larger populations.
There were no other notable patterns or numerical imbalances between treatment groups for
specific categories (system organ class or preferred term) of non-serious adverse events,
including other neurologic, neuro-inflammatory, and thrombotic events, that would suggest a
causal relationship to BNT162b2 vaccine.
Table 19. Frequency of Unsolicited AEs with Occurrence in 21% of Participants in any Treatment Group
from Dose 1 to 1-month After Dose 2, Phase 2/3 Safety Population, 16 Years of Age and Older
BNT162b2 Placebo Total
System Organ Class N=18801 N=18785 N=37586
Preferred Term n (%) n (%) n (%)
General disorders and administration 3521 (18.7) 137 (3.9) 4258 (11.3)
site conditions
Injection site pain 2125 (11.3) 286 (1.5) 2411 (6.4)
Fatigue 1029 (5.5) 260 (1.4) 1289 (3.4)
Pyrexia 1146 (6.1) 61 (0.3) 1207 (3.2)
Chills 999 (5.3) 87 (0.5) 1086 (2.9)
Pain 455 (2.4) 36 (0.2) 491 (1.3)
Musculoskeletal and connective tissue 1387 (7.4) 401 (2.1) 1788 (4.8)
disorders
Myalgia 909 (4.8) 126 (0.7) 1035 (2.8)
Arthralgia 212 (1.1) 82 (0.4) 294 (0.8)
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BNT162b2 Placebo Total
System Organ Class N=18801 N=18785 N=37586
Preferred Term n (%) n (%) n (%)
Nervous system disorders 1158 (6.2) 460 (2.4) 1618 (4.3)
Headache 973 (5.2) 304 (1.6) 1277 (3.4)
Gastrointestinal disorders 565 (3.0) 368 (2.0) 933 (2.5)
Diarrhoea 194 (1.0) 149 (0.8) 343 (0.9)
Nausea 216 (1.1) 63 (0.3) 279 (0.7)
Source: FDA analysis.
Adverse events in any PT = at least one adverse event experienced (regardless of the MedDRA Preferred Term)
%: n/N. n = number of participants reporting at least 1 occurrence of the specified event.
of any event. N = number of participants in the specified group. This value is the denominator for the percentage calculations.
Data analysis cutoff date: November 14, 2020.
Subgroup analyses by age
16 and 17 years of age: the table below represents an FDA-generated summary of unsolicited
AEs consistent with reactogenicity and AEs that occurred at 21% and higher in the BNT162b2
Vaccine Group, classified by MedDRA System Organ Class and Preferred Term.
Table 20. Frequency of Unsolicited Local Reactions and Systemic Adverse Events Reported
Within 7 Days After Each Dose, Phase 2/3 Safety Population, 16 and 17 Years of Age
BNT162b2 Placebo BNT162b2 Placebo
Dose 1 Dose 1 Dose 2 Dose 2
System Organ Class N=53 N=50 N=53 N=50
Preferred Term n (%) n (%) n (%) n (%)
General disorders and
administration site conditions 4 (7.5%) 4 (8.0%) 5 (9.4%) 2 (4.0%)
Injection site pain 3 (5.7) 2 (4.0) : (5.7) 0 (0.0)
Fatigue 1 (1.9) 1 (2.0) 1 (1.9) 1 (2.0)
Pyrexia 1 (1.9) 0 (0.0) 4 (7.5) 0 (0.0)
Chills 1 (1.9) 0 (0.0) 0 (0.0) 0 (0.0)
Nervous system disorders 0 (0.0) 1 (2.0) 1 (1.9) 0 (0.0)
Headache 0 (0.0) 1 (2.0) 1 (1.9) 0 (0.0)
Gastrointestinal disorders 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.0)
Diarrhea 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.0)
Source: FDA analysis.
Adverse events in any PT = at least one adverse event experienced (regardless of the MedDRA Preferred Term)
%: n/N. n = number of participants reporting at least 1 occurrence of the specified event.
N = number of participants in the specified group. This value is the denominator for the percentage calculations.
Data analysis cutoff date: November 14, 2020.
Table 21. Frequency of Unsolicited AEs with Occurrence in 21% of Participants in any Treatment
Group from Dose 1 to 1 Month After Dose 2, Phase 2/3 Safety Population*, 65 Years and Older
BNT162b2 Placebo Total
System Organ Class N=4058 N=4043 N=8101
Preferred Term n (%) n (%) n (%)
General disorders and 577 (14.2) 118 (2.9) 695 (8.6)
administration site
conditions
Injection site pain 361 (8.9) 39 (1.0) 400 (4.9)
Fatigue 175 (4.3) 44 (1.1) 219 (2.7)
Chills 143 (3.5) 19 (0.5) 162 (2.0)
Pyrexia 148 (3.6) 10 (0.2) 158 (2.0)
Pain 60 (1.5) 7 (0.2) 67 (0.8)
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BNT162b2 Placebo Total
System Organ Class N=4058 N=4043 N=8101
Preferred Term n (%) n (%) n (%)
Musculoskeletal and 231 (5.7) 83 (2.1) 314 (3.9)
connective tissue disorders
Myalgia 125 (3.1) 23 (0.6) 148 (1.8)
Arthralgia 42 (1.0) 21 (0.5) 63 (0.8)
Pain in extremity 33 (0.8) 10 (0.2) 43 (0.5)
Nervous system disorders 179 (4.4) 87 (2.2) 266 (3.3)
Headache 127 (3.1) 45 (1.1) 172 (2.1)
Gastrointestinal disorders 127 (3.1) 72 (1.8) 199 (2.5)
Diarrhea 49 (1.2) 26 (0.6) 75 (0.9)
Nausea 40 (1.0) 13 (0.3) 53 (0.7)
Source: FDA analysis.
Adverse events in any PT = at least one adverse event experienced (regardless of the MedDRA Preferred Term)
%: n/N. n = number of participants reporting at least 1 occurrence of the specified event.
of any event. N = number of participants in the specified group. This value is the denominator for the percentage calculations.
* Participants >16 years of age enrolled by October 9, 2020 and received at least 1 dose of vaccine or placebo.
Data analysis cutoff date: November 14, 2020.
FDA independently conducted standard MedDRA queries (SMQs) using FDA-developed
software (MAED) to evaluate for constellations of unsolicited adverse event preferred terms that
could represent various diseases and conditions, including but not limited to allergic, neurologic,
inflammatory, and autoimmune conditions. The SMQs, conducted on the Phase 2/3 all-enrolled
safety population, revealed a slight numerical imbalance of adverse events potentially
representing allergic reactions, with more participants reporting hypersensitivity-related adverse
events in the vaccine group (137 [0.63%]) compared with the placebo group (111 [0.51%]). No
imbalances between treatment groups were evident for any of the other SMQs evaluated.
During review of the EUA request, FDA became aware of two cases of anaphylactic reactions in
vaccine recipients during the start of the vaccination campaign in the United Kingdom following
authorization of the vaccine in that country (approximately 15,000 individuals vaccinated).
These reactions were reported to have occurred in the immediate post-vaccination period in
individuals with medical history of anaphylactic reactions and required treatment with
epinephrine. The component(s) of the vaccine that may have triggered these anaphylactic
reactions are unknown at this time, and the two individuals were not reported to have known
history of allergy to specific components of the vaccine. On further review of hypersensitivity-
related adverse events in the BNT162b development program, none occurred during the
immediate post-vaccination period, none required epinephrine treatment, and none were
otherwise classified as serious (i.e., no reported events of anaphylactoid reactions in the clinical
trials). Participants in clinical trials were excluded if they had a history of significant allergic
reaction to any vaccine or component of BNT162b but were not excluded for history of other
significant allergic reactions.
Immediate AEs (Phase 2/3 safety population)
The frequency of immediate AEs reported in the vaccine group was 0.4% after Dose 1 and
<0.3% after Dose 2 and were mainly consistent with solicited reactogenicity events. In both
study groups, the most frequently reported immediate AE was injection site pain (BNT162b2
vaccine 0.3%, placebo 0.2%). For both study groups, no participant reported an immediate
allergic reaction related to vaccination or to the saline placebo.
Study Withdrawals due to an AE (all-enrolled population)
Of 43,448 enrolled participants, 37 (0.2%) vaccine recipients and 30 (0.1%) placebo recipients
(0.1%), and no adolescents 16 to <18 years of age, withdrew from the study due to an AE. AEs
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in the SOC of General Disorders and Administration Site Conditions (7 vaccine, 3 placebo) was
common, with injection site pain the most frequent (2 vaccine, 0 placebo).
Serious adverse events
Deaths
A total of six (2 vaccine, 4 placebo) of 43,448 enrolled participants (0.01%) died during the
reporting period from April 29, 2020 (first participant, first visit) to November 14, 2020 (cutoff
date). Both vaccine recipients were >55 years of age; one experienced a cardiac arrest 62 days
after vaccination #2 and died 3 days later, and the other participant had pre-existing
atherosclerotic disease and baseline obesity and died 3 days after vaccination #1 The placebo
recipients died from myocardial infarction (n=1), hemorrhagic stroke (n=1) or unknown causes
(n=2); three of the four deaths occurred in the older group (>55 years of age). All deaths
represent events that occur in the general population of the age groups where they occurred, at
a similar rate.
Non-fatal SAEs
In the all-enrolled population of (total N=43,448), the proportions of participants who reported at
least 1 SAE during the time period from Dose 1 to the data cutoff date (November 14, 2020)
were 0.6% in the BNT162b2 vaccine group and 0.5% in the placebo group. The most common
SAEs in the vaccine group which were numerically higher than in the placebo group were
appendicitis (0.04%), acute myocardial infarction (0.02%), and cerebrovascular accident
(0.02%), and in the placebo arm numerically higher than in the vaccine arm were pneumonia
(0.03%), atrial fibrillation (0.02%), and syncope (0.02%). Occurrence of SAEs involving system
organ classes and specific preferred terms were otherwise balanced between treatment groups,
including no imbalance overall in cardiovascular serious adverse events.
Appendicitis was reported as a SAE for 12 participants, and numerically higher in the vaccine
group: 8 vaccine participants ([appendicitis [n=7], appendicitis perforated [n=1]) and 4 placebo
participants (appendicitis [n=2], appendicitis perforated [n=1], complicated appendicitis [n=1]).
All of the vaccine participants (n=8) and 2 placebo participants were younger than 65 years of
age. The cases were considered unrelated to vaccination by the study investigators and
occurred no more frequently than expected in the given age groups. FDA agrees that there is no
clear basis upon which to suspect that this imbalance represents a vaccine-related risk.
Three SAEs reported in the BNT162 group were considered by the investigator as related to
vaccine or vaccine administration: shoulder injury, ventricular arrhythmia, and
lymphadenopathy. The investigator and the sponsor thought that the shoulder injury was
related to vaccine administration. Two SAEs in the BNT162b2 group and none in the placebo
group were considered by the investigator, but not the Sponsor, as related to study vaccination:
ventricular arrhythmia in a participant with known cardiac conditions (n=1), and
lymphadenopathy temporally following vaccination (n=1). In FDA’s opinion following review of
the adverse event narratives, two of these events were considered as possibly related to
vaccine: shoulder injury possibly related to vaccine administration or to the vaccine itself, and
lymphadenopathy involving the axilla contralateral to the vaccine injection site. For
lymphadenopathy, the event was temporally associated and biologically plausible.
Among participants 16 to 17 years of age, there was 1 participant in the vaccine group who
experienced an SAE of facial bones fracture, which was not considered related to study
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intervention by the investigator.
Suspected COVID-19 Cases
As specified in the protocol, suspected cases of symptomatic COVID-19 that were not PCR-
confirmed were not recorded as adverse events unless they met regulatory criteria for
seriousness. Two serious cases of suspected but unconfirmed COVID-19 were reported, both in
the vaccine group, and narratives were reviewed. In one case, a 36-year-old male with no
medical comorbidities experienced fever, malaise, nausea, headache and myalgias beginning
on the day of Dose 2 and was hospitalized 3 days later for further evaluation of apparent
infiltrates on chest radiograph and treatment of dehydration. A nasopharyngeal PCR test for
SARS-CoV-2 was negative on the day of admission, and a chest CT was reported as normal.
The participant was discharged from the hospital 2 days after admission. With chest imaging
findings that are difficult to reconcile, it is possible that this event represented reactogenicity
following the second vaccination, a COVID-19 case with false negative test that occurred less
than 7 days after completion of the vaccination series, or an unrelated infectious process. In the
other case, a 66-year-old male with no medical comorbidities experienced fever, myalgias, and
shortness of breath beginning 28 days post-Dose 2 and was hospitalized one day later with
abnormal chest CT showing a small left-sided consolidation. He was discharged from the
hospital 2 days later, and multiple nasopharyngeal PCR tests collected over a 10-day period
beginning 2 days after symptom onset were negative. It is possible, though highly unlikely, that
this event represents a COVID-19 case with multiple false negative tests that occurred more
than 7 days after completion of the vaccination regimen, and more likely that it represents an
unrelated infectious process.
Among 3,410 total cases of suspected but unconfirmed COVID-19 in the overall study
population, 1,594 occurred in the vaccine group vs. 1816 in the placebo group. Suspected
COVID-19 cases that occurred within 7 days after any vaccination were 409 in the vaccine
group vs. 287 in the placebo group. It is possible that the imbalance in suspected COVID-19
cases occurring in the 7 days postvaccination represents vaccine reactogenicity with symptoms
that overlap with those of COVID-19. Overall though, these data do not raise a concern that
protocol-specified reporting of suspected, but unconfirmed COVID-19 cases could have masked
clinically significant adverse events that would not have otherwise been detected.
Subgroup Analyses
There were no specific safety concerns identified in subgroup analyses by age, race, ethnicity,
medical comorbidities, or prior SARS-CoV-2 infection, and occurrence of solicited, unsolicited,
and serious adverse events in these subgroups were generally consistent with the overall study
population.
Pregnancies
Female study participants of childbearing potential were screened for pregnancy prior to each
vaccination, with a positive test resulting in exclusion or discontinuation from study vaccination.
The study is collecting outcomes for all reported pregnancies that occur after vaccination, or
before vaccination and not detected by pre-vaccination screening tests. Twenty-three
pregnancies were reported through the data cut-off date of November 14, 2020, (12 vaccine, 11
placebo). Study vaccination occurred prior to the last menstrual period (LMP) in 6 participants (4
vaccine, 2 placebo), within 30 days after LMP in 10 participants (4 vaccine, 6 placebo), >30
days after LMP in 2 participants (0 vaccine, 2 placebo), and date of LMP not known in 5
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participants (4 vaccine, 1 placebo). Unsolicited AEs related to pregnancy include spontaneous
abortion and retained products of conception, both in the placebo group. Pregnancy outcomes
are otherwise unknown at this time.
Clinical laboratory evaluations
Clinical laboratory tests (hematology, chemistries) were assessed in study BNT162-01 and
C4591001 Phase 1. The only common laboratory abnormality reported throughout the studies
was transient decreases in lymphocytes 1-3 days after Dose 1, which increased in frequency
with increasing dose, were mostly Grade 1-2, generally normalized at the next laboratory
assessment 6-8 days after Dose 1 and did not occur after Dose 2. Among C4591001 Phase 1
participants who received the 30-ug dose of BNT162b2, transient decreases in lymphocytes
post-Dose 1 occurred in 5 of 12 participants 18-55 years of age and in 4 of 12 participants 65-85
years of age. These transient hematological changes were not associated with clinical
symptoms.
Safety summary
The information provided by the Sponsor was adequate for review and to make conclusions
about the safety of BNT162b2 in the context of the proposed indication and population for
intended use under EVA. The number of participants in the Phase 2/3 safety population
(N=37,586; 18,801 vaccine,18,785 placebo) meets the expectations described in FDA’s
Guidance on Development and Licensure of Vaccines to Prevent COVID-19 for efficacy, and
the median duration of at least 2 months follow-up after completion of the 2-dose primary
vaccination series meets the agency’s expectations described in FDA’s Guidance on its
Emergency Use Authorization for Vaccines to Prevent COVID-19. The all-enrolled population
contained more participants >16 years of age, regardless of duration of follow-up (43,448;
21,720 vaccine, 21,728 placebo). The demographic and baseline characteristics of the all-
enrolled population and the safety population were similar. Although the overall median duration
of follow-up in the all-enrolled population was less than 2 months, because the protocol was
amended to include subpopulations such as individuals with HIV and adolescents, the data from
both populations altogether provide a comprehensive summary of safety.
Local site reactions and systemic solicited events after vaccination were frequent and mostly
mild to moderate. 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%), 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 generally less frequent in adults 255
years of age ($2.8%) as compared to younger participants ($4.6%). Among adverse events of
special interest, which could be possibly related to vaccine, lymphadenopathy was reported in
64 participants (0.3%): 54 (0.5%) in the younger (16 to 55 years) age group; 10 (0.1%) in the
older (>55 years) age group; and 6 in the placebo group. The average duration of these events
was approximately 10 days, with 11 events ongoing at the time of the data cutoff. Bell’s palsy
was reported by four vaccine participants. From Dose 1 through 1 month after Dose 2, there
were three reports of Bell’s palsy in the vaccine group and none in the placebo group. This
observed frequency of reported Bell’s palsy is consistent with the expected background rate in
the general population. There were no other notable patterns or numerical imbalances between
treatment groups for specific categories of non-serious adverse events (including other
neurologic, neuro-inflammatory, and thrombotic events) that would suggest a causal relationship
to BNT162b2 vaccine.
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A total of six deaths occurred in the reporting period (2 deaths in the vaccine group, 4 in
placebo). In the vaccine group, one participant with baseline obesity and pre-existing
atherosclerosis died 3 days after Dose 1, and the other participant experienced cardiac arrest
60 days after Dose 2 and died 3 days later. Of the four deaths in the placebo arm, the cause
was unknown for two of them, and the other two participants died from hemorrhagic stroke
(n=1) and myocardial infarction (n=1), respectively; three deaths occurred in the older group
(>55 years of age). All deaths represent events that occur in the general population of the age
groups where they occurred, at a similar rate.
The frequency of non-fatal serious adverse events was low (<0.5%), without meaningful
imbalances between study arms. The most common SAEs in the vaccine arm which were
numerically higher than in the placebo arm were appendicitis (0.04%), acute myocardial
infarction (0.02%), and cerebrovascular accident (0.02%), and in the placebo arm numerically
higher than in the vaccine arm were pneumonia (0.03%), atrial fibrillation (0.02%), atrial
fibrillation (0.02%) and syncope (0.02%). Appendicitis was the most common SAE in the
vaccine arm. There were 12 participants with SAEs of appendicitis; 8 in the BNT162b2 group.
Of the 8 total appendicitis cases in the BNT162b2 group, 6 occurred in the younger (16 to 55
years) age group and 2 occurred in the older (>55 years) age group (one of the cases in the
older age group was perforated). One of the 6 participants with appendicitis in the younger age
group also had a peritoneal abscess. Cases of appendicitis in the vaccine group were not more
frequent than expected in the general population.
While not observed in the clinical trials, two anaphylactic reactions in the immediate post-
vaccination period have occurred with use of the vaccine in the United Kingdom, in individuals
reported to have prior history of anaphylactic reaction. The component(s) of the vaccine that
may have triggered these anaphylactic reactions are unknown at this time, and the two
individuals were not reported to have known history of allergy to specific components of the
vaccine.
4.3. Study BNT162-01
Design
Study BNT162-01 is an ongoing, first-in-human, Phase 1 dose-level finding study conducted in
Germany to evaluate the safety and immunogenicity of several different candidate vaccines,
including BNT162b2. Twelve adults 18 to 55 years of age received 30ug BNT162b2.
Secondary and exploratory objectives were specified to describe the immune response,
measured by functional antibody titer, antibody binding assay, and cell-mediated immune
responses (cytokines associated with Th1 and Th2 responses to assess for the induction of a
balanced versus Th1 or Th2 dominant immune response) at baseline and various time points
after vaccination, specifically 7 days post Dose 2. Adverse event monitoring was the same as in
study C4591001.
Results
No SAEs were reported in the BNT162-01 safety database included in the EUA submission, and
the safety profile for BNT162b2 in this study was similar to that in the much larger study,
C4591001.
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Evaluable ELISPOT data were available from 39 participants across dose levels of BNT162b2
(data cutoff date was September 17, 2020). Evaluable intracellular cytokine staining and FACS
data were available from 36 participants across dose levels of BNT162b2 (cutoff date was 04
September 2020). Data for serology results for serum neutralizing titers were available for 45
participants across dose levels of BNT162b2 (data cutoff date was September 18, 2020).
Most participants who received both doses of BNT162b2 had evidence of SARS-CoV-2 S$
protein-specific CD4+ (39/39, 100%) and CD8+ (35/39, 89.7%) T cell responses. These T cell
responses were directed against different parts of the antigen, including epitopes in the RBD,
indicating the induction of multi-epitope responses by BNT162b2. Functionality and polarization
of S-specific BNT162b2-induced SARS-CoV-2 T cells were assessed by intracellular
accumulation of cytokines IFNy, IL-2, and IL-4 measured after stimulation with overlapping
peptide pools representing the full-length sequence of the whole SARS-CoV-2 S protein. For
benchmarking, PBMC fractions from 15 convalescent patients with virologically confirmed
COVID-19 were used. The Th1 polarization of the T helper response was characterized by the
IFNy and IL-2 production, and only minor IL-4, production upon antigen-specific (SARS-CoV-2 S
protein peptide pools) re-stimulation. The SARS-CoV-2 neutralizing geometric mean titer
(GMTs) increased over baseline after Dose 1, with a boost effect after Dose 2 that was most
pronounced at the 30 yg dose level.
Thus, the immunogenicity results from Study BNT162-01 showed evidence of antibody-
mediated SARS-CoV-2 neutralization and a Th1 polarization in the cell-mediated cellular
immune responses in healthy adults 18 to 55 years of age, which supports the final dose
selection and prospect of benefit for the enrollment of larger numbers of participants in Study
C4591001.
5. FDA Review of Other Information Submitted in Support of the EUA
5.1. Sponsor’s Plans for Continuing Blinded, Placebo-Controlled Follow-Up
The Sponsor plans to offer vaccination to participants 216 years of age who originally received
placebo and who become eligible for receipt of BNT162b2 according to local or national
recommendations. The Sponsor proposes that these participants will be unblinded upon request
and will have the opportunity to receive BNT162b2 as part of the study. The Sponsor also
proposes that all placebo recipients =16 years of age will be offered BNT162b2 after
completing 6 months of follow-up after Dose 2, if they did not request and receive vaccine
previously. The participants will provide consent to receive vaccination and to continue follow-
up. For these participants, the Sponsor plans a total follow up period of 18 months, with one visit
1-month postvaccination and subsequent phone contacts at 1, 6, and 18 months
postvaccination. Safety and efficacy monitoring during this period will include collection of AEs,
SAEs, and screening and diagnosing COVID-19 cases.
5.2. Pharmacovigilance Activities
Pfizer submitted a Pharmacovigilance Plan (PVP) to monitor safety concerns that could be
associated with Pfizer-BioNTech COVID-19 Vaccine. The Sponsor identified vaccine-associated
enhanced disease including vaccine-associated enhanced respiratory disease as an important
potential risk. Use in pregnancy and lactation and vaccine effectiveness are areas the Sponsor
identified as missing information. In addition to the safety concerns specified by the Sponsor,
FDA requested that the Sponsor update their PVP to include anaphylaxis (including
anaphylactic reactions) as an important potential risk and missing information in pediatric
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participants less than 16 years of age. Division of Epidemiology recommendations are as
follows:
x Mandatory reporting by the Sponsor of the following events to Vaccine Adverse Event
Reporting System (VAERS) within 15 days:
– Vaccine administration errors whether or not associated with an adverse event
– Serious adverse events (irrespective of attribution to vaccination)
– Cases of Multisystem Inflammatory Syndrome in children and adults
– Cases of COVID-19 that result in hospitalization or death
x The Sponsor will conduct periodic aggregate review of safety data and submit periodic
safety reports at monthly intervals. Each periodic safety report is required to contain
descriptive information which includes:
– A narrative summary and analysis of adverse events submitted during the reporting
interval, including interval and cumulative counts by age groups, special populations
(e.g., pregnant women), and adverse events of special interest (AESIs)
– Newly identified safety concerns in the interval
– Actions taken since the last report because of adverse experiences (for example,
changes made to Vaccination Provider fact sheets, changes made to studies or
studies initiated)
x Pfizer, Inc. will conduct post-authorization observational studies to evaluate the association
between Pfizer-BioNTech COVID-19 Vaccine and a pre-specified list of AESIs, along with
deaths and hospitalizations, and severe COVID-19. The study population should include
individuals administered the authorized Pfizer-BioNTech COVID-19 Vaccine under this EUA
in the general US population (16 years of age and older), populations of interest such as
healthcare workers, pregnant women, immunocompromised individuals, and subpopulations
with specific comorbidities. The study should be conducted in large scale databases with an
active comparator. Pfizer, Inc. will provide protocols and status update reports to the IND
19736 with agreed-upon study designs and milestone dates. The Sponsor has proposed the
following three planned active surveillance studies:
– Study Protocol Number C4591008. The Sponsor proposes to survey 20,000 U.S.
health care workers enrolled in the COVID-19 HERO registry about AESI, and other
clinically significant events of interest after vaccination with the Pfizer-BioNTech
COVID-19 Vaccine. Incidence rates of these events in this cohort will be compared
to expected rates. The respondents will receive follow-up surveys for a 30-month
period.
– Study Protocol Number C4591011. This study is an active safety surveillance
evaluation conducted within the Department of Defense Health System Databases
using data derived from electronic health records and medical service claims among
covered U.S. military and their families. Rates of safety events of interest in
vaccinated subjects will be compared to unvaccinated comparators. The study will be
conducted for 30 months.
– Study Protocol Number C4591012. This study is an active surveillance study for
AESIs and other clinically significant events associated with the Pfizer-BioNTech
COVID-19 Vaccine using the Veteran’s Health Administration electronic medical
record database. Vaccinated subjects will be compared to unvaccinated subjects or
to recipients of seasonal influenza vaccine. The study will be conducted for 30
months.
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Of note, the Sponsor will submit plans for a clinical study to assess safety and
immunogenicity in pregnant women and has proposed active surveillance studies
designed to monitor vaccination during pregnancy within populations expected to receive
the vaccine under EVA.
e Mandatory reporting by vaccination providers to VAERS for the following events:
-— Vaccine administration errors whether or not associated with an adverse event
- Serious adverse events (irrespective of attribution to vaccination)
-— Cases of Multisystem Inflammatory Syndrome in children and adults
- Cases of COVID-19 that result in hospitalization or death
e Active surveillance of vaccine recipients via the v-safe program. V-safe is a new
smartphone-based opt-in program that uses text messaging and web surveys from CDC to
check in with vaccine recipients for health problems following COVID-19 vaccination. The
system also will provide telephone follow-up to anyone who reports medically significant
(important) adverse events. Responses indicating missed work, inability to do normal daily
activities, or that the recipient received care from a doctor or other healthcare professional
will trigger the VAERS Call Center to reach out to the participant and collect information for
a VAERS report, if appropriate.
5.3. Non-Clinical Studies
Toxicology studies
To support their EUA request, Pfizer submitted the following general toxicology studies:
e Repeat-dose toxicity study of three LNP-formulated RNA platforms encoding for viral
proteins by repeated intramuscular administration to Wistar Han rats. Study number: 38166.
Reviewed under IND 19736 amendments 0 and 32.
e 17-day intramuscular toxicity study of BNT162B2 (V9) and BNT162B3C In Wistar Han rats
with a 3-week recovery. Study number: 20GR142. Reviewed under IND 19736 amendment
141.
Based on nonclinical toxicity assessments, there are no significant safety issues to report.
The following DART study is still in progress and will be reviewed when submitted:
Combined Fertility and Developmental Study (Including Teratogenicity and Postnatal
Investigations) of BNT162b1, BNT162b2 and BNT162b3 by the Intramuscular Route in the
Wistar Rat.
Other non-clinical studies
Several nonclinical studies in mice and rhesus macaques were conducted to support the safety
and efficacy of BNT162b2. BNT162b2 was highly immunogenic in mice with strong antigen-
binding IgG and high titer neutralizing antibody responses together with a Th1-phenotype CD4+
response, as well as an IFNy+, IL-2+, CD8+ T-cell response, after a single immunization.
BNT162b2 was also assessed for immunogenicity and for protection against an infectious
SARS-CoV-2 challenge in rhesus macaques. Rhesus macaques immunized intramuscularly
had readily detectable S1-binding IgG and SARS-CoV-2 neutralizing titers (NT50) as early as 14
days after a single immunization, with substantial increases following the second immunization.
Animals were challenged with 1.05x10° plaque forming units of SARS-CoV-2 (strain USA-
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qualified. The summaries of the qualification results demonstrate precision, accuracy,
sensitivity, specificity, and reproducibility for each evaluated analytical assay, indicating that
they are suitable for the intended use.
The manufacture of the Pfizer-BioNTech COVID-19 Vaccine is performed at a number of
facilities. For each of these facilities, FDA requested and reviewed information on equipment,
facilities, quality systems and controls, container closure systems as well as other information
as per the guidance, “Emergency Use Authorization for Vaccines to Prevent COVID-19, October
2020”, to ensure that there is adequate control of the manufacturing processes and facilities.
In particular, the following information was assessed:
x Facilities appear to be adequately designed and maintained and manufacturing process,
personnel, air direction and waste flow are suitable for manufacturing.
x Multiple product manufacturing areas and equipment used to manufacture the COVID-
19 vaccine were assessed and cleaning and changeover procedures were evaluated
and appear adequate. Cross-contamination controls appear suitable to mitigate risk of
cross contamination.
x The successful qualification of critical equipment for drug substance and drug product
manufacturing was verified.
x Aseptic process information and validation studies were assessed and appear
acceptable.
x Drug product solution sterilization by filtration was reviewed and appears acceptable.
x Sterilization and depyrogenation of pertinent equipment and materials, including
container/closure components, description and validation studies appear acceptable.
x Utilities qualification studies including HVAC systems, appear adequate. Air cleanliness
of the manufacturing cleanrooms were adequately controlled and maintained.
x Container/closure integrity studies to ensure sterility of drug product in the final container
were conducted and appear adequate.
FDA also reviewed the inspectional histories of each facility in addition to all available
information to ascertain whether each facility meets current good manufacturing practice
requirements. We find that all the facilities are adequate to support the use of the Pfizer-
BioNTech COVID-19 Vaccine under an Emergency Use Authorization.
5.5. Clinical Assay Information
Two clinical diagnostic assays (Cepheid Xpert Xpress RT-PCR assay for the detection of
SARS-CoV-2 in clinical specimens and Roche Elecsys Anti-SARS-CoV-2 assay for the
evaluation of serostatus to SARS-CoV-2) were used to assess clinical endpoints. Both assays
have received FDA authorization under EUA. The Cepheid Xpert Xpress RT-PCR assay is used
to assess viral infection of the subjects before vaccination and to confirm COVID-19 cases
during study follow-up. The Roche Elecsys Anti-SARS-CoV-2 assay is used to assess
serostatus of the subjects before vaccination. Data were submitted to support the suitability of
both the Cepheid Xpert Xpress assay and the Roche Elecsys Anti-SARS-CoV-2 assay for their
intended use in Phase 2/3 clinical studies when performed at Pfizer’s testing facility (Pfizer
Vaccine Research and Development; Pearl River, NY).
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5.6. Inspections of Clinical Study Sites
Bioresearch Monitoring (BIMO) inspections were conducted at six domestic clinical investigator
sites participating in the conduct of study protocol C4591001. Based on the preliminary review
of the inspection reports, the inspections did not reveal problems impacting the data submitted
in support of this EUA.
5.7. EUA Prescribing Information and Fact Sheets
The Prescribing Information, Fact Sheet for Health Care Providers, Fact Sheet for Recipients
were reviewed, and suggested revisions sent to the sponsor. The revised Fact Sheets are
accurate, not misleading, and appropriate for the proposed use of the product under EUA.
6. Benefit/Risk Assessment in the Context of Proposed Indication and Use Under EUA
6.1. Known Benefits
The known benefits among recipients of the proposed vaccine relative to placebo are:
x Reduction in the risk of confirmed COVID-19 occurring at least 7 days after Dose 2
x Reduction in the risk of confirmed COVID-19 after Dose 1 and before Dose 2
x Reduction in the risk of confirmed severe COVID-19 any time after Dose 1
The protocol-specified 2-dose vaccination regimen was highly effective in preventing PCR-
confirmed COVID-19 occurring at least 7 days after completion of the vaccination regimen.
Additional primary efficacy analyses in the all-available efficacy population, including
participants who had protocol violations, showed consistency with outcomes in the primary
analysis population. Efficacy findings were also consistent across various subgroups, including
racial and ethnic minorities, participants aged 65 years and older, and those with one or more of
the following conditions: obesity, diabetes, hypertension, and chronic cardiopulmonary
diseases.
Among participants with no evidence of COVID-19 prior to vaccination, the vaccine was
effective in reducing the risk of COVID-19 and severe COVID-19 after Dose 1. Fewer severe
cases were also observed in the vaccine recipients relative to recipients of placebo during the
follow up period after Dose 1. The findings post Dose 1, from a post-hoc analysis, cannot be the
basis to assess the potential efficacy of the vaccine when administered as a single dose
because the period of observation is limited by the fact that most participants received a second
dose three weeks after the first one.
6.2. Unknown Benefits/Data Gaps
Duration of protection
As the interim and final analyses have a limited length of follow-up, it is not possible to assess
sustained efficacy over a period longer than 2 months.
Effectiveness in certain populations at high-risk of severe COVID-19
Although the proportion of participants at high risk of severe COVID-19 is adequate for the
overall evaluation of safety in the available follow-up period, the subset of certain groups such
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as immunocompromised individuals (e.g., those with HIV/AIDS) is too small to evaluate efficacy
outcomes.
Effectiveness in individuals previously infected with SARS-CoV-2
The primary endpoint was evaluated in individuals without prior evidence of COVID-19 disease,
and very few cases of confirmed COVID-19 occurred among participants with evidence of
infection prior to vaccination. Therefore, available data are insufficient to make conclusions
about benefit in individuals with prior SARS-CoV-2 infection. However, available data, while
limited, do suggest that previously infected individuals can be at risk of COVID-19 (i.e.,
reinfection).
Effectiveness in pediatric populations
The representation of pediatric participants in the study population is too limited to adequately
evaluate efficacy in pediatric age groups younger than 16 years. No efficacy data are available
from participants ages 15 years and younger. Although adolescents 16 to 17 years of age were
included in the overall efficacy analysis, only one confirmed COVID-19 case was reported in this
age group. However, it is biologically reasonable to extrapolate that effectiveness in ages 16 to
17 years would be similar to effectiveness in younger adults. Efficacy surveillance continued
beyond November 14, 2020, and the Sponsor has represented that additional data will be
provided in a BLA.
Future vaccine effectiveness as influenced by characteristics of the pandemic, changes
in the virus, and/or potential effects of co-infections
The study enrollment and follow-up occurred during the period of July 27 to November 14, 2020,
in various geographical locations. The evolution of the pandemic characteristics, such as
increased attack rates, increased exposure of subpopulations, as well as potential changes in
the virus infectivity, antigenically significant mutations to the S protein, and/or the effect of co-
infections may potentially limit the generalizability of the efficacy conclusions over time.
Continued evaluation of vaccine effectiveness following issuance of an EUA and/or licensure
will be critical to address these uncertainties.
Vaccine effectiveness against asymptomatic infection
Data are limited to assess the effect of the vaccine against asymptomatic infection as measured
by detection of the virus and/or detection of antibodies against non-vaccine antigens that would
indicate infection rather than an immune response induced by the vaccine. Additional
evaluations will be needed to assess the effect of the vaccine in preventing asymptomatic
infection, including data from clinical trials and from the vaccine’s use post-authorization.
Vaccine effectiveness against long-term effects of COVID-19 disease
COVID-19 disease may have long-term effects on certain organs, and at present it is not
possible to assess whether the vaccine will have an impact on specific long-term sequelae of
COVID-19 disease in individuals who are infected despite vaccination. Demonstrated high
efficacy against symptomatic COVID-19 should translate to overall prevention of COVID-19-
related sequelae in vaccinated populations, though it is possible that asymptomatic infections
may not be prevented as effectively as symptomatic infections and may be associated with
sequelae that are either late-onset or undetected at the time of infection (e.g., myocarditis).
Additional evaluations will be needed to assess the effect of the vaccine in preventing long-term
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effects of COVID-19, including data from clinical trials and from the vaccine’s use post-
authorization.
Vaccine effectiveness against mortality
A larger number of individuals at high risk of COVID-19 and higher attack rates would be
needed to confirm efficacy of the vaccine against mortality. However, non-COVID vaccines
(e.g., influenza) that are efficacious against disease have also been shown to prevent disease-
associated death.12-15 Benefits in preventing death should be evaluated in large observational
studies following authorization.
Vaccine effectiveness against transmission of SARS-CoV-2
Data are limited to assess the effect of the vaccine against transmission of SARS-CoV-2 from
individuals who are infected despite vaccination. Demonstrated high efficacy against
symptomatic COVID-19 may translate to overall prevention of transmission in populations with
high enough vaccine uptake, though it is possible that if efficacy against asymptomatic infection
were lower than efficacy against symptomatic infection, asymptomatic cases in combination with
reduced mask-wearing and social distancing could result in significant continued transmission.
Additional evaluations including data from clinical trials and from vaccine use post-authorization
will be needed to assess the effect of the vaccine in preventing virus shedding and
transmission, in particular in individuals with asymptomatic infection.
6.3. Known Risks
The vaccine has been shown to elicit increased local and systemic adverse reactions as
compared to those in the placebo arm, usually 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%), fever (14.2%). Adverse reactions
characterized as reactogenicity were generally mild to moderate. The number of subjects
reporting hypersensitivity-related adverse events was numerically higher in the vaccine group
compared with the placebo group (137 [0.63%] vs. 111 [0.51%]). Severe adverse reactions
occurred in 0.0-4.6% of participants, were more frequent after Dose 2 than after Dose 1 and
were generally less frequent in older adults (>55 years of age) (<2.8%) as compared to younger
participants (4.6%). Among reported unsolicited adverse events, lymphadenopathy occurred
much more frequently in the vaccine group than the placebo group and is plausibly related to
vaccination.
Serious adverse events, while uncommon (<1.0%), represented medical events that occur in
the general population at similar frequency as observed in the study. Three SAEs in the
BNT162b2 group were considered related by the investigator, but not the Sponsor, as related to
study vaccination: shoulder injury (n=1), ventricular arrhythmia in a participant with known
cardiac conditions (n=1), and lymphadenopathy temporally related following vaccination (n=1).
We considered two of the events as possibly related to vaccine: the shoulder injury possibly due
to vaccine administration or the vaccine itself and lymphadenopathy. Lymphadenopathy was
temporally associated and biologically plausible.
No specific safety concerns were identified in subgroup analyses by age, race, ethnicity,
medical comorbidities, or prior SARS-CoV-2 infection. Although participants 16 to 17 years of
age were enrolled in the Phase 3 trial, safety data for this age group is limited. However,
available data are consistent with the safety profile in the adult population, and it is biologically
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reasonable to extrapolate the greater safety experience in adults, in particular younger adults, to
the oldest pediatric age group of 16 to 17 years.
While not observed in the clinical trials, two anaphylactic reactions in the immediate post-
vaccination period have occurred with use of the vaccine in the United Kingdom, in individuals
reported to have prior history of anaphylactic reaction. The component(s) of the vaccine that
may have triggered these anaphylactic reactions are unknown at this time, and the two
individuals were not reported to have known history of allergy to specific components of the
vaccine. Risk of allergic reactions, including the potential for severe allergic reactions and the
need for vaccine providers to be able to manage them should they occur and a contraindication
for use in individuals with known allergy to any component of the vaccine, are described in the
vaccine Fact Sheets and Prescribing Information. Additionally, risk of anaphylaxis will be further
evaluated as part of the pharmacovigilance plan for the vaccine.
6.4. Unknown Risks/Data Gaps
Safety in certain subpopulations
There are currently insufficient data to make conclusions about the safety of the vaccine in
subpopulations such as children less than 16 years of age, pregnant and lactating individuals,
and immunocompromised individuals.
Adverse reactions that are very uncommon or that require longer follow-up to be
detected
Following authorization of the vaccine, use in large numbers of individuals may reveal
additional, potentially less frequent and/or more serious adverse events not detected in the trial
safety population of nearly 44,000 participants over the period of follow up at this time. Active
and passive safety surveillance will continue during the post authorization period to detect new
safety signals.
A numerically greater number of appendicitis cases occurred in the vaccine group but occurred
no more frequently than expected in the given age groups and do not raise a clear concern at
this time for a causal relationship to study vaccination. Although the safety database revealed
an imbalance of cases of Bell’s palsy (4 in the vaccine group and none in the placebo group),
causal relationship is less certain because the number of cases was small and not more
frequent than expected in the general population. Further signal detection efforts for these
adverse events will be informative with more widespread use of the vaccine.
Vaccine-enhanced disease
Available data do not indicate a risk of vaccine-enhanced disease, and conversely suggest
effectiveness against severe disease within the available follow-up period. However, risk of
vaccine-enhanced disease over time, potentially associated with waning immunity, remains
unknown and needs to be evaluated further in ongoing clinical trials and in observational studies
that could be conducted following authorization and/or licensure.
7. VRBPAC Meeting Summary
The Vaccines and Related Biological Products Advisory Committee (VRBPAC) convened on
December 10, 2020, to discuss Pfizer’s EUA request. The meeting agenda included: an
overview by FDA on EUA and considerations specific to COVID-19 vaccines; updates from
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CDC on COVID-19 epidemiology, plans for further evaluation of vaccine safety and
effectiveness monitoring during use under an EUA, and operational distribution plans; a
presentation on conduct of placebo-controlled studies in the event that a vaccine becomes
available under EUA; a public comment period; presentations of data from studies of the Pfizer-
BioNTech COVID-19 Vaccine by representatives of Pfizer, an FDA presentation of its
independent review of the data submitted in support of the EUA request, and a discussion and
vote by the VRBPAC.
The VRBPAC was asked to discuss the following points, with no vote:
x Pfizer has proposed a plan for continuation of blinded, placebo-controlled follow-up in
ongoing trials if the vaccine were made available under EUA. Please discuss Pfizer’s plan,
including how loss of blinded, placebo-controlled follow-up in ongoing trials should be
addressed.
x Please discuss any gaps in plans described today and in the briefing documents for further
evaluation of vaccine safety and effectiveness in populations who receive the Pfizer-
BioNTech Vaccine under an EUA.
The committee discussed potential implications of loss of blinded, placebo-controlled follow-up
in ongoing trials including how this may impact availability of safety data to support a biologics
license application. Some pointed out the importance of long-term safety data for the Pfizer-
BioNTech COVID-19 Vaccine as it is made using a technology not used in previously licensed
vaccines. In response to the question whether the ongoing Phase 3 study would still be
sufficiently powered if eligible placebo recipients would be vaccinated, Pfizer asserted that even
with an anticipated loss of placebo-controlled follow-up of 20%, the study would maintain
adequate statistical power and would be positioned to accrue additional data on vaccine
efficacy, including efficacy against severe disease, as well as safety, although unblinding of the
study would reduce interpretability of results. It was pointed out that non-random loss of
placebo recipients from the study, as would be expected when unblinded placebo recipients
would receive vaccination based on Advisory Committee on Immunization Practices (ACIP)
recommendations, would further reduce interpretability of results. There was also discussion of
a blinded trial design proposed by Dean Follman, Ph.D. of NIH in which duration of efficacy
would be compared in clinical trial participants originally vaccinated with the vaccine to those
later administered the vaccine as part of a planned cross-over. Pfizer stated that this design was
considered but would present logistical challenges including the need for reconsenting subjects
and additional study visits.
The lack of data on how the vaccine impacts asymptomatic infection and viral shedding was
also pointed out and that this should be addressed prior to study unblinding. Other committee
members were concerned about limited data available in certain subpopulations such as HIV-
infected individuals, individuals with prior exposure to SARS-CoV-2 and certain demographic
groups.
The committee inquired about information regarding anaphylactoid reactions occurring in 2
individuals vaccinated with the Pfizer-BioNTech vaccine in the UK. Pfizer briefly summarized the
available information, i.e., the two cases of anaphylactoid reactions were in individuals with a
strong past history of allergic reactions both of whom carried an epinephrine auto injector.
These individuals developed symptoms of anaphylactoid reaction shortly after receiving the
vaccine. Both recovered after appropriate treatment. FDA referred to its analysis of safety data
derived from the ongoing pivotal trial that excluded subjects with allergic reactions to previous
vaccine administrations but did not exclude subjects with non-vaccine related allergies. A slight
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numerical imbalance of adverse events potentially representing allergic reactions, with more
participants reporting hypersensitivity-related adverse events in the vaccine group compared
with the placebo group (137 vs. 111). None of these were considered to be serious, and none of
these events occurred in the immediate post-vaccination period. FDA noted that the fact sheet
and prescribing information for Pfizer-BioNTech COVID-19 vaccine will include information
under the contraindications section that the vaccine should not be administered to individuals
with known history of a severe allergic reaction to any component of the vaccine. Under the
warning section, there will be a statement that appropriate medical treatment used to manage
immediate allergic reactions must be immediately available in the event an acute anaphylactic
reaction occurs following administration of Pfizer-BioNTech COVID-19 Vaccine.
Following this discussion, the VRBPAC was asked to vote on whether, based on the totality of
scientific evidence available, the benefits of the Pfizer-BioNTech COVID-19 Vaccine outweigh
its risks for use in individuals 16 years of age and older.
In reference to the voting question, and prior to the committee members casting their votes
committee members asked FDA’s perspective on use of the vaccine in pregnancy. FDA
explained that data from the preclinical developmental and reproductive toxicity study for this
product are expected soon. Even though there are insufficient data to inform vaccine-associated
risks in pregnancy, there are also no data warranting a contraindication. Some committee
members expressed concerns about including adolescents 16 and 17 years of age in the
indication for the vaccine because of the limited amount of safety and efficacy data available in
this population. Other committee members encouraged authorization of the vaccine under EUA
in adolescents because this would support initiating pediatric clinical trials and because benefits
would be expected to outweigh any theoretical risks in this population. Inclusion of vaccines
against COVID-19 in the pediatric vaccination schedule will ultimately likely be needed to
increase the uptake of the vaccine and to reach herd immunity. Pfizer is planning studies in
pediatric subjects using an age-stratified step-down approach. Some committee members
raised concerns about the small number of severe COVID-19 cases and limited conclusions
about the prevention of severe disease based on the study endpoints. FDA pointed out that
vaccine development has a long history and that FDA is not aware of an example of any
vaccine that is effective against mild disease that is not also effective against severe disease
and that even though limited, data for Pfizer-BioNTech COVID-19 Vaccine suggest efficacy
against severe disease.
The results of the vote were as follows: Yes = 17, No = 4, Abstain = 1. Thus, the committee
voted in favor of a determination that based on the totality of scientific evidence available, the
benefits of the Pfizer-BioNTech COVID-19 Vaccine outweigh its risks for use in individuals 16
years of age and older.
8. Overall Summary and Recommendation
Following review of information submitted in support of the EUA request and considering
VRBPAC recommendations from the December 10, 2020 meeting, the review team concludes
that:
x As summarized in Section 2 of this review, the chemical, biological, radiological, or
nuclear (CBRN) agent referred to in the March 27, 2020 EUA declaration by the
Secretary of HHS (SARS-CoV-2) can cause a serious or life-threatening disease or
condition.
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e Based on the totality of scientific evidence available, including data from adequate and
well-controlled trials described in Section 4 of this review, it is reasonable to believe that
the Pfizer-BioNTech COVID-19 vaccine (BNT162b2) may be effective in preventing such
serious or life-threatening disease or condition that can be caused by SARS-CoV-2. In
the planned final primary efficacy analysis of an ongoing randomized, blinded, placebo-
controlled Phase 1/2/3 clinical trial, vaccine efficacy after 7 days post Dose 2 was 95%,
(95% Cl 90.3; 97.6) in participants without prior evidence of SARS-CoV-2 infection and
>94% in the larger group of participants with or without prior infection. Efficacy outcomes
were consistently robust (293%) across demographic subgroups. Secondary and post-
hoc efficacy analyses also suggested efficacy against severe COVID-19, efficacy
against COVID-19 in the time period between Dose 1 and Dose 2, and against COVID-
19 in subjects with evidence of SARS-CoV-2 vaccination prior to vaccination.
e Based on the data summarized in Sections 4 and 5 of this review and assessment of
benefits and risks in Section 6 of this review, the known and potential benefits of the
vaccine outweigh the known and potential risks of the vaccine when used for active
immunization to prevent COVID-19 caused by SARS-CoV-2 in individuals 16 years of
age and older. Known benefits include reduction in the risk of confirmed COVID-19
occurring at least 7 days after Dose 2, reduction in the risk of confirmed COVID-19 after
Dose 1 and before Dose 2, and reduction in the risk of confirmed severe COVID-19 any
time after Dose 1. Potential benefits that could be further evaluated but are not
necessary to support an EUA include prevention of COVID-19 in individuals with
previous SARS-CoV-2 infection, prevention of mortality and long-term complications of
COVID-19, reduction in asymptomatic SARS-CoV-2 infection and reduction of SARS-
CoV-2 transmission. Known risks include common local and systemic adverse reactions
(notably injection site reactions, headache, fever, chills, myalgia, and fatigue, all of which
are usually mild to moderate and lasting a few days, with higher frequency in younger
vaccine recipients compared with older vaccine recipients) and less commonly
lymphadenopathy and allergic reactions. Potential risks that should be further evaluated
include uncommon to rare clinically significant adverse reactions that may become
apparent with more widespread use of the vaccine and with longer duration of follow-up
(including further evaluation of risk of Bell’s palsy and allergic reactions following
vaccination), risks associated with vaccination of specific populations such as children
younger than 16 years of age and pregnant and breastfeeding women, and whether
vaccine-enhanced disease could occur with waning of immunity.
e As summarized in Section 2 of this review, there is no adequate, approved, and
available alternative to the product to prevent COVID-19 caused by SARS-CoV-2 in
individuals 16 years of age and older.
The review team therefore recommends issuance of an EVA for use of the Pfizer-BioNTech
COVID-19 Vaccine for active immunization to prevent COVID-19 caused by SARS-CoV-2 in
individuals 16 years of age and older.
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9. References
1. Zhu N, Zhang D, Wang W, et al. A Novel Coronavirus from Patients with Pneumonia in
China, 2019. The New England journal of medicine. 2020;382(8):727-733.
2. Coronaviridae Study Group of the International Committee on Taxonomy of V. The
species Severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV
and naming it SARS-CoV-2.
3. Lu R, Zhao X, Li J, et al. Genomic characterisation and epidemiology of 2019 novel
coronavirus: implications for virus origins and receptor binding. Lancet (London,
England). 2020;395(10224):565-574.
4. Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 Cell Entry Depends on
ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell.
2020;181(2):271-280.e278.
5. Federal Food, Drug and Cosmetic Act, 21 U.S.C. § 360bbb–3 and 360bbb-3b. (2011).
6. FDA. Guidance for Industry: Development and Licensure of Vaccines to Prevent COVID-
19. June 2020. https://www.fda.gov/regulatory-information/search-fda-guidance-
documents/development-and-licensure-vaccines-prevent-covid-19.
7. National Vaccine Injury Compensation Program. Vaccine Injury Table, Revised and
Effective March 21, 2017. https://www.hrsa.gov/sites/default/files/hrsa/vaccine-
compensation/vaccine-injury-table.pdf.
8. International Coalition of Medicines Regulatory Authorities. Statement on continuation of
vaccine trials. http://www.icmra.info/drupal/en/covid-
19/statement on continuation of vaccine trials. 2020.
9. Krause PR, Fleming TR, Longini IM, et al. Placebo-Controlled Trials of Covid-19
Vaccines - Why We Still Need Them. The New England journal of medicine. 2020.
10. Wendler D, Ochoa J, Millum J, Grady C, Taylor HA. COVID-19 vaccine trial ethics once
we have efficacious vaccines. Science. 2020:eabf5084.
11. Roush SW, Murphy TV, Vaccine-Preventable Disease Table Working Group, the.
Historical Comparisons of Morbidity and Mortality for Vaccine-Preventable Diseases in
the United States. JAMA. 2007;298(18):2155-2163.
12. Verhees RAF, Dondorp W, Thijs C, Dinant GJ, Knottnerus JA. Influenza vaccination in
the elderly: Is a trial on mortality ethically acceptable? Vaccine. 2018;36(21):2991-2997.
13. Flannery B, Reynolds SB, Blanton L, et al. Influenza Vaccine Effectiveness Against
Pediatric Deaths: 2010–2014. 2017;139(5):e20164244.
14. Rolfes MA, Flannery B, Chung JR, et al. Effects of Influenza Vaccination in the United
States During the 2017-2018 Influenza Season. Clinical infectious diseases : an official
publication of the Infectious Diseases Society of America. 2019;69(11):1845-1853.
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10. Appendix A. Charlson Comorbidity Index
This index is based on a list of 19 conditions identified from diagnoses in hospital and physician
data. Each condition is assigned a weight from 1 to 6. The index score is the sum of the weights
for all identified conditions (Charlson et al., 1987). An index score of 0 indicates no comorbid
conditions, while higher scores indicate a greater level of comorbidity.
Charlson Index Diagnoses: Cancer, Chronic Pulmonary Disease, Diabetes without
Complications, Congestive Heart Failure, Cerebrovascular Disease, Dementia, Renal Disease,
Peripheral Vascular Disease, Myocardial Infarction, Diabetes with Complications, Paraplegia
and Hemiplegia, Connective Tissue Disease-Rheumatic Disease, Peptic Ulcer Disease, Mild
Liver Disease, Metastatic Carcinoma, Moderate or Severe Liver Disease,
/AIDS.
Reference: Charlson ME, Pompei P, Ales KL, et al. A new method of classifying prognostic
comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987; 40(5):373–
383. [PubMed: 3558716]
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