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Clinical Reviewer: Susan K. Wollersheim, MD
STN:125742/45
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sBLA Clinical Review Memorandum
Application Type Supplemental Biologics License Application
(sBLA )
STN 125742/45
CBER Received Date December 16, 2021
PDUFA Goal Date June 17, 2022
Division / Office DVRPA / OVRR
Priorit y Review (Yes/No ) Yes
Reviewer Name
Susan K. Wollersheim, MD
Review Completion Date /
Stamped Date July 8, 2022
Supervisory Concurrence
Lucia Lee, M.D.; Team Leader
CRB1/DVRPA/OVRR
Maria Allende, M.D.; Chief,
CRB1/DVRPA/OVRR
Applicant BioNTech Manufacturing GmbH (in partnership
with Pfizer, Inc. )
Established Name COVID-19 Vaccine, mRNA
(Proposed ) Trade Name Comirnat y
Pharmacolo gic Class Vaccine
Formulation, including Adjuvants Each 0.3 mL dose contains 30 ȝJ modified
mRNA encoding SARS-CoV-2 spike
glycoprotein, encapsulated in lipid nanoparticles
(LNP)
Dosage Form and Route of
Administration Suspension for intramuscular injection
Dosin g Regimen Two 0.3 mL doses, 3 weeks apart
Indication(s) and Intended
Population(s) Active immunization to prevent coronavirus
disease 2019 (COVID-19) caused by severe
acute respiratory sy ndrome coronavirus 2
(SARS-CoV-2) in individuals 12 through 15
years of age
Orphan Desi gnated (Yes/No ) No
Clinical Reviewer: Susan K. Wollersheim, MD
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TABLE OF CONTENTS
GLOSSARY ....................................................................................................................... 4
1. EXECUTIVE SUMMARY ................................................................................................... 5
1.1 Demographic Information: Subgroup Demographics and Analysis Summary.................... 7
1.2 Patient Experience Data ................................................................................................... .. 8
2. CLINICAL AND REGULATORY BACKGROUND ................................................................... 8
2.1 Disease or Health-Related Condition(s) Studied ................................................................ 8
2.2 Currently Available, Pharmacologically Unrelated Treatment(s)/Intervention(s) for the
Proposed Indication(s) ...................................................................................................... 10
2.3 Safety and Efficacy of Pharmacologically Related Products ............................................ 11
2.4 Previous Human Experience with the Pr oduct (Including Foreign Experience) ............... 12
2.5 Summary of Pre- and Post-submission Regulatory Activity Related to the Submission .. 13
2.6 Other Relevant Background Information........................................................................... 13
3. SUBMISSION QUALITY AND GOOD CLINICAL PRACTICES ............................................... 14
3.1 Submission Quality and Completeness ............................................................................ 14
3.2 Compliance With Good Clinical Prac tices And Submission Integrity ............................... 14
3.3 Financial Disclosures ..................................................................................................... ... 14
4. SIGNIFICANT EFFICACY /SAFETY ISSUES RELATED TO OTHER REVIEW DISCIPLINES ........ 15
4.1 Chemistry, Manufacturi ng, and Controls .......................................................................... 15
4.2 Assay Validation ................................................................................................................ 15
4.3 Nonclinical Pharmaco logy/Toxicology .............................................................................. 15
4.5 Statistical ............................................................................................................... ............ 15
4.6 Pharmacovigilance ......................................................................................................... ... 16
4.7 Risk-Benefit Assessment .................................................................................................. 16
5. SOURCES OF CLINICAL DATA AND OTHER INFORMATION CONSIDERED IN THE REVIEW ... 16
5.1 Review Strategy ........................................................................................................... ..... 16
5.2 BLA/IND Documents That Serve as the Basis for the Clinical Review ............................. 17
5.3 Overview of Clinical Studies ............................................................................................. 18
5.4 Consultations ............................................................................................................. ....... 18
5.4.1 Advisory Committee Meeting................................................................................... 18
5.5 Literature Reviewed ....................................................................................................... ... 18
6. DISCUSSION OF INDIVIDUAL STUDIES /CLINICAL TRIALS ................................................. 21
6.1 Study C4591001 ............................................................................................................ ... 21
6.1.1 Objectives and Endpoints ........................................................................................ 21
6.1.2 Design Overview ..................................................................................................... 22
6.1.3 Population .............................................................................................................. .. 23
6.1.4 Study Treatments or Agents Mandated by the Protocol ......................................... 23
6.1.5 Directions for Use .................................................................................................... 2 4
6.1.6 Sites and Centers .................................................................................................... 24
6.1.7 Surveillance/Monitoring ........................................................................................... 24
6.1.8 Endpoints and Criteria for Study Success ............................................................... 25
6.1.9 Statistical Considerations & Statistical An alysis Plan ............................................. 25
6.1.10 Study Population and Disposition .......................................................................... 25
6.1.11 Vaccine Effectiveness ........................................................................................... 34
6.1.12 Safety Analyses ..................................................................................................... 40
6.1.13 Study Summary and Conclusions ......................................................................... 51
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7. INTEGRATED OVERVIEW OF EFFICACY .......................................................................... 51
8. INTEGRATED OVERVIEW OF SAFETY ............................................................................. 51
9. ADDITIONAL CLINICAL ISSUES ..................................................................................... 51
9.1 Special Populations........................................................................................................ ... 51
9.1.1 Human Reproduction and Pregnancy Data............................................................. 51
9.1.2 Use During Lactation ............................................................................................... 52
9.1.3 Pediatric Use and PREA Considerations ................................................................ 52
9.1.4 Immunocompromised Individuals ............................................................................ 52
9.1.5 Geriatric Use ........................................................................................................... . 52
10. CONCLUSIONS .......................................................................................................... 52
11. RISK-BENEFIT CONSIDERATIONS AND RECOMMENDATIONS ......................................... 54
11.1 Risk-Benefit Considerations ............................................................................................ 5 4
11.2 Risk-Benefit Summary and Assessment......................................................................... 58
11.3 Discussion of Regu latory Options ................................................................................... 59
11.4 Recommendations on Regu latory Actions ...................................................................... 60
11.5 Labeling Review and Recommendations ....................................................................... 60
11.6 Recommendations on Postmarketing Actions ................................................................ 60
APPENDIX A CHARLSON COMORBIDITY INDEX .................................................................. 60
APPENDIX B COVID-19 AND SEVERE COVID-19 CASE DEFINITIONS ................................... 60
APPENDIX C COMIRNATY -ATTRIBUTABLE MYOCARDITIS /PERICARDITIS RISKS ................... 61
Clinical Reviewer: Susan K. Wollersheim, MD
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GLOSSARY
AE adverse event
AESI adverse event of special interest
BLA Biologics License Application
BNT162b2 Pfizer-BioNTech COVID-19 Vaccine
CBER Center for Biologics Evaluation and Research CDC Centers for Disease Control and Prevention
CI confidence interval
CMC chemistry, manufacturing, and controls
COVID-19 coronavirus disease 2019
EUA emergency use authorization
FDA Food and Drug Administration
FDCA Federal Food, Drug, and Cosmetic Act
ICU intensive care unit
IND investigational new drug application
LNP lipid nanoparticle
MIS-C multisystem inflamma tory syndrome in children
NAAT nucleic acid amplification-based test
PREA Pediatric Research Equity Act
PT Preferred Term
RT-PCR reverse transcription-polymerase chain reaction
SAE serious adverse event
sBLA supplemental Biologics License Application SARS-CoV-2 severe acute respiratory syndrome coronavirus 2
SOC System Organ Class
US United States
VAERS Vaccine Adverse Event Reporting System
VE vaccine efficacy
VRBPAC Vaccines and Related Biological Products Advisory Committee
VSD Vaccine Safety Datalink
WHO World Health Organization
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1. Executive Summary
On December 16, 2021, BioNTech Manufacturing GmbH, Inc. submitted a
supplemental Biologics License Application (sBLA) for Comirnaty (COVID-19 Vaccine,
mRNA; also referred to as BNT162b2 during clinical development and the Pfizer-
BioNTech COVID-19 Vaccine as authorized under EUA) to extend the currently
approved indication for active immunization to prevent coronavirus disease 2019
(COVID-19) caused by severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2) to include individuals 12 thr ough 15 (hereafter 12-15) years of age. The
primary immunization series consists of 2 intramuscular doses ( ȝJ each dose)
administered 3 weeks apart. Comirnaty contains SARS-CoV-2 spike glycoprotein (S)
antigens encoded in RNA formulated in lipid nanoparticles (LNPs). Encapsulation of the vaccine mRNA into LNPs protects the RNA from degradation by RNases and enables
transfection of host cells after intramuscular delivery.
Study C4591001, the main study to support the safety and effectiveness of BNT162b2,
is an ongoing randomized clinical trial which has enrolled a total of 2260 participants
(1131 BNT162b2, 1129 saline placebo) 12-15 ye ars of age. Vaccine effectiveness in
the adolescent age group was inferred by immunobridging based on a comparison of
SARS-CoV-2 50% neutralization antibody titers at 1 month after Dose 2 in 190
participants 12-15 years of age with those of 170 young adults 16 through 25 (hereafter
16-25) years of age (the most clinically relevant subgroup of the study population in
whom vaccine efficacy [VE] has been demons trated). Descriptive analyses of VE were
also conducted in participants 12-15 years of age to evaluate the efficacy of BNT162b2
to prevent laboratory-confirmed symptomatic COVID- RFFXUULQJ GD\V DIWHU 'RVH
in participants without serological or virol ogical evidence of past SARS-CoV-2 infection
before and during the vaccination regimen. Planned safety analyses in all participants
12-15 years of age included evaluation of: 1) local reactions, systemic events, and
antipyretic/pain medication use from Day 1 through Day 7 after each dose; 2) non-
serious unsolicited adverse events (AEs) from Dose 1 through 1 month after Dose 2; 3)
serious adverse events (SAEs) from Dose 1 through 6 months after Dose 2; and deaths
and serious adverse events from Dose 1 through the end of the study.
Effectiveness and safety data accumulated in the study through March 13, 2021, which
included median follow-up of 2 months after Dose 2, supported FDA’s May 10, 2021
issuance of an emergency use authorization (EUA) for use of BNT162b2 in individuals
12-15 years of age . Following issuance of the EUA, st udy participants 12-15 years of
age were progressively unblinded to their treatment assignment (when eligible for
vaccination per national and local public health prioritization recommendations), and placebo recipients could choose to receive BNT162b2 with continued active
unblinded/open-label follow-up in the study. This sBLA submission included updated
efficacy analyses of COVID-19 cases accrued during blinded placebo-controlled follow-
up through September 2, 2021, representing up to 6 months of follow up after Dose 2
for participants in the safety population. A total of 99.4% participants received 2 doses
in the study. The median follow-up for both safety and efficacy after Dose 2 of adolescent participants in the blinded placebo-controlled period was 4.4 months. Updated safety analyses included in the sB LA submission evaluated data accumulated
in both blinded and unblinded follow-up through September 2, 2021. The sBLA safety database included 1113 study participants originally randomized to BNT162b2 who
completed at least 6 months of total (blinded and open label) safety follow-up after
Dose 2, with a median total follow-up duration of 8.4 months.
Clinical Reviewer: Susan K. Wollersheim, MD
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In the planned immunobridging analysis, based on the March 13, 2021 data cutoff, the
geometric mean ratio (GMR) of neutralizing antibody titers (adolescents to young
adults) was 1.77 (95% CI: 1.50, 2.09), meeting the success criterion (lower bound of the
95% CI for the GMR >0.67). In the updated descriptive efficacy analyses, based on the
September 2, 2021 data cutoff including a median of 4.4 months blinded placebo-
controlled follow-up, vaccine efficacy after 7 days post Dose 2 was assessed. Among a
total of 28 confirmed symptomatic cases of COVID-19 in the trial in participants without
evidence of prior infection with SARS-CoV-2, all cases of COVID-19 were in the
placebo group (n=1129), and no cases were in the Pfizer-BioNTech vaccine group
(n=1131). Vaccine efficacy was 100%, (95% CI: 86.8, 100.0). There were no cases of
severe COVID-19 accrued during blinded, placebo-controlled follow-up. The SARS-
CoV-2 variants of concern identified from COVID-19 cases in this age group from the
September 2, 2021 data cutoff included B.1.1.7 (Alpha); all cases were accrued prior to
the emergence of the Delta and Omicron variants.
The safety population from the September 2, 2021 data cutoff included 1131 BNT162b2
recipients and 1129 placebo recipients 12-15 years of age with up to 6 months of safety follow-up post-dose 2 during the blinded placebo-controlled time period. During the
placebo-controlled phase, the most commonly reported solicited adverse reactions in
the BNT162b2 group were pain, redness and sw elling at the injection site, fatigue, and
headache. Adverse reactions other than solicited reactogenicity events identified from
the clinical trial data include myocarditis, lymphadenopathy in regional proximity to the
vaccination site, and nausea. One (1) adolescent who had myocarditis after Dose 2 of
BNT162b2 had resolution of symptoms with conservative management. In the
additional safety follow-up data submitted in this sBLA, between the two data cutoff
dates (March 13, 2021 and September 2, 2021), there were otherwise no notable
patterns between treatment groups for specific categories of serious or non-serious adverse events (including neurologic, neuro-inflammatory, and thrombotic events) that
would suggest a causal relationship to BNT162b2. There were no reported deaths or
pregnancies in participants 12-15 years of age.
Despite more recent real-world evidence from the Omicron predominant period indicating decreased vaccine effectiveness and waning effectiveness against more mild
COVID-19 compared to that demonstrated in c linical trials during circulation of previous
variants, available evidence indicates a 2-do se series continues to provide substantial
protection against more severe COVID-19 and its serious outcomes caused by
currently circulating SARS-CoV-2 variants. Consequently, the World Health Organization (WHO) and national regulatory and public health authorities continue to
endorse use of currently available COVID-19 vaccines for use in primary vaccination.
The risk profile of Comirnaty is now informed by intensive post-authorization and post-
approval safety surveillance following hundreds of millions of doses, including post-
authorization safety surveillance in millions of adolescents 12-15 years of age. Post-
authorization and post-approval safety surveillance and observational studies to date
have not identified any new serious adve rse reactions; anaphylaxis, myocarditis and
pericarditis remain the important identified risks associated with Comirnaty. Based on
evidence from passive surveillance and observational studies, the risk of
myocarditis/pericarditis is greatest following Dose 2 of the vaccine series and is greater
among males 16-17 years of age (currently included in the population approved for use
of Comirnaty) compared to females and compared to older and younger males.
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The clinical data submitted in this applicat ion, and benefit-risk considerations as
outlined above, support approval of Comirnaty fo r use in individuals 12-15 years of age
for active immunization to prevent symptomatic coronavirus disease 2019 (COVID 19)
caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
1.1 Demographic Information: Subg roup Demographics and Analysis Summary
The table below summarizes demographic representation of study participants 12-15
years of age who enrolled in the Phase 3 portion of the ongoing study C4591001 and
were randomized to a two-dose series of BNT162b2 or placebo.
Table 1. Randomized Participants 12-15 Years of Age, by Subgroup, Study C4591001
Subgroup BNT162b2 Placebo Total
Total 12-15 years of age 1131 1129 2260
Gender: Female 564 544 1108
Gender: Male 567 585 1152
Ethnicity: Hispanic/Latino 132 130 262
Ethnicity: Non-Hispanic/Non-Latino 997 996 1993
Ethnicity: Not reported 2 3 5
Race: White 970 962 1932
Race: Black/African American 52 57 109
Race: All others 109 110 219
Source: FDA-generated table.
The demographic characteristics of the safety and efficacy populations were 85.5%
White, 51.0% male, and 88.2% non-Hispanic/non-Latino ethnicity. Subgroup analyses
of vaccine effectiveness (although limited by small numbers in some subgroups) did not
suggest meaningful differences in effectiveness across genders, ethnic groups,
geographies, or for participants with obesity or medical comorbidities associated with
high risk of severe COVID-19. No clinically meaningful differences in the occurrence of
solicited AEs, unsolicited AEs or SAEs we re observed by ethnicity, race, or sex
subgroups.
Clinical Reviewer: Susan K. Wollersheim, MD
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1.2 Patient Experience Data
Data Submitted in the Application
Check if
Submitted
Type of Data Section Where Discussed,
if Applicable
܆ Patient-reported outcome
տ Observer-reported outcome
տ Clinician-reported outcome
տ Performance outcome
տ Patient-focused drug development meeting
summary
տ FDA Patient Listening Session
տ Qualitative studies (e.g., individual
patient/caregiver interviews, focus group
interviews, expert interviews, Delphi Panel)
տ Observational survey studies
տ Natural history studies
տ Patient preference studies
տ Other: (please specify)
܈ If no patient experience data were submitted
by Applicant, indicate here. N/A
Check if
Considered
Type of Data Section Where Discussed,
if Applicable
տ Perspectives shared at patient stakeholder
meeting
տ Patient-focused drug development meeting
տ FDA Patient Listening Session
տ Other stakeholder meeting summary report
տ Observational survey studies
տ Other: (please specify)
2. Clinical and Regulatory Background
2.1 Disease or Health-Related Condition(s) Studied
SARS-CoV-2 is a zoonotic coronavirus that emerged in late 2019 and was identified in
patients with pneumonia of unknown cause. SARS-CoV-2 is the causative agent 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.
Symptoms associated with SARS-CoV-2 infection in individuals less than 18 years of
age are similar to those in adults, but are generally milder, with fever and cough most
commonly reported (Irfan et al. 2021; Liguoro et al. 2020). Other symptoms in children include nausea and vomiting, diarrhea, dyspnea, nasal symptoms, rashes, fatigue and
abdominal pain (Irfan et al. 2021). Most children with COVID-19 recover within 1 to 2
weeks. Estimates of asymptomatic infection in children vary from 15 to 50% of
infections (Assaker et al. 2020; Poline et al. 2021). However, COVID-19 associated
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hospitalizations and deaths have occurred in adolescents (see below), and for some
children, COVID-19 symptoms may continue for weeks to months after their initial
illness (Office of National Statistics 2021).
The SARS-CoV-2 pandemic continues to present a challenge to global health and, as
of July 6, 2022, has caused over 551 milli on cases of COVID-19, including 6.3 million
deaths worldwide (Johns Hopkins Coronavirus Resource Center 2021). In the US, more
than 87 million cases and 1 million deaths have been reported to the Centers for
Disease Control and Prevention (CDC) (CDC 2021a; CDC 2021b). Of the total COVID-
19 cases reported in the US to date, 4.7% occurred among individuals 12-15 years of
age (CDC 2021c).
Following EUA of the first COVID-19 vaccine in December 2020, COVID-19 cases and
deaths in the US declined sharply during the first half of 2021. The emergence of the
Delta variant, variable implementation of public health measures designed to control
spread, and continued transmission among unv accinated individuals were major factors
in the resurgence of COVID-19 in the US, leading to the Delta variant-associated peak
in September of 2021 and the more recent surge in cases attributed to the Omicron variant. As of the week ending July 2, 2022, the Omicron variant BA.4/BA.5 sub-
lineages comprised the majority of the tested strains in the US (CDC 2021d). Among
cases of COVID-19 in individuals less than 18 years of age from the COVID-NET
network, approximately 8597 have resulted in hospitalization. (CDC 2021e). As of July
6, 2022, 408 deaths from COVID-19 have been reported in the US in the 12–15-year
age group (CDC 2021c).
The most common underlying medical conditions among hospitalized children were
obesity (31.9%), neurologic disorders (14.8%), and asthma (14.5%). Obesity was
associated with increased risk of severe disease. Available evidence suggests that highest risk groups include children with special healthcare needs, including genetic,
neurologic, metabolic conditions, or with c ongenital heart disease (CDC 2021f). As in
the adult population, COVID-19 in children disproportionally affects underrepresented
racial and ethnic groups, with hospitalizati ons and deaths more frequent among Native
American/Alaskan, Hispanic or Latin American, and non-Hispanic Black children than among White children (McCormick et al. 2021; Kim et al. 2020).
Following observation of an increased incidence of myocarditis in 2020 compared with
2019, several studies have suggested an association between COVID-19 and
myocarditis (Murk et al. 2021; Daugherty et al. 2021). While the overall incidence of
myocarditis following COVID-19 infection is low, persons with COVID-19 have a nearly
16-fold increase in risk for myocarditis, compared to individual s without COVID-19.
Myocarditis may also present as part of the multisystem inflammatory syndrome in
children (MIS-C), usually 3 to 5 weeks after a SARS-CoV-2 infection. MIS-C is a rare
but serious COVID-19-associated condition that occurs in less than 1% of children with
confirmed SARS-CoV-2 infection (Dufort et al. 2020). MIS-C presents with persistent
fever, laboratory evidence of inflammation, and at least 2 affected organs. In severe
cases, hypotension and shock can occur. Between May 2020 and May 31, 2022, the
CDC received reports of 8525 cases and 96 deaths that met the definition for MIS-C;
the median age of participants was 9 years with 19.2% of the cases occurring in
adolescents 12-15 years of age. Males comprised 61% of cases, and 57% were
reported in children who were reported as Hispanic or Black (CDC 2021g). Up to 66.7%
of patients with MIS-C had cardiac involvement (Feldstein et al. 2021), including left
Clinical Reviewer: Susan K. Wollersheim, MD
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ventricular dysfunction, mitral or tricuspid regurgitation, coronary artery aneurysms,
and/or arrhythmias (Farooqi et al. 2021). One study of outcomes in children with MIS-C
followed up to 9 months found that while 76% children with MIS-C required intensive
care unit (ICU) admission and therapy with inotropes or pressors, most symptoms,
including cardiovascular manifestations, resolved within 1 to 4 weeks (Farooqi et al.
2021). Limited data are available on long-term outcomes in MIS-C.
2.2 Currently Available, Pharmacologically Unrelated Treatment(s)/Intervention(s) for
the Proposed Indication(s)
The antiviral remdesivir is currently approved by the FDA for the treatment of COVID-19
in adults and pediatric patients (28 days of age and older and weighing at least 3 kg)
with positive results of direct SARS-CoV-2 te sting who are hospitalized, or who are not
hospitalized and have mild-to-moderate COVID-19 and are at high risk for severe
COVID-19. Additionally, the immune modulator baricitinib is approved by the FDA for
the treatment of COVID-19 in hospitalized adults requiring supplemental oxygen, non-
invasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation
(ECMO).
Other pharmacological products for pre-exposure prophylaxis of COVID-19, post-exposure prophylaxis and/or treatment of COVID-19 that have received emergency use
authorization are as follows:
Antivirals: Paxlovid (nirmatrelvir tablets and ritonavir tablets, co-packaged for oral use)
is authorized under EUA for the treatment of mild-to-moderate COVID-19 in adults and
pediatric patients (12 years of age and older weighing at least 40 kg) with positive
results of direct SARS-CoV-2 testing, and wh o are at high risk for progression to severe
COVID-19, including hospitalization or death. Molnupiravir is authorized under EUA for
the treatment of mild-to-moderate COVID-19 in adults with positive results of direct
SARS-CoV-2 testing, and who are at high risk for progression to severe COVID-19, including hospitalization or death, and for whom alternative COVID-19 treatment
options authorized by the FDA are not accessible or clinically appropriate.
SARS-CoV-2-targeting monoclonal antibodies: Bebtelovimab is authorized under EUA
for the treatment of mild-to-moderate COVID-19 in adults and pediatric patients 12
years of age and older weighing at least 40 kg with positive results of direct SARS-CoV-
2 testing, who are at high risk for progr ession to severe COVID-19 and for whom
alternative COVID-19 treatment options approved or authorized by FDA are not
accessible or clinically appropriate. Tixagevimab co-packaged with cilgavimab is
authorized under EUA as pre-exposure prophylaxis for prevention of COVID-19 in
certain adults and pediatric individuals (12 years of age and older weighing at least 40
kg).
Immune modulators: Baricitinib is authorized for the treatment of COVID-19 in
hospitalized patients 2 to less than 18 years of age who require supplemental oxygen,
non-invasive or invasive mechanical ventilation, or extracorporeal membrane
oxygenation (ECMO). Tocilizumab is authorized for the treatment of COVID-19 in hospitalized adults and pediatric patients (2 years of age and older) who are receiving
systemic corticosteroids and require supplemental oxygen, non-invasive or invasive
mechanical ventilation, or ECMO.
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COVID-19 convalescent plasma with high antibody titer is authorized for emergency
use as a treatment for patients with COVID-19 in patients with immunosuppressive
disease or receiving immunosuppressive trea tment, in inpatient or outpatient settings.
2.3 Safety and Efficacy of Pharmacologically Related Products
On August 23, 2021, the Pfizer-BioNTech COVID-19 vaccine (Comirnaty) was
approved for use as a two-dose primary series for active immunization to prevent
COVID-19 caused by SARS-CoV-2 in individuals 16 years of age and older.
Additionally, the Pfizer-BioNTech COVID-19 Vaccine is authorized for emergency use
as a: three-dose primary series for indivi duals 6 months through 4 years of age, a two-
dose primary series for individuals 5 years of age and older, a third primary series dose
for individuals 5 years of age and older with certain types of immunocompromise. The
Pfizer-BioNTech COVID-19 vaccine is also authorized as: a first booster dose in
individuals 5-17 years of age and older to be administered at least 5 months after
completion of a primary series, a first booster dose in individuals 18 years of age and
older after completion of primary vaccination with any authorized or approved COVID-
19 vaccine (with the same interval as authorized for a booster dose with the vaccine
used for primary vaccination), and a second booster dose at least four months after a
first booster dose of any authorized or approved COVID-19 vaccine in individuals 50 years of age and older and individuals 12-49 years of age with certain types of
immunocompromise. Each of the authorized and approved primary series and booster
doses are administered according to the age group: 3 ȝJ for 6 months through 4 years
of age, 10 ȝJ for 5 through 11 years of age, and 30 ȝJ for 12 years old and older.
Safety and efficacy data supporting approval (Comirnaty) and authorizations for Pfizer-BioNTech COVID-19 Vaccine are detailed in the decision memoranda available on the
FDA website .
On January 31, 2022, FDA approved the Moderna COVID-19 vaccine (Spikevax) for
use as a two-dose primary series for active immunization to prevent COVID-19 in
individuals 18 years of age and older. Addi tionally, the Moderna COVID-19 vaccine is
authorized for emergency use as a: 2 dose primary series for individuals 6 months of
age and older, third primary series dose for individuals 6 months of age and older with
certain types of immunocompromise, homol ogous or heterologous first booster dose
administered after completion of primary va ccination to individuals 18 years of age and
older (the authorized dosing interval for a homologous booster is at least 5 months after
completion of a primary series, and the authorized interval for a heterologous booster is
the same as that authorized for a booster dose of the vaccine used for primary
vaccination), and homologous or heterologous second booster dose administered at
least 4 months after the first booster dose to individuals 50 years of age and older and
individuals 18-49 years of age with certain types of immunocompromise. Safety and
efficacy data supporting approval (Spikevax) and authorizations for Moderna COVID-19
Vaccine are detailed in the decision memoranda available on the FDA website .
The Janssen COVID-19 Vaccine is authorized for use in individuals 18 years of age and
older for whom other FDA-authorized or approved COVID-19 vaccines are not
accessible or clinically appropriate, or who elect to receive the Janssen COVID-19
Vaccine because they would otherwise not receive a COVID-19 vaccine. Safety and
efficacy data supporting authorization for the Jannsen COVID-19 Vaccine are detailed
in the decision memoranda available on the FDA website . The vaccine is authorized for
use in these individuals as a single pr imary vaccination dose and as a single
Clinical Reviewer: Susan K. Wollersheim, MD
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homologous or heterologous booster dose (the dosing interval for a homologous
booster is at least 2 months after the single primary vaccination dose, and the dosing
interval for a heterologous booster is the same as that authorized for a booster dose of
the vaccine used for primary vaccination).
2.4 Previous Human Experience with the Product (Including Foreign Experience)
Clinical trial experience
EUA of the Pfizer-BioNTech COVID-19 Vaccine (also referred to as BNT162b2) was
based on the following data: In individuals 16 years of age enrolled in a Phase 2/3
portion of an ongoing study (n=~22000 vaccine, n=~22000 placebo), vaccine efficacy
(VE) was 95% to prevent PCR-confirmed COVID-19 occurring at least 7 days after
completion of a 2-dose series. Common solicited adverse reactions after vaccination were injection site reactions, fatigue, headache, muscle pain, chills, and joint pain,
which were generally mild to moderate and lasted a few days. Adverse reactions other
than solicited reactogenicity events identified from the clinical trial data include
lymphadenopathy in regional proximity to the vaccination site and potentially Bell’s
Palsy (the latter from a small numerical imbalance of temporally associated events).
Vaccine effectiveness in participants 12-15 years of age (n=1131 vaccine, n=1129
placebo) was inferred by immunobridging, based on a comparison of SARS-CoV-2 50% neutralization antibody titers (SARS-CoV-2 mNG microneutralization assay) at 1 month
after Dose 2, to participants 16-25 years of age, and supported by a supplemental
efficacy analysis showing VE after 7 days post Dose 2 was 100% (95% CI: 75.3; 100.0)
in study participants without evidence of pr ior SARS-CoV-2 infection and 100% (95%
CI: 78.1; 100.0) in participants with or without evidence of prior SARS-CoV-2 infection.
Common solicited adverse reactions after vaccination were injection site reactions,
fatigue, headache, muscle pain, chills, and joint pain, which were generally mild to
moderate and lasted a few days. Of the unsolicited adverse events (AEs) reported
(5.8% from each treatment group), lymphadenopathy was considered related to the
vaccine, which was also observed in older age groups. Serious adverse events, while
uncommon (<0.5%), represented medical events expected to occur among individuals
in this age group, and available data did not suggest a causal relationship to vaccine.
Post-EUA
As discussed in Section 2.1 above, since the issuance of the EUA, published
observational studies have supported the effectiveness of BNT162b2 to prevent
COVID-19, including high-level protection against severe disease, hospitalization, and
death, although recent evidence indicates decreased primary series (2-dose) vaccine
effectiveness since emergence of Omicron variant and its sub-lineages in the US (CDC
2022). Despite decreased effectiveness against Omicron compared with previous variants, authorized and approved COVID-19 vaccines based on the ancestral (Wuhan)
strain continue to provide substantial protection against severe COVID-19 and
associated serious outcomes, and the World Health Organization and various national
regulatory and public health authorities, including FDA, continue to endorse their use for
primary series vaccination in COVID-19 vaccine-naïve individuals (EMA 2022; FDA
2022; WHO 2022).
During the post-EUA surveillance period, ca ses of myocarditis and pericarditis were
reported after vaccination, as well as rare cases of anaphylaxis (see Section 4.6 ).
Clinical Reviewer: Susan K. Wollersheim, MD
STN:125742/45
13
Please see CBER pharmacovigilance review er’s memorandum for a more detailed
review of post-authorization myocarditis/pericarditis risk and details about the
Applicant’s ongoing post-authorization studies.
2.5 Summary of Pre- and Post-submission Regulatory Activity Related to the
Submission
Prior to sBLA submission
¾ EUA 27034
x November 20, 2020: 6XEPLVVLRQ RI (8$ UHTXHVW IRU LQGLYLGXDOV \HDUV RI DJH
x December 11, 2020: Issuance of (8$ IRU LQGLYLGX DOV \HDUV of age
x April 9, 2021: Submission of EUA request for individuals 12-15 years of age
x May 10, 2021: Issuance of EUA a mendment to include individuals 12-15 years of
age
x June 25, 2021: EUA amendment to include warning statement and associated
information regarding myocarditis and pericarditis in the Fact Sheet for
Vaccination Providers and the Fact Sheet for Recipients and Caregivers
¾ IND 19736 major milestones in advance of this sBLA submission
x April 22, 2020: IND 19736 submission, first subject enrolled on April 29, 2020
x October 15, 2020: first subject 12-15 years of age enrolled to Study C4591001
x November 18, 2020-April 2, 2021: Request for Comments and Advice re: Study
C4591001 Placebo Recipients
x August 3, 2021: Request for Comments and Advice re: submission of an sBLA to
extend the indication to include adolescents 12-15 years of age
2.6 Other Relevant Background Information
In June 2020, FDA published guidance on th e Development and Licensure of Vaccines
to Prevent COVID-19 . In October 2020, FDA published guidance on Emergency Use
Authorization for Vaccines to Prevent COVID-19 (revised February 2021) .
On October 22, 2020, a Vaccines and Relate d Biological Products Advisory Committee
(VRBPAC) meeting was held to discuss considerations for development, EUA and
licensure of vaccines to prevent COVID- 19. The VRBPAC endorsed the principles
outlined in the June and October FDA guidance documents regarding safety and effectiveness data to support EUA and licensure and expectations for continued post-authorization and post-approval evaluation of COVID-19 vaccines.
On June 10, 2021, a VRBPAC meeting was held to discuss considerations for EUA and
licensure of COVID-19 vaccines in pediatric age groups. The VRBPAC endorsed the
use of immunobridging to infer effectiveness of COVID-19 vaccines in pediatric age
groups and pediatric safety databases of at least 500-1500 vaccine recipients per age
group, depending on the age group being evaluated, with at least 6 months of follow-up
to support licensure.
Clinical Reviewer: Susan K. Wollersheim, MD
STN:125742/45
14
3. SUBMISSION QUALITY AND GOOD CLINICAL PRACTICES
3.1 Submission Quality and Completeness
The submission was adequately organized and integrated to accommodate the conduct
of a complete clinical review.
3.2 Compliance With Good Clinical Practices And Submission Integrity
Sponsor responsibilities were transferred from BioNTech SE to Pfizer Inc. for the
conduct of clinical study C4591001, including co mpliance with Good Clinical Practice as
per 21 CFR 312. Bioresearch Monitoring inspections of three clinical sites in study
C4591001 did not identify deficiencie s that would affect the integrity of the clinical data
submitted in this sBLA.
3.3 Financial Disclosures
Study C4591001
Disclosure start date: April 29, 2020. Disclosure Cut-off Date: November 3, 2021
Was a list of clinical investigators provided? ; Yes տ No
Total number of investigators identified: 340
Number of investigators who are sponsor employees (including both full-time and part-time
employees): 0
Number of investigators with disclosable financial interests/arrangements (Form FDA 3455): 3
If there are investigators with disclosable financial interests/arrangements, identify the number
of investigators with interests/arrangements in each category (as defined in 21 CFR 54.2(a), (b), (c) and (f)):
Compensation to the investigator for conducting the study where the value could be
influenced by the outcome of the study: 0
Significant payments of other sorts: 1
Proprietary interest in the product tested held by investigator: 0
Significant equity interest held by investigator in sponsor of covered study: 2
Is an attachment provided with details of the disclosable financial
interests/arrangements? ; Yes տ No
Is a description of the steps taken to minimize potential bias provided?
; Yes տ No
Number of investigators with certification of due diligence (Form FDA 3454, box 3): 4
Is an attachment provided with the reason? ; Yes տ No
The investigators with disclosable financial interests represented 0.9% (n=3/340) of the total investigators who participated in covered clinical studies.
Efforts reported to eliminate bias for the covered studies consisted of the following:
x Randomized, double-blind and multicenter study design as well as pre-specified
statistical methods as per the statistical analysis plan
x Frequent monitoring of investigator trial sites and auditing of study sites
Clinical Reviewer: Susan K. Wollersheim, MD
STN:125742/45
15
x Validity of data collected was confirmed by standard monitoring procedures
x Data processing involved cleaning checks (querying data through electronic edit
checks) to ensure that errors were identified and corrected
x Data were reviewed by clinicians and queries were generated in case of
inconsistencies during the course of the trial
x The study report underwent review by the project team and Quality Control; and
x Study sites performing safety evaluations were determined acceptable based on
appropriate certification or historical performance and/or qualifications and credentials.
Reviewer Comment : The Applicant satisfactorily addressed possible study
investigator financial interests that could impact clinical data quality.
4.
SIGNIFICANT EFFICACY /SAFETY ISSUES RELATED TO OTHER REVIEW DISCIPLINES
4.1 Chemistry, Manufacturing, and Controls
The CBER CMC reviewer identified no issues that would impact the conclusions of the
clinical review.
4.2 Assay Validation
The SARS-CoV-2 mNG microneutralization assay measures neutralizing antibodies
(50% inhibition titers) against SARS-CoV-2 using Vero cell monolayers in a 96-well
plate format. The SARS-CoV-2 mNG virus is derived from the USA_WA1/2020 strain
that had been rescued by reverse genetics and engineered to express a fluorescent
reporter gene (mNeonGreen) upon productive infection of cells. The validation protocol (that includes evaluation of dilutional linearity, precision, limits of quantification, and limit
of detection) and the results of the validat ion study, executed at Pfizer Hackensack
Meridian Health Center (Nutley, New Jersey), were submitted to support the suitability
of the assay for testing of clinical trial immunogenicity samples.
Two clinical diagnostic assays (Cepheid Xper t Xpress reverse transcription-polymerase
chain reaction [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).
4.3 Nonclinical Pharmacology/Toxicology
No toxicology studies were submitted to this sBLA.
4.5 Statistical
No major statistical issues were identified by CBER statistical reviewers in this
application. The key statistical analyses for safety and efficacy were confirmed by
CBER statistical reviewers.
Clinical Reviewer: Susan K. Wollersheim, MD
STN:125742/45
16
4.6 Pharmacovigilance
Post-authorization safety surveillance has not identified any new serious adverse
reactions associated with BNT162b2, incl uding among individuals 12-15 years of age
who received the vaccine under EUA, other than anaphylaxis, myocarditis and
pericarditis. The risk of anaphylaxis associated with BNT162b2 appears to be similar in
magnitude to the risk of anaphylaxis following approved preventive vaccines in general and can be managed with standard vaccination practices. The risk of
myocarditis/pericarditis appears to be greatest in individuals under the age of 40, in
particular in males following Dose 2, and have been highest in males 12 through 17
years of age (~70.2 verified cases per million doses within 7-days following dose 2
administration among males ages 16-17 years and 45.7 verified cases per million doses within 7-days following dose 2 among males ages 12-15 years as per CDC presentation
to the ACIP on January 5, 2022). Although some cases required intensive care support,
available data from short-term follow- up suggest that most individuals have had
resolution of symptoms with conservative management. Information is not yet available
about potential long-term sequelae.
Please see the CBER Pharmacovigilance Plan review memorandum for further details.
4.7 Risk-Benefit Assessment
FDA conducted a quantitative benefit-risk assessment of the myocarditis risk to inform
the review of Pfizer and BioNTech’s s upplemental Biological Licensure Application
(sBLA) for use of mRNA COVID-19 vaccines in individuals 12-15 years of age. For
myocarditis risk, the real-world data suggests a rate ranging from 46-71 per million post 2nd dose (see Appendix C for an extended list of studies) among individuals 12-15 years
of age, and Vaccine Adverse Event Reporting System (VAERS) data suggests a lower
risk compared to individuals 16-17 years of age, who are included in the age group for
which Comirnaty is already approved for use. The FDA benefit-risk assessment
concluded that the benefit-risk balance of the Comirnaty 2-dose primary series is favorable in individuals 12-15 years of age and supports licensure of the vaccine for use
in this age group.
For further details, please refer to the review memorandum from the Analytics and
Benefit-Risk Assessment Team, Office of Biostatistics and Epidemiology, CBER.
5.
SOURCES OF CLINICAL DATA AND OTHER INFORMATION CONSIDERED IN THE REVIEW
5.1 Review Strategy
Clinical data that were available as of March 13, 2021, from Phase 3 Study C4591001
participants 12-15 years of age enrolled from October 15, 2020, were previously
submitted in support of an EUA request and reviewed by FDA. See the Adolescent EUA
Review Memorandum for the Pfizer COVID-19 Vaccine .
Clinical Reviewer: Susan K. Wollersheim, MD
STN:125742/45
17
This sBLA contains new clinical data, as follows:
Study C4591001
¾ Phase 3
For participants 12-15 years of age:
x SDIHW\ WR months after Dose 2 among study participants with follow-up during
the blinded placebo-controlled and/ or open-label follow-up periods
x Updated efficacy for all participants in the efficacy analysis populations with
confirmed COVID-19 cases during the blinded placebo-controlled follow-up
period through September 2, 2021.
Only safety and effectiveness data in individuals 12-15 years of age, the population for
intended use, who received the final vaccine formulation (BNT162b2 30 μg) are
presented in this clinical memorandum.
Post-authorization effectiveness data from observational studies referenced in Section
2 and Section 11 are limited to published literature and were not submitted as part of
the licensure application. Therefore, FDA has not independently reviewed and confirmed the data or assessed the study designs for potential sources of bias.
5.2 BLA/IND Documents That Serve as the Basis for the Clinical Review
The primary source of data considered for review of this investigational vaccine were
documents submitted to STN 125742/0. The following sections were reviewed in
support of this application: Module 1, all sections: Administrative Information and Prescribing Information
Section 2.2 Introduction
Section 2.5 Clinical Overview
Section 5.2 Tabular Listing of All Clinical Studies
Section 5.3.5.1 Clinical Study Reports
During the sBLA review period, the Applicant submitted a total of 5 amendments in
response to CBER’s requests for clinical information.
Table 2. Amendments to the sBLA 125742/45 (submitted December 16, 2021)
Amendment
Number Date Submitted Description
2 February 2, 2022 Response to 1/19/22 re: datasets
4 March 11, 2022 Response to 3/7/22 clinical-statistical comments re: updated
immunobridging analyses and solicited adverse reaction frequencies.
8 April 29, 2021 Response to 4/20/22 first set of labeling comments
11 May 9, 2022 Response to 5/4/22 clinical-statistical comments re: nausea events
12 May 10, 2022 Labeling comments
Source: FDA-generated table.
The amendments satisfactorily addressed all clinical requests sent during the review
period, and salient responses from the amendments were incorporated into this
memorandum.
Supportive information from EUA 27034/132 and clinical study protocols reviewed
under IND 19736 were also referenc ed during the review cycle.
Clinical Reviewer: Susan K. Wollersheim, MD
STN:125742/45
18
5.3 Overview of Clinical Studies
An interim report from one ongoing clinical study was submitted on December 16, 2021,
to support approval and licensure of Pfizer-BioNTech COVID-19 Vaccine (BNT162b2)
in individual 12-15 years of age. Study C4591001 is a multicenter Phase 1/2/3
randomized, blinded, placebo-controlled safety, immunogenicity, and efficacy study.
Table 3. Study C4591001, Participants 12 Through 15 Years of Age
Study Number/
Countries Description BNT162b2 (30 μg)
N Placebo (Saline)
N Study
Status
C4591001
USA Phase 1/2/3,
randomized, placebo-
controlled, observer-
blind; to evaluate
safety, immunogenicity and efficacy of COVID-19
vaccine Total: 1131
Total: 1129
Ongoing
N=Number of randomized participants as of September 2, 2021.
Study C4591001 began in April 2020 (first participant, first visit); participants 12-15 years of age: first participant, first
visit was October 15, 2020 (implemented according to protocol amendment 7).
5.4 Consultations
5.4.1 Advisory Committee Meeting
The most critical issues involving data to support safety and effectiveness of this
vaccine were covered in the October 2020, December 2020, and June 2021 VRBPAC
meetings. More complete information concerning the risk of myocarditis/pericarditis has
become available in post-EUA surveillance and observational studies. FDA’s
assessment of this information did not impact the overall benefit/risk considerations to an extent that VRBPAC input was needed to guide a licensure decision for use in
individuals 12-15 years of age.
5.5 Literature Reviewed
Assaker, R., Colas, A. E., Julien-Marsollier, F., et al. (2020). Presenting symptoms of
COVID-19 in children: a meta-analysis of published studies. British journal of
anaesthesia , 125(3), e330–e332. https://doi.org/10.1016/j.bja.2020.05.026
Centers for Disease Control and Prevention (2021a). COVID Data Tracker (website)
https://covid.cdc.gov/covid-data-tracker/#trends dailytrendscases, Accessed July 6,
2022.
Centers for Disease Control and Prevention (2021b). COVID-19 Vaccine Effectiveness
in Children and Adults. Presented at the meeting of the Advisory Committee on
Immunization Practices, September 22, 2021.
https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2021-09-22/04-
COVID-Link-Gelles-508.pdf . Accessed July 6, 2022.
Centers for Disease Control and Prevention (2021c). COVID Data Tracker (website)
https://covid.cdc.gov/covid-data-tracker/#demographics . Accessed July 6, 2022.
Clinical Reviewer: Susan K. Wollersheim, MD
STN:125742/45
19
Centers for Disease Control and Prevention, (2021d). COVID Data Tracker (website)
https://covid.cdc.gov/covid-data-tracker/#nowcasting . Accessed July 6, 2022.
Centers for Disease Control and Prevention (2021e). COVID Data Tracker
(website).Counts of Hospitalizations by Age from the COVID-NET Network (data
downloaded on October 17, 2021. https://covid.cdc.gov/covid-dat a-
tracker/#covidnet-hospitalization-network . Accessed July 6, 2022.
Centers for Disease Control and Prevention, (2021f). COVID Data Tracker (website)
https://covid.cdc.gov/covid-data-tracker/#pediatric-data . Accessed July 6, 2022.
Centers for Disease Control and Prevention (2021g). Health Department-Reported
Cases of Multisystem Inflammatory Synd rome in Children (MIS-C) in the United
States. May 31, 2022. https://covid.cdc.gov/covid-dat a-tracker/#mis-national-
surveillance . Accessed July 6, 2022.
Centers for Disease Control and Prevention (2022). Updates on COVID-19 Vaccine
Effectiveness during Omicron. Slide presentation at a meeting of the Vaccines and Related Biological Products Advisory Committee, June 28, 2022.
https://www.fda.gov/media/159499/download . Accessed July 8, 2022.
Daugherty, S. E., Guo, Y., Heath, K., et al . (2021). Risk of clinical sequelae after the
acute phase of SARS-CoV-2 infection: retrospective cohort study. BMJ (Clinical
research ed.) , 373, n1098. https://doi.org/10.1136/bmj.n1098
Dufort E.M. et al. (2020). COVID-19: Multisystem inflammatory syndrome in children
(MIS-C) clinical features, evaluation, and diagnosis. N Engl J Med.
2020;383(4):347-358.
https://www.nejm.org/doi/10.1056/NEJMoa2021756?url ver=Z39.88-
2003&rfr id=ori:rid:crossref.org&rfr dat=cr pub%20%200pubmed
EMA (2022). Global regulators agree on key principles on adapting vaccines to tackle
virus variants. https://www.ema.europa.eu/en/news/global-r egulators-agree-key-
principles-adapting-vaccines-tackle-virus-variants . Accessed July 6, 2022.
FDA (2022). Coronavirus (COVID-19) Update: FDA Recommends Inclusion of Omicron
BA.4/5 Component for COVID-19 Vaccine Booster Doses. FDA Statement released
June 30, 2022. https://www.fda.gov/news-e vents/press-
announcements/coronavirus-covid-19-update-fda-recommends-inclusion-omicron-
ba45-component-covid-19-vaccine-booster . Accessed July 8, 2022.
Farooqi, K. M., Chan, A., Weller, R. J., et al. (2021). Longitudinal Outcomes for
Multisystem Inflammatory Syndrome in Children. Pediatrics , 148(2), e2021051155.
https://doi.org/10.1542/peds.2021-051155
Feldstein, L. R., Tenforde, M. W., Friedm an, K. G., et al. (2021). Characteristics and
Outcomes of US Children and Adolesce nts With Multisyst em Inflammatory
Syndrome in Children (MIS-C) Compared With Severe Acute COVID-19. JAMA ,
325(11), 1074–1087. https://doi.org/10.1001/jama.2021.2091
Clinical Reviewer: Susan K. Wollersheim, MD
STN:125742/45
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Irfan, O., Muttalib, F., Tang, K., Jiang, L., Lassi, Z. S., & Bhutta, Z. (2021). Clinical
characteristics, treatment and outcomes of paediatric COVID-19: a systematic
review and meta-analysis. Archives of disease in childhood , 106(5), 440–448.
Advance online publication. https://doi.org/10.1136/archdischild-2020-321385
Johns Hopkins Coronavirus Resource Center (2021). https://coronavirus.jhu.edu/ ,
Accessed July 6, 2022.
Kim, L., Whitaker, M., O'Halloran, A., Kambhampati, A., et al. (2020). Hospitalization
Rates and Characteristics of Children Aged <18 Years Hospitalized with Laboratory-
Confirmed COVID-19 - COVID-NET, 14 States, March 1-July 25, 2020. MMWR .
Morbidity and mortality weekly report, 69(32), 1081–1088.
https://doi.org/10.15585/mmwr.mm6932e3
Liguoro, I., Pilotto, C., Bonanni, M., et al. (2020). SARS-COV-2 infection in children and
newborns: a systematic review. European journal of pediatrics , 179(7), 1029–1046.
https://doi.org/10.1007/s00431-020-03684-7
McCormick, D. W., Richardson, L. C., Young, P. R., et al. (2021). Deaths in Children
and Adolescents Associated With COVID-19 and MIS-C in the United States.
Pediatrics , 148(5), e2021052273. https://doi.org/10.1542/peds.2021-052273
Murk, W., Gierada, M., Fralick, M., et al. (2021). Diagnosis-wide analysis of COVID-19
complications: an exposure-crossover study. CMAJ : Canadian Medical Association
journal = journal de l'Association medicale canadienne , 193(1), E10–E18.
https://doi.org/10.1503/cmaj.201686
Office of National Statistics (2021). Updated estimates of the prevalence of ongoing
symptoms following coronavirus (COVID-19) infection in the UK.
https://www.ons.gov.uk/peoplepopulationandcommunity/healthandsocialcare/conditi
onsanddiseases/datasets/alldatarelatingtoprevalenceofongoingsymptomsfollowingc
oronaviruscovid19infectionintheuk . Accessed July 6, 2022.
Poline, J., Gaschignard, J., Leblanc, C., et al. (2021). Systematic Severe Acute
Respiratory Syndrome Coronavirus 2 Screening at Hospital Admission in Children:
A French Prospective Multicenter Study. Clinical infectious diseases: an official
publication of the Infectious Diseases Society of America , 72(12), 2215–2217.
https://doi.org/10.1093/cid/ciaa1044
WHO (2022) Interim statement on the compos ition of current COVID-19 vaccines.
https://www.who.int/news/item/17-06 -2022-interim-statement-on--the-composition-
of-current-COVID-19-vaccines . Accessed July 8, 2022.
Clinical Reviewer: Susan K. Wollersheim, MD
STN:125742/45
21
6. DISCUSSION OF INDIVIDUAL STUDIES /CLINICAL TRIALS
6.1 Study C4591001
NCT04368728
Title: Phase 1/2/3, Placebo-Controlled, Randomized, Observer-Blind, Dose-Finding
Study to Evaluate the Safety, Tolerability, Immunogenicity, and Efficacy of SARS-COV-
2 RNA Vaccine Candidates Against COVID-19 in Healthy Individuals
Reviewer Comment: The protocol for this ongoing study has been amended over
time to add study populations, interventions, and analyses not included in the
original design and not pertinent to this sBLA. The study design as described herein reflects objectives, endpoints, and monitoring pertaining to safety,
immunogenicity, and efficacy evaluations in individuals 12-15 years of age
following a 2-dose BNT162b2 primary series, according to protocol amendment
18, which was the version implemented at the time of the September 2, 2021 data
cutoff. Secondary/exploratory objectives per taining to booster vaccination (e.g., 3
rd
BNT162b2 dose), and evaluation of modified BNT162b2 vaccine formulations
were beyond the scope of this sBLA, and therefore not presented in this clinical review. Additionally, the sBLA submission did not include data to address vaccine
effectiveness against asymptomatic COVID-19 infection, based on seroconversion
or surveillance PCR testing; thus, study objectives pertaining to asymptomatic
infection are not presented.
6.1.1 Objectives and Endpoints
The objectives and endpoints are presented below are for the adolescent population
enrolled into the Phase 3 portion of the study.
Secondary Immunogenicity objective: To demonstrate the noninferiority of the
immune response to prophylactic BNT162b2 in participants 12-15 years of age compared to participants 16-25 years of age.
Endpoint: SARS-CoV-2 neutralizing titers in participants with no serological or
virological evidence (up to 1 month after receipt of the second dose) of past
SARS-CoV-2 infection
Primary safety objective : To characterize the safety of BNT162b2.
Endpoints: solicited local adverse reactions (injection site pain, redness, swelling),
solicited systemic AEs (fever, fatigue, headache, chills, vomiting, diarrhea, new or
worsened muscle pain, and new or worsened joint pain), AEs, SAEs
Descriptive efficacy objectives
1. To evaluate the efficacy of BNT162b2 against confirmed COVID-19 occurring from
7 days after Dose 2 in participants without evidence of SARS-CoV-2 infection
before vaccination.
Endpoint: COVID-19 incidence per 1000 person-years of follow-up based on
laboratory-confirmed nucleic acid amplification-based test (NAAT) in participants
with no serological or virological evidence (up to 7 days after Dose 2) of past
SARS-CoV-2 infection
Clinical Reviewer: Susan K. Wollersheim, MD
STN:125742/45
22
2. To evaluate the efficacy of BNT162b2 against confirmed COVID-19 occurring from
7 days after Dose 2 in participants with and without evidence of SARS-CoV-2
infection before vaccination.
Endpoint: COVID-19 incidence per 1000 person-years of follow-up based on
laboratory-confirmed NAAT
For the study objectives described above, NAAT could be confirmed in a central or local
laboratory. Evidence of past SARS-CoV-2 infection (before Dose 1) was documented
serologically or virologically.
6.1.2 Design Overview 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.
Participants were randomized 1:1 to receive 2 doses of either BNT162b2 or placebo, 21
days apart. Adolescents 12-15 years of age were added to the protocol during Phase 3,
following a review of safety data in young adult participants, and enrollment began in
the United States on October 15, 2020.
The protocol-specified evaluation for vacci ne effectiveness in participants 12-15 years
of age was an immunobridging evaluation co mparing SARS-CoV-2 50% neutralizing
antibody titers at 1 month after Dose 2 with those of young adults 16-25 years of age
(the most clinically relevant subgroup of the study population in whom VE has been
demonstrated).
Supplementary to the immunobridging analysis, adolescents were followed for potential
cases of COVID-19 to assess VE using the same methods as for participants 16 years
of age and older (see Appendix B for COVID-19 and Severe COVID-19 Case
Definitions). The primary efficacy endpoint of Study C4591001 was VE against
laboratory-confirmed COVID-19 in participants without prior SARS-CoV-2 infection. A
second primary efficacy endpoint included participants with and without prior SARS
CoV-2 infection. COVID case definitions may be found in the review of the EUA for
individuals 16 years of age and older ( Pfizer COVID-19 Vaccine EUA Review Memo
Dec 2020 ). Efficacy against COVID-19 disease was assessed with descriptive analyses
in study participants 12-15 years of age.
Per protocol, since May 10, 2021, following issuance of the Emergency Use
Authorization for the Pfizer-BioNTech COVID-19 Vaccine for individuals 12-15 years of
age, Phase 3 participants 12-15 years of age in the vaccine and placebo groups were progressively unblinded to their treatment assignment (when eligible per local
recommendations). Participants initially randomized to the placebo group were offered
BNT162b2 vaccination at a time no later than the 6-month follow-up visit after the
second placebo vaccination. For participants unblinded to his/her vaccine assignment,
follow-up evaluations thereafter were conducted in an open-label manner.
Reviewer Comment: During the blinded placebo-controlled time period, study staff
who prepared and administered the study interventions were unblinded to the
treatment assignment, due to differences in appearance of BNT162b2 and saline
placebo, and study investigators/personn el collecting and evaluating safety and
efficacy information were blinded to the participants’ treatment assignment
Clinical Reviewer: Susan K. Wollersheim, MD
STN:125742/45
23
(observer-blinded). In the package insert, double-blind refers only to the study
investigators/personnel collecting and eval uating safety and efficacy information
and the participant.
After BNT162b2 became available for emergency use, participants who elected to
receive BNT162b2 were unblinded to their initial study intervention assignment. The Applicant and site personnel who are responsible for the ongoing conduct of
the study remain blinded to the data from participants whose treatment assignment
has not been disclosed.
6.1.3 Population
Phase 3
Key inclusion criteria
x Healthy or had pre-existing stable chronic medical conditions
x \HDUV of age.
x At higher risk for acquiring COVID-19 (including, but not limited to, use of mass
transportation, relevant demographics, frontline essential workers).
Key exclusion criteria
x Previous clinical (based on COVID-19 symptoms/signs alone, if a SARS-CoV-2
NAAT result was not available) or microbiological (based on COVID-19
symptoms/signs and a positive SARS-CoV-2 NAAT result) diagnosis of COVID-19
x Known or suspected immunodeficiency, or received/planning treatment with
immunosuppressive therapy, including cytotoxic agents or systemic corticosteroids,
or planned receipt throughout the study
x Women who are pregnant or breastfeeding
x Receipt of blood/plasma products or immunoglobulin, from 60 days before study
intervention administration or planned receipt throughout the study.
Criteria for temporarily delaying enrollment/randomization/study intervention
administration
x Current febrile illness (T & RU RWKHU DFXWH LOOQHVV ZLWKLQ KRXUV EHIRUH VWXG\
intervention administration, including symptoms that could represent a potential
COVID-19 illness: new or increased cough; new or increased shortness of breath,
chills, new or increased muscle pain, new loss of taste/smell, sore throat, diarrhea,
vomiting.
x Receipt or planning to receive a seasonal or pandemic influenza vaccine within 14
days, or any other non-study vaccine within 28 days, before or after study
vaccination.
x Receipt of short-term (<14 days) syste mic corticosteroids. Study intervention
administration should be delayed until systemic corticosteroid use has been
discontinued for at least 28 days. Inhaled/nebulized, intra-articular, intrabursal, or topical (skin or eyes) corticosteroids are permitted.
6.1.4 Study Treatments or Agents Mandated by the Protocol
The BNT162b2 ( ȝJ vaccine candidate was selected for further evaluation in Phase
2/3. BNT162b2 contains a nucleoside-modified messenger RNA that encodes the viral
spike (S) glycoprotein of SARS-CoV-2 encaps ulated in a lipid nanoparticle. Each dose
also includes the following ingredients: lip ids ((4-hydroxybutyl)azanediyl)bis(hexane-
Clinical Reviewer: Susan K. Wollersheim, MD
STN:125742/45
24
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 phos phate, sodium chlori de, dibasic sodium
phosphate dihydrate, and sucrose.
6.1.5 Directions for Use
Two doses of BNT162b2 (0.3 mL per dose) were administered 3 weeks apart. Each
dose was injected intramuscularl y into the deltoid muscle.
See the full prescribing information for further information regarding preparation of
BNT162b2.
6.1.6 Sites and Centers
A total of 29 clinical sites enrolled parti cipants 12-15 years of age for Study C4591001
in the United States.
6.1.7 Surveillance/Monitoring
Efficacy
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 an RT-PCR test (e.g., Cepheid; FDA authorized under EUA), or other sufficiently validated NAAT, to
detect SARS-CoV-2. Case ascertainment is based on central laboratory NAAT results,
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).
Safety
Solicited AEs (local and systemic reactions, and antipyretic/pain medication usage from
Day 1 through Day 7 after each dose) were assessed for all participants 12-15 years of
age. Additionally, all unsolicited AEs were collected from Dose 1 to 1 month after the
Dose 2, and all SAEs from Dose 1 to 6 months after Dose 2. The planned safety follow-
up for currently enrolled adolescents is a maximum of 26 months (i.e., through 24
months after vaccination #2) and will include collection of deaths and related SAEs
reported after 6 months post-Dose 2.
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.
After BNT162b2 was granted emergency use authorization for this age group (May 10,
2021), unblinding procedures were initiated to vaccinate the placebo group. Please see
Section 6.1.10.1 (Population enrolled/analyzed) for additional details.
Clinical Reviewer: Susan K. Wollersheim, MD
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6.1.8 Endpoints and Criteria for Study Success
Immunogenicity endpoint for adolescents 12 through 15 years of age
x GMR: the ratio of the geometric mean of SARS-CoV-2 neutralizing titers in the two
age groups (12-15 years and 16-25 years) 1 month after completion of vaccination,
in participants without serological or virological evidence of past SARS CoV-2
infection before and during vaccination regimen.
x Immunobridging success would be demonstrated upon rejection of the null
hypothesis: GMR of neutralizing antibody titers (adolescents to young adults) <0.67-
fold, i.e., the lower bound of the 95% CI for the GMR is >0.67.
x Immunobridging also included a descri ptive analysis of the difference in
seroresponse rates (adolescents minus young adults) among participants without
prior evidence of SARS-CoV-2 infection. Seroresponse was defined as a 4-fold
rise in SARS-CoV-2 50% neutralizing titers from before vaccination to 1 month after
Dose 2.
6.1.9 Statistical Considerations & Statistical Analysis Plan
The estimands to evaluate the immunogenicity objectives were based on evaluable
populations for immunogenicity ( Section 6.1.10.1 ). These estimands estimated the
vaccine effect in the setting where partic ipants follow the study schedules and protocol
requirements as directed. One of the secondary objectives in the Phase 3 part of the
study was to evaluate noninferiority of the immune response to prophylactic BNT162b2
in participants 12-15 years of age compared to the response in participants 16-25 years
of age at 1 month after Dose 2. The (D ose 2) evaluable immunogenicity population was
used for the following hypothesis testing: H 0 OQ ȝ 2) – OQ ȝ 1 OQ where ln (0.67)
corresponds to a 1.5- IROG PDUJLQ IRU QRQLQIHULRULW\ OQ ȝ 2 DQG OQ ȝ 1) are the natural log of
the geometric mean of SARS-CoV-2 neutralizing titers from BNT162b2 recipients 12 to
15 years of age and 16 to 25 years of age, respectively, measured 1 month after Dose 2. If the lower limit of the 95% CI for the GMR (12-15 years of age to 16-25 years of
age) was >0.67, the noninferiority objective was met.
Solicited safety analyses were based on participants who received at least one dose of
the vaccine and responded yes or no to any reaction within 7 days of each dose.
Unsolicited safety analyses were based on the safety population, which consisted of
participants randomized in the Phase 2/3 study who received at least one dose of the
vaccine, analyzed according to the vaccine received. Safety endpoints were
summarized descriptively for the number of participants within the analysis set reporting at least one event in each category.
6.1.10 Study Population and Disposition
6.1.10.1 Populations Enrolled/Analyzed
The study protocol was revised to allow participants 12-15 years of age who originally
received placebo the opportunity to receive BNT162b2 following local or national
recommendations or following completion of the active safety surveillance period,
following issuance of the EUA (protocol amendment 10). On May 10, 2021, the process of disclosing vaccine assignments for all trial participants 12-15 years of age began
(following issuance of the EUA for use of the Pfizer-BioNTech COVID-19 vaccine in
individuals 12-15 years of age). Hence, for each trial participant, there are 2 periods in
Clinical Reviewer: Susan K. Wollersheim, MD
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26
the study: enrollment into the observer-blind phase until the date of vaccine disclosure
and the time in the study after disclosure. Participants who originally were randomized
to BNT162b2 are continuing to be followed for safety as specified in the protocol. The
safety data for participants who originally were randomized to and received placebo
prior to disclosure of vaccine assignment include blinded data that contribute to
controlled assessment of safety, immunogenici ty, and efficacy compared to individuals
who randomly assigned to BNT162b2. Afte r vaccine treatment disclosure and the
administration of BNT162b2, the placebo par ticipants can no longer be used for direct
comparison with those who originally were randomized to BNT162b2. Even though
individuals were unblinded on different days a fter May 10, 2021, the difference in the
total blinded follow-up duration is minor between the treatment arms. Thus, the analysis
of the observer-blinded, placebo-controlled portion of the study as well as the open-
label portion is reported in frequencies, such that the number of participants within the
analysis set reporting at least one event in each category is displayed.
Safety data presented for Phase 3 of Study C4591001, based on the data cutoff date of
September 2, 2021, include:
1. Blinded placebo-controlled period: Dose 1 to unblinding date, with a median follow-
up duration of 4.4 months:
x Participants with up to ~6 months of follow-up after Dose 2 (N=2260; BNT162b2
group N=1131 and placebo group N=1129).
2. Open-label observational period: from time of unblinding to data cutoff date, with a
median follow-up duration of 4.0 months for both groups:
x Participants originally randomized to BNT162b2 (N=1107)
x Participants originally randomized to placebo who then received BNT162b2
(N=1010)
x Only unsolicited AEs (AEs, SAEs and adverse events of special interest
[AESIs]) were assessed during this time period.
3. Cumulative follow-up from Dose 1 to at least 6 months after Dose 2, with a median
follow-up duration of 8.4 months after Dose 2.:
x Participants originally randomized to BNT162b2 (inclusive of blinded data and
open-label data through the September 2, 2021 data cutoff). (Total N=1113).
Reviewer Comment: The safety data from time period of Dose 1 to 1 month post
Dose 2 (solicited local and systemic reactions, and unsolicited adverse events from
Dose 1 through 1 month post Dose 2) were previously reviewed ( Adolescent EUA
Review Memo ).
A graphic of these three different time periods taken into consideration for the
evaluation of the safety data is displayed in Figure 1 , below.
Clinical Reviewer: Susan K. Wollersheim, MD
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Figure 1. Phase 2/3 Safety Analyses: Time Period and Analysis Groups
Source: STN 125742.45 c4591001-ado-mth6-report-body.pdf. Figure 2 (p 78).
1. Will vary by participant. Adverse event data analyzed from Dose 1 to unblinding date, or from unblinding date to data
cutoff date.
2. Up to ~6 months after Dose 2.
3. Cumulative BNT162b2 follow-up to at least 6 months after Dose 2.
Analysis populations
Population Description
Dose 2 evaluable
immunogenicity All eligible randomized participants who receive 2 doses of the
vaccine to which they are randomly assigned, within the predefined
window, have at least 1 valid and determinate immunogenicity result
after Dose 2, have blood collection within an appropriate win dow after
Dose 2, and have no other important protocol deviations as determined by the clinician.
Dose 2 all-available immunogenicity All randomized participants who receive at least 2 doses of the study
intervention with at least 1 valid and determinate immunogenicity result after Dose 2.
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 dose of vaccine.
2. All randomized participants who complete 2 vaccination doses.
Safety All randomized participants who receive at least 1 dose of the study
intervention.
Clinical Reviewer: Susan K. Wollersheim, MD
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Data analysis cutoff dates:
x March 13, 2021 (Phase 2/3 immunobridging analysis, explorator y vaccine efficacy
analysis and safety follow-up previously revi ewed in support of the Pfizer-BioNTech
COVID-19 Vaccine EUA amendment for use of a 2-dose primary series in
adolescents 12-15 years of age)
x September 2, 2021 (Phase 2/3 updated exploratory vaccine efficacy analysis and
safety follow-up)
Reviewer Comment: All of the COVID-19 cases analyzed through the March 13,
2021 cutoff occurred during the ancestral (Wuhan with D614G mutation) predominant period, while additional case s analyzed through the September 2,
2021 cutoff all occurred during May 2021 or earlier and therefore occurred prior to
the emergence of the Delta and Omicron variants.
6.1.10.2 Demographics
The Dose 2 evaluable immunogenicity popul ation included 245 participants 12-15 years
of age (209 in the Pfizer BioNTech COVID-19 Vaccine group and 36 in the placebo
group) and 218 participants 16-25 years of age (186 in the Pfizer BioNTech COVID-19
Vaccine group and 32 in the placebo group). Please refer to the Adolescent EUA
Review Memo for the description of demographics for this population.
The demographic characteristics of the evaluable efficacy population in participants 12-
15 years of age for the VE analyses (N=1005 vaccine group, N=978 placebo group) are similar to the baseline characteristics of the Dose 1 all-available efficacy population.
The Dose 1 all-available efficacy popul ation of 12-15-year-olds (BNT162b2 N=1131,
placebo N=1129) were the same individuals as the 12-15-year-olds in the safety
population ( Table 4 ).
The safety population included 2260 participants 12-15 years of age (1131 in the
BNT162b2 group and 1129 in the placebo group). The median age was 14 years, and
all participants live in the US. Overall, the safety population was 49.0% female; 85.5%
White, 4.8% African American, 6.3% Asian, and <3% from other racial groups; 11.6% of
participants were Hispanic/Latino. One or more comorbidities that increase the risk of
severe COVID-19 disease were present among 21.7% of participants. Only 4.2% of
participants had evidence of prior SARS-CoV-2 infection. The demographics were
balanced between the treatment groups. Table 4 presents the specific demographic
characteristics in the studied population.
Table 4. Demographics and Other Baseline Characteristics, Participants 12 Through 15
Years of Age, Safety Population (Data Cutoff September 2, 2021)
Characteristic BNT162b2
(30 ȝJ
(Na=1131)
nb (%) Placebo
(Na=1129)
nb (%) Total
(Na=2260)
nb (%)
Sex: Female 564 (49.9) 544 (48.2) 1108 (49.0)
Sex: Male 567 (50.1) 585 (51.8) 1152 (51.0)
Age at Vaccination: Mean years (SD) 13.6 (1.11) 13.6 (1.11) 13.6 (1.11)
Age at Vaccination: Median (years) 14.0 14.0 14.0
Age at Vaccination: Min, max (years) (12, 15) (12, 15) (12, 15)
Race: American Indian or Alaska Native 4 (0.4) 3 (0.3) 7 (0.3)
Clinical Reviewer: Susan K. Wollersheim, MD
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Characteristic BNT162b2
(30 ȝJ
(Na=1131)
nb (%) Placebo
(Na=1129)
nb (%) Total
(Na=2260)
nb (%)
Race: Asian 72 (6.4) 71 (6.3) 143 (6.3)
Race: Black or African American 52 (4.6) 57 (5.0) 109 (4.8)
Race: Native Hawaiian or Other Pacific Islander 3 (0.3) 0 3 (0.1)
Race: White 970 (85.8) 962 (85.2) 1932 (85.5)
Race: Multiracial 24 (2.1) 29 (2.6) 53 (2.3)
Race: Not reported 6 (0.5) 7 (0.6) 13 (0.6)
Ethnicity: Hispanic or Latino 132 (11.7) 130 (11.5) 262 (11.6)
Ethnicity: Not Hispanic or Latino 997 (88.2) 996 (88.2) 1993 (88.2)
Ethnicity: Not reported 2 (0.2) 3 (0.3) 5 (0.2)
Obesity: Yesc 143 (12.6) 128 (11.3) 271 (12.0)
Obesity: No 988 (87.4) 1001 (88.7) 1989 (88.0)
Comorbidities: Yesd 249 (22.0) 242 (21.4) 491 (21.7)
Comorbidities: No 882 (78.0) 887 (78.6) 1769 (78.3)
Baseline evidence of prior SARS-CoV-2 infection:
Negativee 1083 (95.8) 1078 (95.5) 2161 (95.6)
Baseline evidence of prior SARS-CoV-2 infection: Positive
f 46 (4.1) 50 (4.4) 96 (4.2)
Baseline evidence of prior SARS-CoV-2 infection: Missing 2 (0.2) 1 (0.1) 3 (0.1)
Country: United States of America 1131 (100.0) 1129 (100.0) 2260 (100.0)
Source: STN 125742.45 c4591001-508-compliant tables-12-15 years.doc, Table F, Pages 10-11.
Abbreviation: SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2.
a. N = number of subjects in the specified group, or the total sample. This value is the denominator for the percentage
calculations.
b. n = Number of subjects with the specified characteristic.
c. Subjects who had a BMI at or above the 95th percentile from the CDC growth chart.
d. Number of subjects who have 1 or more comorbidities that increase the risk of severe COVID-19 disease: defined as
VXEMHFWV ZKR KDG DW OHDVW RQH RI WKH &KDUOVRQ FRPRUELGLW\ LQGH[ FDWHJRU\ RU %0, th percentile.
e. Positive N-binding antibody result at Visit 1, positive NAAT result at Visit 1, or medical history of COVID-19.
f. Negative N-binding antibody result and negative NAAT result at Visit 1 and no medical history of COVID-19.
6.1.10.3 Subject Disposition
The overall study disposition tables are presented below in Table 5 (Blinded Follow-up
Time Period) and Table 6 (Open-label Unblinded Follow-up Time Period). Overall, few
participants were discontinued or lost to follow-up and these discontinuations were
generally balanced between treatment groups.
A total of 4 (0.4%) Phase 2/3 original BNT162b2 participants received Dose 1 of
BNT162b2 during the blinded placebo-controlled follow-up period and then received
Dose 2 of BNT162b2 during the open-label follow-up period (when they were
unblinded). Among all 1107 participants originally randomized to BNT162b2 and
included in open-label follow-up, 45 (4.0%) withdrew from the study during open-label
follow-up ( Table 6 ), and 21 of the 23 participants who withdrew for “other reasons” were
enrolled into Study C4591031 to evaluate a booster dose of BNT162b2.
During the open-label follow-up period, most participants originally randomized to the
placebo group for Doses 1 and 2 of study vaccine received BNT162b2 as Doses 3 and
4 (89.4% and 87.8%, respectively) of study vaccine. Most participants who received
Dose 3 but not Dose 4 were within the 3-week window between the two doses as of the
data cutoff date. There were few participants in this group (n=6; 0.5%) who were withdrawn from the study, and most were due to withdrawals by the participant. The
Clinical Reviewer: Susan K. Wollersheim, MD
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number of participants originally randomiz ed to the placebo group who were unblinded
and received BNT162b2 was 1010.
Table 5. Study Disposition of Phase 2/3 Randomized Participants 12 Through 15 Years of
Age, Blinded Follow-Up Period
Disposition BNT162b2
ȝJ
(Na=1134)
nb (%) Placebo
(Na=1130)
nb (%) Total
(Na=2264)
nb (%)
Randomized 1134 (100.0) 1130 (100.0) 2264 (100.0)
Not vaccinated 3 (0.3) 1 (0.1) 4 (0.2)
Original blinded placebo-controlled follow-up period - - -
Vaccinated 1131 (99.7) 1129 (99.9) 2260 (99.8)
Dose 1 1131 (99.7) 1129 (99.9) 2260 (99.8)
Dose 2 1124 (99.1) 1117 (98.8) 2241 (99.0)
Discontinued from original blinded placebo-
controlled vaccination periodc 3 (0.3) 14 (1.2) 17 (0.8)
Reason for discontinuation - - -
No longer meets eligibility criteria 0 7 (0.6) 7 (0.3)
Protocol deviation 0 2 (0.2) 2 (0.1)
Adverse event 1 (0.1) 0 1 (0.0)
Physician decision 1 (0.1) 0 1 (0.0)
Withdrawal by subject 0 1 (0.1) 1 (0.0)
Withdrawal by parent/guardian 0 1 (0.1) 1 (0.0)
Other 1 (0.1) 3 (0.3) 4 (0.2)
Unblinded before 1-month post–Dose 2 visit 12 (1.1) 21 (1.9) 33 (1.5)
Completed 1-month post–Dose 2 visit 1113 (98.1) 1096 (97.0) 2209 (97.6)
Withdrawn from the study 5 (0.4) 14 (1.2) 19 (0.8)
Withdrawn after Dose 1 and before Dose 2 0 0 0
Withdrawn after Dose 2 and before 1-month
post–Dose 2 visit 0 3 (0.3) 3 (0.1)
Withdrawn after 1-month post–Dose 2 visit 5 (0.4) 11 (1.0) 16 (0.7)
Reason for withdrawal from the study - - -
Withdrawal by subject 1 (0.1) 7 (0.6) 8 (0.4)
Withdrawal by parent/guardian 1 (0.1) 5 (0.4) 6 (0.3)
Lost to follow-up 3 (0.3) 2 (0.2) 5 (0.2)
Source: STN 125742.45 c4591001-508-compliant tables-12-15 years.doc, Table B, Pages 2-4.
a. N = number of randomized participants in the specified group, or the total sample. This value is the denominator for
the percentage calculations.
b. n = Number of participants with the specified characteristic.
c. Original blinded placebo-controlled vaccination period is defined as the time period from Dose 1 to 1-month post–Dose
2 visit.
d. Open-label vaccination period is defined as the time period from Dose 3 (first dose of BNT162b2 [30 μg]) to 1-month
post–Dose 4 (second dose of BNT162b2 [30 μg]) visit.
Table 6. Study Disposition of Phase 2/3 Randomized Participants 12 Through 15 Years of
Age, Open-Label (Unblin ded) Follow-Up Period
Disposition BNT162b2
(30 ȝJ
(Na=1134)
nb (%) Placebo
(Na=1130)
nb (%)
Open-label follow-up period - -
Originally randomized to BNT162b2 1107 (97.6) -
Received Dose 2/unplanned dose 4 (0.4) -
Completed 1-month post–Dose 2 visit 15 (1.3) -
Completed 6-month post–Dose 2 visit 1065 (93.9) -
Clinical Reviewer: Susan K. Wollersheim, MD
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Disposition BNT162b2
(30 ȝJ
(Na=1134)
nb (%) Placebo
(Na=1130)
nb (%)
Withdrawn from the study 45 (4.0) -
Withdrawn before 6-month post–Dose 2 visit 25 (2.2) -
Withdrawn after 6-month post–Dose 2 visit 20 (1.8) -
Reason for withdrawal from the study - -
Withdrawal by subject 7 (0.6) -
Withdrawal by parent/guardian 7 (0.6) -
Lost to follow-up 6 (0.5) -
Protocol deviation 1 (0.1) -
No longer meets eligibility criteria 1 (0.1) -
Other 23 (2.0) -
Originally randomized to placebo - 1108 (98.1)
Withdrawn from the study after unblinding and before
Dose 3 - 47 (4.2)
Received Dose 3 (first dose of %17E > ȝJ@ - 1010 (89.4)
5HFHLYHG 'RVH VHFRQG GRVH RI %17E > ȝJ@ - 992 (87.8)
Discontinued from open-label vaccination periodd - 5 (0.4)
Reason for discontinuation from open-label vaccination period - -
Protocol deviation - 4 (0.4)
Withdrawal by subject - 1 (0.1)
Completed 1-month post–Dose 4 visit - 933 (82.6)
Withdrawn from the study - 6 (0.5)
Withdrawn after Dose 3 and before Dose 4 - 5 (0.4)
Withdrawn after Dose 4 and before 1-month post–Dose 4 visit - 0
Withdrawn after 1-month post–Dose 4 visit - 1 (0.1)
Reason for withdrawal from the study
Withdrawal by subject - 3 (0.3)
Lost to follow-up - 2 (0.2)
Protocol deviation - 1 (0.1)
Source: STN 125742.45 c4591001-508-compliant tables-12-15 years.doc, Table B, Pages 2-4.
a. N = number of randomized participants in the specified group, or the total sample. This value is the denominator for
the percentage calculations. b. n = Number of participants with the specified characteristic.
c. Original blinded placebo-controlled vaccination period is defined as the time period from Dose 1 to 1-month post–Dose
2 visit.
d. Open-label vaccination period is defined as the time period from Dose 3 (first dose of BNT162b2 [30 μg]) to 1-month
post–Dose 4 (second dose of BNT162b2 [30 μg]) visit.
The duration of blinded follow-up after completion of the 2-dose vaccine series in the
safety population is displayed in Table 7 . Because this study is ongoing, and
participants were unblinded to their study intervention following issuance of the EUA
Amendment in May 2021 or at their 6-month follow-up visit, the number of participants
with blinded follow-up decreases beyond 6 months, as expected .
Clinical Reviewer: Susan K. Wollersheim, MD
STN:125742/45
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Table 7. Blinded Follow-up Duration After Dose 2, Participants 12-15 Years of Age, Safety
Population
Length of Follow-upc Vaccine Group
(as Administered)
BNT162b2
Na =1131
nb (%) Vaccine Group
(as Administered)
Placebo
Na =1129
nb (%) Total
Na =2260
nb (%)
<4 Months 345 (30.5) 356 (31.5) 701 (31.0)
4 Month to <5 months 528 (46.7) 532 (47.1) 1060 (46.9)
0RQWKV WR PRQWKV 106 (9.4) 97 (8.6) 203 (9.0)
0RQWKV 152 (13.4) 144 (12.8) 296 (13.1)
Source: STN 125742.45 c4591001-508-compliant tables-12-15 years.doc, Table A, page 1
a. N = number of participants in the specified group, or the total sample. This value is the denominator for the
percentage calculations.
b. n = number of participants with the specified characteristic.
c. Length of follow-up is the total exposure from Dose 2 to cutoff date or the date of unblinding, whichever date was
earlier.
The number of original BNT162b2 recipients in the safety population with months
duration of total (blinded and open-label) follow-up from Dose 2 to the data cutoff date
for was 1113 (98.4%).
Disposition is further presented below in Table 8 (efficacy analysis populations) and
Table 9 (Safety population). Overall, few participants were discontinued or lost to follow-
up, and these and other analysis population exclusions were generally balanced between treatment groups.
For immunogenicity analyses, the Sponsor pl anned to select a random sample of 280
participants in the BNT162b2 group for each of the two age groups as an
immunogenicity subset for immunobridging. Please refer to the Adolescent EUA Review
Memo for the description of disposition for this population.
For the evaluable efficacy population, most participants who were excluded from the
analysis had not received all vaccinations as randomized or did not receive Dose 2
within the predefined window (i.e., 19 to 42 days after Dose 1).
Table 8. Disposition of Participants 12 Through 15 Years of Age, Efficacy Population
(Data Cutoff September 2, 2021)
Disposition BNT162b2
ȝJ
na (%) Placebo
na (%) Total
na (%)
Randomizedb 1134
(100.0) 1130
(100.0) 2264
(100.0)
Dose 1 all-available efficacy population 1131
(99.7) 1129
(99.9) 2260
(99.8)
Subjects without evidence of infection before Dose 1 1083
(95.5) 1078
(95.4) 2161
(95.5)
Subjects excluded from Dose 1 all-available efficacy
population 3 (0.3) 1 (0.1) 4 (0.2)
Reason for exclusionc - - -
Did not receive at least 1 vaccination 3 (0.3) 1 (0.1) 4 (0.2)
Dose 2 all-available efficacy population 1123
(99.0) 1117
(98.8) 2240
(98.9)
Subjects without evidence of infection prior to 7 days after Dose 2 1061
(93.6) 1037
(91.8) 2098
(92.7)
Clinical Reviewer: Susan K. Wollersheim, MD
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Disposition BNT162b2
ȝJ
na (%) Placebo
na (%) Total
na (%)
Subjects excluded from Dose 2 all-available efficacy
population 11 (1.0) 13 (1.2) 24 (1.1)
Reason for exclusionc - - -
Did not receive 2 vaccinations 10 (0.9) 13 (1.2) 23 (1.0)
Unblinded prior to 7 days after Dose 2 1 (0.1) 0 1 (0.0)
Evaluable efficacy (7 days) population 1119
(98.7) 1109
(98.1) 2228
(98.4)
Subjects without evidence of infection prior to 7 days
after Dose 2 1057
(93.2) 1030
(91.2) 2087
(92.2)
Subjects excluded from evaluable efficacy (7 days) population 15 (1.3) 21 (1.9) 36 (1.6)
Reason for exclusionc - - -
Randomized but did not meet all eligibility criteria 1 (0.1) 1 (0.1) 2 (0.1)
Did not receive all vaccinations as randomized or did not receive Dose 2 within the predefined window (19-42 days after Dose 1) 14 (1.2) 19 (1.7) 33 (1.5)
Unblinded prior to 7 days after Dose 2 1 (0.1) 0 1 (0.0)
Had other important protocol deviations on or prior to 7 days after Dose 2 0 3 (0.3) 3 (0.1)
Source: STN 125742.45 c4591001-508-compliant tables-12-15 years.doc, Table E, Pages 8-9.
a. n = Number of subjects with the specified characteristic.
b. These values are the denominators for the percentage calculations.
c. Subjects may have been excluded for more than 1 reason.
The safety population included a total of 226 0 participants: 1131 participants in the
BNT162b2 group and 1129 participants in the placebo group.
Table 9. Disposition of Participants 12 Throug h 15 Years of Age, Safety Population (Data
Cutoff September 2, 2021)
Disposition BNT162b2
ȝJ
(Na=1131)
nb (%) Placebo
(Na=1129)
nb (%) Total
(Na=2260)
nb (%)
Vaccinated 1131
(100.0) 1129
(100.0) 2260 (100.0)
Completed 1 dose 1131
(100.0) 1129
(100.0) 2260 (100.0)
Completed 2 doses 1124 (99.4) 1117
(98.9) 2241 (99.2)
Safety population 1131
(100.0) 1129
(100.0) 2260 (100.0)
Participants excluded from safety population - - 4
Reason for exclusion - - -
Participant did not receive study vaccine - - 4
Completed at least 6 months follow-up after Dose 2 in
blinded placebo-controlled follow-up period 152 (13.4) 144 (12.8) 296 (13.1)
Completed at least 6 months follow-up after Dose 2 in blinded and open-label follow-up period 1113 (98.4) - -
Completed 1-month post–Dose 2 visit (vaccination period) 1113 (98.4) 1096
(97.1) 2209 (97.7)
Clinical Reviewer: Susan K. Wollersheim, MD
STN:125742/45
34
Disposition BNT162b2
ȝJ
(Na=1131)
nb (%) Placebo
(Na=1129)
nb (%) Total
(Na=2260)
nb (%)
Discontinued from vaccination period but continued in the
study up to 1-month post–Dose 2 visit 3 (0.3) 14 (1.2) 17 (0.8)
Discontinued after Dose 1 and before Dose 2 3 (0.3) 10 (0.9) 13 (0.6)
Discontinued after Dose 2 and before 1-month post–Dose 2 visit 0 4 (0.4) 4 (0.2)
Reason for discontinuation from vaccination period - - -
No longer meets eligibility criteria 0 7 (0.6) 7 (0.3)
Protocol deviation 0 2 (0.2) 2 (0.1)
Adverse event 1 (0.1) 0 1 (0.0)
Physician decision 1 (0.1) 0 1 (0.0)
Withdrawal by subject 0 1 (0.1) 1 (0.0)
Withdrawal by parent/guardian 0 1 (0.1) 1 (0.0)
Other 1 (0.1) 3 (0.3) 4 (0.2)
Withdrawn from study before 1-month post–Dose 2 visit 0 3 (0.3) 3 (0.1)
Withdrawn after Dose 1 and before Dose 2 0 0 0
Withdrawn after Dose 2 and before 1-month post–Dose 2 visit 0 3 (0.3) 3 (0.1)
Reason for withdrawal
Withdrawal by parent/guardian 0 2 (0.2) 2 (0.1)
Withdrawal by subject 0 1 (0.1) 1 (0.0)
Source: STN 125742.45 c4591001-508-compliant tables-12-15 years.doc, Table D, Pages 6-7.
a. N = number of participants in the specified group, or the total sample. This value is the denominator for the
percentage calculations.
b. n = Number of participants with the specified characteristic.
6.1.11 Vaccine Effectiveness 6.1.11.1 Analyses of Secondary Endpoint
Immunogenicity
The immune response to BNT162b2 in adolescents 12-15 years of age was noninferior
to that observed in young adults 16-25 years of age, based on SARS-CoV-2 50%
neutralizing titers at 1 month after Dose 2 in participants without prior evidence of
SARS-CoV-2 infection. The geometric mean titer (GMT) ratio of adolescent to young
adult neutralizing antibody titers was 1.77 (2-sided 95% CI: 1.5, 2.09), meeting the 1.5-
fold non-inferiority criterion (i.e., lower bound of the 2-sided 95% CI for GMR >0.67).
Clinical Reviewer: Susan K. Wollersheim, MD
STN:125742/45
35
Table 10. Geometric Mean SARS-CoV-2 Neutralizing Titers (NT50)a 1 Month After
BNT162b2 Dose 2 in Participants 12 Through 15 and 16 Through 25 Years of Age,
Participants Without Evidence of Infection up to 1 Month After Dose 2, Dose 2 Evaluable
Immunogenicity Population
Study Group 12-15 Years
N=190
GMT
(95% CI) 16-25 Years
N=170
GMT
(95% CI) GMT Ratio
[12-15 Years/
16-25 Years]
(95% CI) Met Predefined
Success
Criterionb
BNT162b2 1253.6
(1117.7, 1406.1) 708.1
(625.9, 801.1) 1.77
(1.50, 2.09) Yes
Source: STN 125742.45 amendment 4. Appendix 1-immunobridging-data-c4591001.pdf. Page 8.
a. SARS-CoV-2 NT50 were determined using the SARS-CoV-2 mNeonGreen Virus Microneutralization Assay. The
assay uses a fluorescent reporter virus derived from the USA_WA1/2020 strain and virus neutralization is read on Vero
cell monolayers. The sample NT50 is defined as the reciprocal serum dilution at which 50% of the virus is neutralized.
b. Noninferiority is declared if the lower bound of the 2-sided 95% CI for the GMR is greater than 0.67. N=Number of participants with valid and determinate assay results for the specified assay at 1 month after Dose 2. GMT=geometric mean titer
The GMR of SARS CoV-2 neutralizing titers one month after Dose 2 did not vary by
demographic subgroup, although some subgroups were too small to evaluate by
protocol-specified methods.
Please refer to the Adolescent EUA Review Memo for additional analyses of the
immunogenicity results.
Reviewer Comment: The GMT calculations for the analyses presented above
are based on the SARS-CoV-2 mNeonGreen Virus Microneutralization lower
level of quantification titer of 41. The GMT analyses for the EUA submission for
this age group were based on the limit of detection for the assay, which is a titer
of as the lower range cutoff. The clinical reviewer’s conclusions, based on
the updated immunogenicity analyses presented in this sBLA, are unchanged
from the conclusions in the Adolescent EUA review memo.
Vaccine Effica cy
For the VE evaluation of BNT162b2 against confirmed COVID-19 was evaluated in
participants without evidence of prior SARS-CoV-2 infection prior to 7 days after Dose
2. Cases were counted from 7 days after Dose 2. Descriptive analyses of VE in adolescents 12-15 years of age were conducted with all cases accrued during blinded
follow-up to a data cutoff date of March 13, 2021 to support issuance of the EUA
Amendment for use of the Pfizer-BioNTech COVID-19 Vaccine in this age group on
May 10, 2021. 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 100.0% (95% CI: 75.3, 100.0). The case split was 0 COVID-19 cases in the
BNT162b2 group compared to 16 COVID-19 cases in the placebo group. Please refer
to the Adolescent EUA Review Memo for additional details from that analysis time point.
Updated efficacy analyses
Updated efficacy analyses were perform ed with additional confirmed COVID-19 ca ses
accrued during blinded placebo-controlled follow-up through September 2, 2021,
representing a median of 6 months of follow-up after Dose 2 for participants in the
efficacy population. All of the following updated primary and secondary VE analyses are
from this blinded placebo-controlled follow-up period through the September 2, 2021
data cutoff. (b) (4)
Clinical Reviewer: Susan K. Wollersheim, MD
STN:125742/45
36
For the first updated efficacy endpoint, VE 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 updated efficacy endpoint, VE 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.
For participants without evidence of SARS-CoV-2 infection prior to 7 days after Dose 2,
the updated VE against confirmed COVID-19 occurring at least 7 days after Dose 2 was
100.0%. The case split was 0 COVID-19 cases in the BNT162b2 group compared to 28
COVID-19 cases in the placebo group ( Table 11 ).
Table 11. Updated Vaccine Efficacy Against Confirmed COVID-19 in Participants Without
Evidence of Prior SARS-CoV-2 Infection, Participants 12-15 Years of Age, Evaluable
Efficacy Population (Data Cutoff September 2, 2021)
Endpoint BNT162b2
(Na =1057)
Cases
n1b
Surveillance Timec
(n2d) Placebo
(Na =1030)
Cases
n1b
Surveillance Timec
(n2d) Vaccine Efficacy
%
(95% CI)e
First COVID-19
Occurrence from 7 days after Dose 2 0
0.343
(1043) 28
0.322
(1019) 100.0
(86.8, 100.0)
Source: STN 125742.45 c4591001-interim-ado-mth6-report-body.pdf, Table 12, Page 67
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 (ie, 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.
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. Confidence interval (CI) for VE is derived based on t he Clopper and Pearson method adjusted for surveillance time.
For participants with and without evidence of SARS-CoV-2 infection before and during
vaccination regimen, the updated VE against confirmed COVID-19 occurring at least 7
days after Dose 2 was 100.0%, with 0 and 30 cases in the BNT162b2 and placebo groups, respectively ( Table 12 ).
Clinical Reviewer: Susan K. Wollersheim, MD
STN:125742/45
37
Table 12. Updated Vaccine Efficacy Against Confirmed COVID-19 in Participants With or
Without Evidence of Prior SARS-CoV-2 Infect ion, Participants 12-15 Years of Age,
Evaluable Efficacy Population (Data Cutoff September 2, 2021)
Endpoint BNT162b2
(Na =1119)
Cases
n1b
Surveillance Timec
(n2d) Placebo
(Na =1109)
Cases
n1b
Surveillance Timec
(n2d) Vaccine Efficacy %
(95% CI)e
First COVID-19
Occurrence from 7
days after Dose 2 0
0.362
(1098) 30
0.345
(1088) 100.0
(87.5, 100.0)
Source: STN 125742.45 c4591001-interim-ado-mth6-report-body.pdf, Table 13, Page 69
Abbreviations: SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2.
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. Confidence interval (CI) for VE is derived based on the Clopper and Pearson method adjusted for surveillance time.
Multiple Cases of COVID-19
One participant in the placebo group had two positive central laboratory COVID-19
NAAT results with corresponding COVID-19 illness visits. Baseline SARS CoV-2 NAAT
testing at Visit 1 was positive, with a corresponding negative serology for N-binding antibody.
Subgroup Analyses of VE
Because there were no confirmed COVID-19 cases in the BNT162b2 group, all VE
estimates are 100%, with varying 95% confidence interval lower bounds, depending upon the case split for the specific subgroup. The low total number of cases, all of
which occurred in the placebo group, limits the interpretability of the VE results because
of the wide confidence intervals, but are displayed for completeness.
Table 13. Subgroup Analyses of Vaccine Efficacy by Demographic and Baseline
Characteristics: Updated Vaccine Efficacy Against Confirmed COVI D-19 in Participants
With or Without Evidence of Prior SARS-CoV-2 Infection, Evaluable Efficacy Population
Subgroup BNT162b2
(Na =1119)
Cases n1b
Surveillance
Timec (n2d) Placebo
(Na =1109)
Cases n1b
Surveillance
Timec (n2d) Vaccine
Efficacy (%)
(95% CIe)
Overall 0
0.362 (1098) 30
0.345 (1088) 100.0
(87.5, 100.0)
Age group: 12-13 years 0
0.180 (521) 13
0.168 (503) 100.0
(69.3, 100.0)
Age group: 14-15 years 0
0.183 (577) 17
0.178 (585) 100.0
(76.5, 100.0)
Sex: Female 0
0.179 (548) 12
0.169 (527) 100.0
(66.1, 100.0)
Sex: Male 0
0.183 (550) 18
0.177 (561) 100.0
(78.0, 100.0)
Ethnicity: Hispanic or Latino 0
0.045 (127) 7
0.040 (125) 100.0
(37.8, 100.0)
Clinical Reviewer: Susan K. Wollersheim, MD
STN:125742/45
38
Subgroup BNT162b2
(Na =1119)
Cases n1b
Surveillance
Timec (n2d) Placebo
(Na =1109)
Cases n1b
Surveillance
Timec (n2d) Vaccine
Efficacy (%)
(95% CIe)
Ethnicity: Not Hispanic or Latino 0
0.317 (969) 23
0.304 (960) 100.0
(83.3, 100.0)
Race: Black or African American 0
0.019 (47) 2
0.021 (56) 100.0
(-492.9, 100.0)
Race: White 0
0.309 (945) 28
0.291 (926) 100.0
(86.8, 100.0)
Country: United States 0
0.362 (1098) 30
0.345 (1088) 100.0
(87.5, 100.0)
Source: STN 125742.45 c4591001-508-efficacy tables-12-15, Table L, Page 20
Abbreviations: N-binding = SARS-CoV-2 nucleoprotein–binding; NAAT = nucleic acid amplification test;
SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2.
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. Confidence interval (CI) for VE is derived based on the Clopper and Pearson method adjusted for surveillance time.
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.
Clinical Reviewer: Susan K. Wollersheim, MD
STN:125742/45
39
Figure 2. Updated Cumulative Incidence Curves for the First COVID-19 Occurrence After
Dose 1, All-Available Efficacy Population (data cutoff September 2, 2021)
Source: Adapted from STN 125742.45 c4591001-interim-ado-mth6-report-body.pdf, Figure 1, Page 73
An updated analysis of the number of confirmed COVID-19 cases following Dose 1 was
conducted with the all-available efficacy population, for all participants regardless of
evidence of prior infection through 7 days after Dose 2, and at time intervals following
completion of the vaccine series ( Table 14 ).
Table 14. Updated Vaccine Efficacy after Dose 1, Dose 1 All-Available Efficacy Population
Efficacy Endpoint Subgroup BNT162b2
(Na =1131)
Cases
n1b
Surveillance Timec
(n2d) Placebo
(Na =1129)
Cases
n1b
Surveillance Timec
(n2d) Vaccine
Efficacy %
(95% CI)e
First COVID-19 occurrence after
Dose 1 3
0.450 (1109) 48
0.434 (1114) 94.0
(81.3, 98.8)
After Dose 1 to before Dose 2 3
0.065 (1109) 12
0.065 (1114) 75.1
(7.6, 95.5)
Dose 2 to 7 days after Dose 2 0
0.021 (1103) 5
0.021 (1100) 100.0
(-8.7, 100.0)
'D\V DIWHU 'RVH 0
0.364 (1102) 31
0.348 (1095) 100.0
(87.9, 100.0)
'D\V after Dose 2 to <2
Months after Dose 2 0
0.146 (1102) 17
0.142 (1095) 100.0
(76.3, 100.0)
0RQWKV DIWHU 'RVH WR Months after Dose 2 0
0.156 (1065) 10
0.149 (1029) 100.0
(57.3, 100.0)
Clinical Reviewer: Susan K. Wollersheim, MD
STN:125742/45
40
Efficacy Endpoint Subgroup BNT162b2
(Na =1131)
Cases
n1b
Surveillance Timec
(n2d) Placebo
(Na =1129)
Cases
n1b
Surveillance Timec
(n2d) Vaccine
Efficacy %
(95% CI)e
0RQWKV DIWHU 'RVH 0
0.062 (770) 4
0.056 (732) 100.0
(-37.7, 100.0)
Source: STN 125742.45 c4591001-interim-ado-mth6-report-body.pdf, Table 15, Page 72
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 Dose 1 to the end of the surveillance period.
d. n2 = Number of participants at risk for the endpoint.
e. Confidence interval (CI) for VE is derived based on the Clopper and Pearson method adjusted for surveillance time.
The VE estimate for the prevention of COVID-19 disease after Dose 1 in the all-
available efficacy population is 94.0%. 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 3 weeks after a single dose, especially given the
small number of total confirmed COVID-19 cases overall.
6.1.11.2 Analyses of Secondary Endpoints
There were no reports of severe COVID-19 cases (and no cases of MIS-C) in
participants 12-15 years of age.
6.1.11.4 Dropouts and/or Discontinuations The number of participants who dropped out and/or discontinued from the study did not
affect the interpretation of the vaccine efficacy outcomes. Refer to Section 6.1.12.7 for
details regarding dropouts and/or discontinuations.
6.1.11.5 Exploratory and Post Hoc Analyses
Sequencing Data from Centrally Confirmed COVID-19 Cases
Enrollment of adolescents 12-15 year of age in the Phase 3 portion of Study C4591001
was from October 15, 2020 through the data cutoff date of September 2, 2021. Sequence data were available for 29 of 30 SARS-CoV-2 variants identified from
COVID-19 cases; 7 were B.1.1.7 (Alpha) and 29 were categorized as Other.
Reviewer Comment: All confirmed COVID-19 cases in the updated efficacy
analyses occurred between November 2020 and May 2021, prior to the circulation
of the B.1.61.2 (Delta) and B.1.1.529 (Omicron) variants in the US.
6.1.12 Safety Analyses
The Phase 2/3 safety data presented in this section are categorized in following time
periods:
1. Blinded placebo-controlled period: Dose 1 to unblinding date, with a median follow-
up duration of 4.4 months:
x Participants with up to ~6 months after Dose 2 (N=2260; BNT162b2 group
N=1131 and placebo group N=1129).
x Solicited local and systemic Adverse Reactions were assessed for 7 days
following vaccination in all participants.
Clinical Reviewer: Susan K. Wollersheim, MD
STN:125742/45
41
2. Open-label observational period: from time of unblinding to data cutoff date, with a
median follow-up duration of 4.0 months for both groups:
x Participants originally randomized to BNT162b2 (N=1107)
x Participants originally randomized to placebo who then received BNT162b2
(N=1010)
x Only unsolicited AEs (AEs, SAEs and adverse events of special interest
[AESIs]) were assessed during this time period.
3. Cumulative follow-up from Dose 1 to at least 6 months after Dose 2, with a median
follow-up duration of 8.4 months after Dose 2.
x Participants originally randomized to BNT162b2 (inclusive of blinded data and
open-label data through the September 2, 2021 data cutoff). (N=1113 )
Reviewer Comment: Interpretation of safety data from the open-label observational
period are limited because there was no longer a placebo group for safety comparisons in the unblinded portion of the study.
6.1.12.1 Methods
Please see Section 6.1.7 .
6.1.12.2 Overview of Adverse Events
Overview of adverse events
Table 15 below presents an overview of adver se events reported, which includes
immediate unsolicited adverse events, solicited local and systemic reactions,
unsolicited adverse events reported from Dose 1 to 1 month after Dose 2 and from
Dose 1 to the September 2, 2021 data cutoff or participant unblinding, whichever was
earlier, in the safety population.
Table 15. Safety Overview, Participants 12-15 Years of Age, Safety Population
Event BNT162b2
na/Nb (%) Placebo
na/Nb (%)
Immediate unsolicited AE within 30 minutes after vaccination: Dose 1 0/1131 (0.0) 4/1129 (0.4)
Immediate unsolicited AE within 30 minutes after vaccination:
Dose 2 2/1124 (0.2) 3/1117 (0.3)
Solicited injection site reaction within 7 daysa: Dose 1 976/1127 (86.6) 271/1127 (24.0)
Solicited injection site reaction within 7 daysa: Dose 2 872/1097 (79.5) 198/1078 (18.4)
Solicited systemic AE within 7 daysa: Dose 1 877/1127 (77.8) 636/1127 (56.4)
Solicited systemic AE within 7 daysa: Dose 2 904/1097 (82.4) 440/1078 (40.7)
Dose 1 through 1 Month after Dose 2b: Unsolicited non-
serious AE 72/1131 (6.4) 76/1129 (6.7)
Dose 1 through 1 Month after Dose 2b: SAE 4/1131 (0.4) 1/1129 (0.1)
Dose 1 to data cutoff or participant unblinding (whichever is
earlier)b: Any unsolicited AE 95/1131 (8.4) 113/1129 (10.0)
Dose 1 to data cutoff or participant unblinding (whichever is
earlier)b: SAE 10/1131 (0.9) 2/1129 (0.2)
Dose 1 to data cutoff or participant unblinding (whichever is
earlier)b: Withdrawal due to AE 1/1131 (0.1) 0
Dose 1 to data cutoff or participant unblinding (whichever is
earlier)b: Death 0 0
Source: STN 125742.45 c4591001-508-compliant-tables 12-15 years.pdf, Table P, page 25 and STN 125742.45.7
response-14march2022.pdf, Table 2, pages 5-8.
Clinical Reviewer: Susan K. Wollersheim, MD
STN:125742/45
42
Note: Medical Dictionary for Regulatory Activities (v24.0) coding dictionary applied.
Note: Immediate AE refers to an AE reported in the 30-minute observation period after vaccination.
a. N: number of participants in the specified age group in the reactogenicity subset of the safety population with data
available for the adverse event.
b. N: number of participants in the safety population.
Reviewer Comment: Since the last data cutoff on March 13, 2021 (described in
the Adolescent EUA Review Memo ) to this S eptember 2, 2021 data cutoff, there
have been no additional reports of immedi ate unsolicited AEs or local or
systemic reactions. A total of 16 new un solicited non-serious AEs were reported
from Dose 1 through 1 month after Dose 2 (n=6 and n=10 in the BNT162b2 and
placebo groups, respectively), none of which were serious or led to withdrawal.
These new reported non-serious AEs were consistent with events described in
the EUA Review Memo. Please refer to the Adolescent EUA Review Memo for
details.
Immediate AEs
The immediate AEs that occurred were consistent with solicited reactions/events
(injection site pain, headache, dizziness, fatigue, chills) reported among participants in
the reactogenicity subset during the first 7 days following vaccination.
One (1) BNT162b2 recipient and 1 placebo recipient reported symptoms on the day of
vaccination that were consistent with pre-syncope (after BNT162b2 Dose 2 and after
placebo dose 1, respectively). Vasovagal reactions are not uncommon in adolescents
following vaccinations and other medica l procedures involving needlesticks; the
Prescribing Information and Fact Sheet for Healthcare Providers for the authorized
Pfizer-BioNTech COVID-19 Vaccine include a wa rning about measures to avoid injury
following vasovagal/syncopal episodes in the immediate post-vaccination period.
Anaphylaxis
No anaphylactic reactions to BNT162b2 were reported through the cutoff date of
September 2, 2021.
Solicited local reactions and systemic adverse events
Solicited Local Reactions
For BNT162b2 recipients in both age groups, injection site pain was the most frequent
solicited local adverse reaction. The median ons et for all solicited local reactions after
either BNT162b2 dose was Day 1 (day of va ccination) to Day 3, and the median
duration was 1-3 days. Local reactions occurred more frequently after Dose 1 than after Dose 2. Injection site reactions following both doses were mostly mild to moderate.
Injection site reactions were more frequent in the BNT162b2 group than in the placebo
group.
Table 16. Frequency of Solicited Local React ions, by Maximum Severity, Within 7 Days
After Each Dose, Participants 12 Through 15 Years of Age, Safety Populationa
Reaction BNT162b2
Dose 1
N =1127
n (%) Placebo
Dose 1
N =1127
n (%) BNT162b2
Dose 2
N =1097
n (%) Placebo
Dose 2
N =1078
n (%)
Pain at the injection site
b: Anyd 971 (86.2) 263 (23.3) 866 (78.9) 193 (17.9)
Clinical Reviewer: Susan K. Wollersheim, MD
STN:125742/45
43
Reaction BNT162b2
Dose 1
N =1127
n (%) Placebo
Dose 1
N =1127
n (%) BNT162b2
Dose 2
N =1097
n (%) Placebo
Dose 2
N =1078
n (%)
Pain at the injection
siteb: Mild 467 (41.4) 227 (20.1) 466 (42.5) 164 (15.2)
Pain at the injection site: Moderate 493 (43.7) 36 (3.2) 393 (35.8) 29 (2.7)
Pain at the injection site: Severe 11 (1.0) 0 7 (0.6) 0
Rednessc: Anyd 65 (5.8) 12 (1.1) 55 (5.0) 10 (0.9)
Rednessc: Mild 44 (3.9) 11 (1.0) 29 (2.6) 8 (0.7)
Redness: Moderate 20 (1.8) 1 (0.1) 26 (2.4) 2 (0.2)
Redness: Severe 1 (0.1) 0 0 0
Swellingc: Anyd 78 (6.9) 11 (1.0) 54 (4.9) 6 (0.6)
Swellingc: Mild 55 (4.9) 9 (0.8) 36 (3.3) 4 (0.4)
Swelling: Moderate 23 (2.0) 2 (0.2) 18 (1.6) 2 (0.2)
Swelling: Severe 0 0 0 0
Source: EUA 27034.132, c4591001--12-15-tables-figures.docx, Tables R and R.1, pages 18-19.
Reactions and use of antipyretic or pain medication were collected in the electronic diary (e-diary) from Day 1 to Day 7
after each dose.
%:n/N. n=number of participants in the specified age group with the specified reaction. N=number of reactogenicity
subset participants in the specified age group reporting at least 1 yes or no response for the specified reaction after the
specified dose. a. All randomized participants in the reactogenicity subset who received at least 1 dose of the study intervention.
b. Mild: does not interfere with activity; moderate: interferes with activity; severe: prevents daily activity. c. 0LOG WR FP PRGHUDWH WR FP VHYHUH ! FP
d. Any local reaction: any redness >2.0 cm, any swelling >2.0 cm, or any pain at the injection site.
Solicited Systemic Reactions
Among BNT162b2 recipients in both age groups, fatigue and headache were most
common. The median onset of systemic events after either BNT162b2 dose occurred
on Day 1 to Day 4, with resolution after a median duration of 1 day, except fatigue and
chills which resolved within a median of 1-2 days. Solicited systemic AEs following both doses were mostly mild to moderate. The frequency and severity of systemic AEs was
higher after BNT162b2 Dose 2 than Dose 1, except for vomiting and diarrhea, which
was generally similar for both doses. Systemic AEs were more frequently reported in
BNT162b2 recipients than in the placebo group.
Table 17. Frequency of Solicited Systemic Reactions, by Maximum Severity, Within
7 Days After Each Dose, Participants 12 Through 15 Years of Age, Safety Populationa
Reaction BNT162b2
Dose 1
N=1127
n (%) Placebo
Dose 1
N=1127
n (%) BNT162b2
Dose 2
N=1097
n (%) Placebo
Dose 2
N=1078
n (%)
Fever: Ԩ 114 (10.1) 12 (1.1) 215 (19.6) 7 (0.6)
Fever: Ԩ to 38.4Ԩ 74 (6.6) 8 (0.7) 107 (9.8) 5 (0.5)
Fever: >38.4 Ԩ to 38.9Ԩ 29 (2.6) 2 (0.2) 83 (7.6) 1 (0.1)
Fever: >38.9 Ԩ to 40.0Ԩ 10 (0.9) 2 (0.2) 25 (2.3) 1 (0.1)
Fever: Ԩ 1 (0.1) 0 0 0
Fatigueb : Anye 677 (60.1) 457 (40.6) 726 (66.2) 264 (24.5)
Fatigueb: Mild 278 (24.7) 250 (22.2) 232 (21.1) 133 (12.3)
Fatigue: Moderate 384 (34.1) 199 (17.7) 468 (42.7) 127 (11.8)
Fatigue: Severe 15 (1.3) 8 (0.7) 26 (2.4) 4 (0.4)
Clinical Reviewer: Susan K. Wollersheim, MD
STN:125742/45
44
Reaction BNT162b2
Dose 1
N=1127
n (%) Placebo
Dose 1
N=1127
n (%) BNT162b2
Dose 2
N=1097
n (%) Placebo
Dose 2
N=1078
n (%)
Headacheb: Anye 623 (55.3) 396 (35.1) 708 (64.5) 264 (24.5)
Headacheb: Mild 361 (32.0) 256 (22.7) 302 (27.5) 170 (15.8)
Headache: Moderate 251 (22.3) 131 (11.6) 384 (35.0) 93 (8.6)
Headache: Severe 11 (1.0) 9 (0.8) 22 (2.0) 1 (0.1)
Chillsb: Anye 311 (27.6) 109 (9.7) 455 (41.5) 74 (6.9)
Chillsb: Mild 195 (17.3) 82 (7.3) 221 (20.1) 53 (4.9)
Chills: Moderate 111 (9.8) 25 (2.2) 214 (19.5) 21 (1.9)
Chills: Severe 5 (0.4) 2 (0.2) 20 (1.8) 0
Vomitingc: Anye 31 (2.8) 10 (0.9) 29 (2.6) 12 (1.1)
Vomitingc: Mild 30 (2.7) 8 (0.7) 25 (2.3) 11 (1.0)
Vomiting: Moderate 0 2 (0.2) 4 (0.4) 1 (0.1)
Vomiting: Severe 1 (0.1) 0 0 0
Diarrhead: Anye 90 (8.0) 82 (7.3) 65 (5.9) 44 (4.1)
Diarrhead: Mild 77 (6.8) 72 (6.4) 59 (5.4) 39 (3.6)
Diarrhea: Moderate 13 (1.2) 10 (0.9) 6 (0.5) 5 (0.5)
Diarrhea: Severe 0 0 0 0
New or worsened muscle painb: Anye 272 (24.1) 148 (13.1) 355 (32.4) 90 (8.3)
New or worsened muscle painb: Mild 125 (11.1) 88 (7.8) 152 (13.9) 51 (4.7)
New or worsened muscle pain: Moderate 145 (12.9) 60 (5.3) 197 (18.0) 37 (3.4)
New or worsened muscle pain: Severe 2 (0.2) 0 6 (0.5) 2 (0.2)
New or worsened joint painb: Anye 109 (9.7) 77 (6.8) 173 (15.8) 51 (4.7)
New or worsened joint painb: Mild 66 (5.9) 50 (4.4) 91 (8.3) 30 (2.8)
New or worsened joint pain: Moderate 42 (3.7) 27 (2.4) 78 (7.1) 21 (1.9)
New or worsened joint pain: Severe 1 (0.1) 0 4 (0.4) 0
Use of antipyretic or pain medicationf 413 (36.6) 111 (9.8) 557 (50.8) 95 (8.8)
Source: STN 125742.45.7 response-14march2022.pdf, Table 2, pages 5-8.
Reactions and use of antipyretic or pain medication were collected in the electronic diary (e-diary) from Day 1 to Day 7
after each dose.
%:n/N. n=number of participants in the specified age group with the specified characteristic.
N=number of reactogenicity subset participants in the specified age group reporting at least 1 yes or no response for the
specified reaction after the specified dose.
a All randomized participants in the reactogenicity subset who received at least 1 dose of the study intervention. b Mild: does not interfere with activity; moderate: some interference with activity; severe: prevents daily activity.
c Mild: 1 to 2 times in 24 hours; moderate: >2 times in 24 hours; severe: requires intravenous hydration.
d 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.
e Any systemic event: any fever Ӌ38.0rC, any fatigue, any vomiting, any chills, any diarrhea, any headache, any new or
worsened muscle pain, or any new or worsened joint pain.
f Severity was not collected for use of antipyretic or pain medication.
Reviewer comment: Minor revisions were made to the solicited systemic
reactions since the EUA was issued for this age group in May 2021, because of a delayed data synchronization for e-diary data upload from one placebo
recipient. This resulted in no changes to local reactions and minor changes for
headache, chills and diarrhea (n=1 for each) for systemic reactions. Conclusions
regarding reactogenicity were unchanged.
Subgroup analyses
Among 12-15-year-old BNT162b2 recipients, the frequencies of solicited local and
systemic reactions were generally similar among males and females.
Clinical Reviewer: Susan K. Wollersheim, MD
STN:125742/45
45
After Dose 2, Hispanic/Latino vaccine recipients reported notably lower rates for certain
systemic AEs and higher rates for certain local reactions than non-Hispanic/non-Latino
vaccine recipients.
x any fever: 9.4% (95%CI 4.9, 15.8) vs. 21.0% (95% CI 18.5, 23.7)
x any headache: 51.6% (95%CI 42.6, 60.5) vs. 66.3% (95% CI 63.2, 69.3)
These findings were accompanied by less antipyretic use after Dose 2 among
Hispanic/Latino vaccine recipients compared with non-Hispanic/Latino vaccine
recipients.
x any injection site swelling: 11.4% (95%CI 6.5, 18.0) vs. 4.7% (95% CI 3.4, 6.2)
x any injection site pain: 89.4% (95%CI 82.8, 94.1) vs. 79.1% (95% CI 76.4, 81.6)
Reactogenicity after Dose 1 was similar among Hispanic/Latino and non-Hispanic/non-
Latino vaccine recipients.
The frequencies of solicited local reactions and systemic AEs were generally similar by race. While the proportions of African Amer ican, Asian and other racial groups in the
study were reflective of the general distri bution in the US population, the numbers of
BNT162b2 recipients in these racial groups are too small (total n=157) to make
definitive conclusions.
Reactogenicity in BNT162b2 recipients who were SARS-CoV-2 positive prior to Dose 1
(n=46) was similar to the overall population of vaccine recipients, but the number of
subjects was too small to make definitive conclusions.
Unsolicited Non-serious AEs
Dose 1 through 1 month after Dose 2
Overall, among 12-15-year-olds, approximately 6.5% and 6.8% of participants in each
treatment group (BNT162b2 and placebo, respectively) reported at least 1 non-serious
AE from Dose 1 through 1 month after Dose 2 in ongoing follow-up. Differences in
frequencies of AEs between the vaccine and placebo groups were notable for fever with
onset within 7 days after vaccination, nausea and lymphadenopathy.
Reactogenicity
Five (0.4%) BNT162b2 and 0 placebo recipi ents reported fever. AEs in the Medical
Dictionary for Regulatory Activities System Organ Class (SOC) General disorders and
administration site conditions were most frequently reported of all non-serious,
unsolicited AEs in the BNT162b2 and placebo groups, of which injection site pain (0.6% BNT162b2, 0.6% placebo) and fatigue (0.6% BNT162b2, 0.4% placebo) were most
common.
Nausea
Five (0.4%) BNT162b2 and 2 (0.2%) placeb o recipient reported nausea. AEs in the
Medical Dictionary for Regulatory Activities System Organ Class (SOC) Gastrointestinal Disorders were the second most frequently reported of all non-serious, unsolicited AEs
in the BNT162b2 and placebo groups, of which nausea (0.4% BNT162b2, 0.2%
placebo) and diarrhea (0.3% BNT162b2, 0.1% placebo) were most common.
Lymphadenopathy A total of 9 (0.7%) BNT162b2 recipients and 2 (0.2%) placebo recipients reported
lymphadenopathy. Of those, 7 (0.6%) BNT162b2 recipients and 1 (0.1%) placebo
Clinical Reviewer: Susan K. Wollersheim, MD
STN:125742/45
46
recipient were considered related to study intervention by the investigator; all of the
events occurred within 2-10 days after study intervention and were located mainly in the
arm/neck (axillary, cervical, supraclavicular lymph nodes). The majority of events were
mild, with one moderate event reported in the BNT162b2 group. The median onset of
lymphadenopathy following BNT162b2 was 5 days after Dose 1, with a shorter median
onset of 4 days following Dose 2 of BNT162b2. Median duration of lymphadenopathy was 6 days in the BNT162b2 group and 25.5 days in the placebo group. Three
additional reports of lymphadenopathy (2 BNT1 62b2 recipients and 1 placebo recipient)
were assessed as unrelated by the study investigator due to onset 28 days after Dose 2
in the 2 BNT162b2 recipients and concurrent infectious mononucleosis in the placebo
recipient. FDA agrees with the investigator’s assessments.
A total of 16 new unsolicited non-serious AEs occurred since the time of the EUA for
this age group from Dose 1 through 1 month after Dose 2 (n=6 and n=10 in the
BNT162b2 and placebo groups, respectively), none of which were serious or led to
withdrawal. These new reported non-serious AEs in BNT162b2 recipients were
consistent with reactogenicity events (chills, fa tigue, injection site pain, injection site
swelling, pyrexia) or common events for this age group (sports injuries, infections, acne).
Dose 1 to data cutoff date or participant ’s unblinding date (whichever was earlier)
Other than reactogenicity, nausea and lymphadenopathy reported from Dose 1 through
1 month after Dose 2, there were no other notable patterns between treatment groups
for specific categories (SOC and Preferred Term (PT)) of non-serious adverse events,
including Bell’s palsy, facial paralysis/paresis, other neurologic, neuro-inflammatory,
and thrombotic events, that would suggest a causal relationship to BNT162b2 vaccine.
Open-label observational follow-up: from parti cipant unblinding to the September 2,
2021 data cutoff
Original BNT162b2 recipients
Overall, 1107 original BNT162b2 recipients were followed after unblinding. Of these, 18
(1.6%) participants reported any adverse event; 4 (0.4%) participants had at least 1
occurrence of an event that was consider ed related to the vaccine, and 3 (0.3%)
participants had at least 1 occurrence of an event that was graded as severe.
Overall, the rates of AEs in all System Organ Classes (SOCs) after the unblinding date
decreased or remained similar to those in the blinded placebo-controlled period. The
most commonly reported events occurred in the SOC of General disorders and administration site conditions with 4 (0.4%) participants reporting at least 1 event, and
the Preferred Term (PT) Injection site pain had the highest number of participants
(n=3).
Of the 4 participants who reported at least 1 event considered related to the vaccine,
the events were similar to reactogenicity events, reflecting AEs within 7 days of
vaccination or events reported more t han 7 days from vaccination indicating either
recurrent or prolonged reactogenicity symptom s. Note that one participant can report
multiple events.
The most common SOCs and PTs are listed below:
x 4 participants reported at least 1 event in the SOC General disorders and
administration site conditions: Injection site pain (3), Fatigue (2), Pyrexia (2) and
Pain (1).
Clinical Reviewer: Susan K. Wollersheim, MD
STN:125742/45
47
x 2 participants reported at least 1 event in the SOC Nervous system disorders:
Headache (2) and Dizziness (1).
Placebo recipients who were unblinded and received BNT162b2
Overall, 1010 original placebo participants were unblinded and received BNT162b2.
The number of participants reporting any AE and at least 1 related AE were 265
(26.2%) and 242 (24.0%), respectively. The number of participants reporting severe
AEs was 12 (1.2%).
After participants who originally received placebo were unblinded and then received
BNT162b2, events related to reactogenicity were not reported using an e-diary but were
reported as unsolicited AEs. Because an e-diary was not used after original placebo
recipients received open-label BNT162b2, in comparison to participants randomized to
BNT162b2 from Dose 1 to the unblinding date, the frequencies for any AE and at least
1 related AE for participants who originally received placebo and then received
BNT162b2 are greater (26.2% and 24.0%) than the frequencies (8.4% and 3.2%) for
participants who originally received BNT162b2, respectively. However, the frequencies
for severe AEs were similar (1.2% versus 1.1%).
Immediate adverse events after either BNT162b2 dose (Dose 3 or 4, for original
placebo recipients), were low in frequency (n=7 [0.7%]) Most immediate AEs after
BNT162b2 were primarily injection site reactions, with injection site pain (n=6 [0.6%])
most frequently reported and 1 participant with injection site erythema.
Most AEs reported from Dose 3 (first dose of BNT162b2) to the data cutoff were in SOCs with reactogenicity events.
x general disorders and administration site conditions (225 [22.3%])
x nervous system disorders (75 [7.4%])
x musculoskeletal and connective tissue disorders (48 [4.8%])
x gastrointestinal disorders (20 [2.0%])
The most frequently reported AEs were injection site pain (15.5%), fatigue (10.3%),
headache (7.0%), pyrexia (6.3%), chills (4.5%), myalgia (3.8%), pain (3.5%), nausea (1.2%), pain in extremity (0.9%), vomiting (0.7%), malaise (0.7%), and injection site
erythema (0.5%).
To examine the time period for collection of reactogenicity event s, an analysis of AEs
reported within 7 days after each vaccine dose was evaluated. Preferred terms (PTs) reported from Dose 3 to 7 days after Dose 3 and from Dose 4 to 7 days after Dose 4
were in the SOCs of general disorders and administration site conditions (injection site
pain, fatigue, chills, pyrexia, and pain), nervous system disorders (headache),
musculoskeletal and connective tissue disorders (myalgia), and gastrointestinal
disorders (nausea) and represented the majority of PTs reported in those SOCs. These events appear to be attributable to common local and systemic reactions known to
occur after receipt of BNT162b2. One participant reported a nonserious AE of right
axillary lymphadenitis on Day 6 after Dose 3, which was moderate in severity and
resolved after 24 days. The investigator assessed this AE as related to the study
intervention, and FDA agrees with the investigator assessment.
Clinical Reviewer: Susan K. Wollersheim, MD
STN:125742/45
48
Placebo-controlled and Open-label follow up from Dose 1 to 6 Months after Dose 2:
Original BNT162b2 Participants
A total of 1113 participants who originally received BNT162b2 had at least 6 months of
follow-up post-Dose 2 . Of these, 98 (8.8%) participant s reported at least 1 AE, and 34
(3.1%) participants reported at least 1 related AE . The most frequently reported AEs
were reactogenicity events: General disorders and administration site conditions reported in 16 (1.4%), Musculoskeletal and connective tissue disorders reported in 8
(0.7%), Nervous system disorders reported in 16 (1.4%) and Gastrointestinal disorders
reported in 16 (1.4%). Additionally, all 9 of the reports of lymphadenopathy occurred
from Dose 1 to 1 month after Dose 2 and none were reported from 1 month to 6 months
after Dose 2.
When frequencies of AEs for participants with at least 6 months of follow-up time are
examined by time since the second dose, the frequency of AEs and related AEs is 6.3%
and 3.1% through 1 month after Dose 2 compared with 3.1% and no related events
from 1 month after Dose 2 to 6 months after Dose 2.
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 or unsolicited in these subgroups we re generally consistent with the overall
study population.
6.1.12.3 Deaths
There were no deaths during the reporting period of Dose 1 to the September 2, 2021
data cutoff date.
6.1.12.4 All Serious Adverse Events (SAEs)
Dose 1 through 1 month after Dose 2
SAEs from Dose 1 through up to 30 days after Dose were reported by 4 (0.4%)
BNT162b2 recipients and 1 (0.1%) placebo reci pients, all of whom were SARS-CoV-2
negative at baseline.
BNT162b2 group:
x 3 participants, all with pre-existing anxiety and depression, were hospitalized for
medical management of depression exacerbation that started 7 days after Dose 1, 1
day after Dose 2, and 15 days after Dose 1, respectively. All 3 participants reported
treatment with a selective serotonin reuptake inhibitor (SSRI) that began within 1-2
months prior to vaccination. Worsening suicidal ideas with initial SSRI treatment in
adolescents is a recognized risk and provides a reasonable alternative explanation for depression exacerbation in these BNT162b2 recipients.
x One participant experienced an SAE reported as generalized neuralgia, and also
reported 3 concurrent non-serious AEs (abdominal pain, abscess, gastritis) and 1
concurrent SAE (constipation) within the same week. The participant was eventually
diagnosed with functional abdominal pain. The event was reported as ongoing at
the time of the cutoff date.
Clinical Reviewer: Susan K. Wollersheim, MD
STN:125742/45
49
Placebo group:
x One participant was hospitalized for appendicitis 19 days after Dose 2. The event
resolved after 2 days, and the participant continued in the study.
Dose 1 to data cutoff date or participant ’s unblinding date (whichever was earlier)
SAEs were reported by 10 (0.9%) and 2 (0.2%) of participants in the BNT162b2 and
placebo groups, respectively. Since the time of the EUA data cutoff, 6/10 of these SAEs were reported by BNT162b2 recipients and none were reported by placebo recipients;
the events were similar in nature to those that occurred from Dose 1 through 1 month
after Dose 2, described above , but the 6 new SAEs (anal abscess, femur fracture,
conversion disorder, suicidal ideation [n=3]) occurred at longer time intervals since
vaccination which further decreases the lik elihood of relatedness to BNT162b2. All
SAEs were assessed by the investigator as not related to study intervention and FDA
agrees with the assessment that the SAEs were unlikely to be related to study
intervention.
Open-label follow-up: from participant unblinding to the September 2, 2021 data cutoff
Original BNT162b2 recipients
Overall, 1107 original BNT162b2 recipients were followed after unblinding. Of these, 4
(0.4%) participants reported at least 1 SAE , none of which were considered related to
vaccination and FDA agrees with those asse ssments. Two participants experienced
appendicitis 148 and 177 days after Dose 2, 1 participant experienced an upper limb
fracture and 1 participant reported syringomelia.
Placebo recipients who were unblinded and received BNT162b2
Overall, 1010 original placebo recipients were unblinded and received BNT162b2. The
number of participants reporting SAEs was 6/1010 (0.6%), four of which were
considered not related by the investigator (ep ilepsy in participant with family history of
epilepsy, traumatic renal injury, major depression, somnolence) and two of which were
considered related to vaccination by the investigator:
x One participant had myocarditis 3 days after Dose 4 (second BNT162b2 dose),
which presented with acute chest pain and recent cough, runny nose and low
grade fever. The participant was evaluated in an emergency room, found to
have EKG findings consistent with myocarditis, elevated troponin levels and a
positive respiratory PCR panel result for rhinovirus (negative for enterovirus,
Parvovirus B19 and SARS CoV-2 PCR). The participant was hospitalized for
pain management until troponin levels normalized after 2 days. The participant
has since returned to normal physical activities and continues outpatient follow
up with a cardiologist. FDA agrees that this SAE was possibly related to
vaccination; myocarditis is a known identified risk following BNT162b2
vaccination.
x One participant had appendicitis 4 days after Dose 4 (second BNT162b2 dose)
which resolved within a day following appendectomy. While this SAE occurred
within several days of vaccination, FDA considers this event as unrelated to
vaccine because there is no clear basis upon which to suspect that cases of
appendicitis represent a vaccine-related event. Additionally, postmarketing
safety surveillance comparing appendicitis incidence in vaccinated versus
unvaccinated individuals has not supported appendicitis as an adverse reaction.
Clinical Reviewer: Susan K. Wollersheim, MD
STN:125742/45
50
Placebo-controlled and Open-label follow up from Dose 1 to 6 Months after Dose 2:
Original BNT162b2 Participants
A total of 1113 participants who originally received BNT162b2 had at least 6 months of
follow-up post-Dose 2. SAEs were reported by 10 (0.9%) participants.
In the first month after Dose 2, 0.3% participants reported SAEs. From 1 month post
Dose 2 to 6 months after Dose 2, the frequency of SAEs was 0.8%. The following
SOCs did not occur from Dose 1 through 1 month after Dose 2, but were reported from
1 month after Dose 2 to 6 months after Dose 2:
x Infections and infestations (anal abscess and appendicitis: 0 vs 2 (0.2%)
x Congenital, familial and genetic disorders (syringomelia): 0 vs 1 (0.1%)
x Injury, poisoning, and procedural complications (femur fracture): 0 vs 1 (0.1%)
x Gastrointestinal disorders (abdominal pain, constipation in the same participant): 0
vs 1 (0.1%)
The frequency of SAEs reported in the psychiatric disorders SOC was similar from
Dose 1 to 1 month after Dose 2 (n=3) versus 1 month after Dose 2 to 6 months after
Dose 2 (n=4). None of these SAEs were considered related to the study intervention,
and FDA agrees with the investigator’s assessment.
No AEs leading to withdrawal were reported during the blinded and open-label follow-up
periods in the group of original BNT162b2 recipi ents with at least 6 months of follow-up
after Dose 2.
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 non-
fatal serious adverse events in these subgroups were generally consistent with the
overall study population.
6.1.12.7 Dropouts and/or Discontinuations
Dose 1 to data cutoff date or participant ’s unblinding date (whichever was earlier)
From Dose 1 to the unblinding date, 1 (0.1%) participant in the BNT162b2 group had an
AE of pyrexia (104.7ºF 1 day after Dose 1) leading to withdrawal that was assessed by
the investigator as related to study intervention. FDA agrees with the investigator
assessment.
Open-label follow-up: from participant unbli nding to the September 2, 2021 data cutoff
Placebo recipients who unblinded to receive BNT162b2 )URP 'RVH ILUVW GRVH RI %17E ȝJ DGPLQLVWUDWLRQ WR WK H GDWD FXWRII GDWH
there were no original placebo recipien ts who were withdrawn because of AEs.
Original BNT162b2 Participants
From the unblinding date to the data cutoff date, there were no original BNT162b2
recipients who were withdrawn because of AEs.
Placebo-controlled and Open-label follow up from Dose 1 to 6 Months after Dose 2:
Original BNT162b2 Participants
From Dose 1 to 6 months after Dose 2 during the blinded and open-label follow-up time
periods, no participants with at least 6 months of follow-up time after Dose 2 withdrew
because of AEs.
Clinical Reviewer: Susan K. Wollersheim, MD
STN:125742/45
51
6.1.13 Study Summary and Conclusions
This randomized, blinded, placebo-controlled multinational clinical trial evaluated the
safety, immunogenicity, and efficacy of a two-dose primary series of BNT162b2 in a
total of 2260 participants 12-15 years of age. A total of 99.4% participants received 2
doses, and the median duration of follow-up after Dose 2 in the blinded placebo-
controlled period was 4.4 months. A total of 1010 original placebo recipients were unblinded and received BNT162b2, with a median open-label follow-up duration of 4.0
months after unblinding. A total of 1113 original BNT162b2 recipients had total (blinded
and open-label) follow-up duration of at least 6 months after Dose 2, with a median total
follow-up duration of 8.4 months after Dose 2.
Vaccine effectiveness was inferred by immunobridging based on a comparison of
SARS-CoV-2 50% neutralization antibody titers at 1 month after Dose 2 in participants
12-15 years of age with those of young adults 16-25 years of age (the most clinically
relevant subgroup of the study population in whom VE has been demonstrated). In the
planned immunobridging analyses, the GMR of neutralizing antibody titers (adolescents
to young adults) was 1.77 (95% CI: 1.50, 2.09), meeting the success criterion (lower
bound of the 95% CI for the GMR >0.67). Immunogenicity outcomes were consistent across demographic subgroups. In the updated descriptive efficacy analyses, VE after 7
days post Dose 2 was 100%, (95% CI: 86.8; 100.0) in participants 12-15 years of age
without prior evidence of SARS-CoV-2 infection and 100% in the group of participants
with or without prior infection. There were no cases of severe COVID-19.
Local and/or systemic solicited reactions following vaccination were generally of short
duration and occurred more commonly in the BNT162b2 group than the placebo group,
which included pain at the injection site (90.5%), fatigue (77.5%), headache (75.5%),
chills (49.2%), muscle pain (42.2%), fever (24.3%), joint pain (20.2%), injection site
swelling (9.2%), and injection site redness (8.6%). Overall, SAEs were infrequently reported by participants in both groups. Adverse reactions other than solicited
reactogenicity events identified from the clinical trial data include myocarditis,
lymphadenopathy and nausea (the latter from a small numerical imbalance of
temporally associated events, likely consistent with reactogenicity). There were no
reported deaths or pregnancies. Study conclusions are somewhat limited by the small sample size and exclusion of participants with certain types of immunocompromise.
7.
INTEGRATED OVERVIEW OF EFFICACY
Not applicable (only 1 study included in this sBLA)
8. INTEGRATED OVERVIEW OF SAFETY
Not applicable (only 1 study included in this sBLA)
9. ADDITIONAL CLINICAL ISSUES
9.1 Special Populations
9.1.1 Human Reproduction and Pregnancy Data
There were no pregnancies reported from participants 12-15 years of age. As part of
the postmarketing surveillance, the Applicant will perform a pregnancy registry study to
assess pregnancy and infant outcomes after exposure to BNT162b2 during pregnancy
Clinical Reviewer: Susan K. Wollersheim, MD
STN:125742/45
52
among pregnant women aged 18 years or older who reside in the US or Canada.
(Study C4591022). Additionally, a randomized controlled trial in pregnant women (Study
C4591015) is ongoing.
9.1.2 Use During Lactation
It is not known if BNT162b2 is secreted in human breast milk. Data are not available to
assess the effects of BNT162b2 on the breastfed infant or on milk production.
9.1.3 Pediatric Use and PREA Considerations
The safety and effectiveness data from study C4591001 participants 12-15 years of age
fulfill the Pediatric Research Equity Act (PREA) requirement for assessment of the
vaccine in this age group. As a condition of the August 2021 FDA approval of
Comirnaty for use in individuals 16 years of age and older, the Applicant must also complete and submit results of assessments of the vaccine in pediatric age groups from
birth through <12 years.
9.1.4 Immunocompromised Individuals
Similar to other preventive vaccines, a 2-dose primary series of Comirnaty may have
decreased effectiveness in immunocompromised individuals compared with healthy
individuals. Based on published reports of low antibody responses and breakthrough
infections among significantly immunocom promised individuals (mainly solid organ
transplant recipients) who received the tw o-dose vaccination series under EUA, the
EUA for the Pfizer COVID-19 Vaccine allows fo r a third dose, at least 28 days following
the second dose, in individuals at least 5 years of age who have undergone solid organ
transplantation, or who are diagnosed with c onditions that are considered to have an
equivalent level of immunocompromise.
9.1.5 Geriatric Use
Comirnaty is approved for use in individuals 65 years of age and older, and geriatric
use is not relevant to the review of this BLA supplement. Older adult participants were
also enrolled to Study C4591001, and the data were reviewed with the original BLA
submission (see BLA Clinical Review Memo ). Am ong all participants (N=22026) who
were originally randomized to BNT162b2 in this study and included in the safety
population, 20.7% (n=4552) were 65 years of age and older and 4.2% (n=925) were 75
years of age and older. The effectiveness in geriatric participants was consistent with
that seen in younger adult participants, and no safety concerns specific to the geriatric
age group were identified. The reported frequencies of adverse reactions, including
myocarditis/pericarditis, are lower in the geriatric age group compared with younger
adults and adolescents.
10. CONCLUSIONS
The clinical data submitted to the sBLA include results of a randomized, blinded,
placebo-controlled clinical trial that evaluated the safety and efficacy of BNT162b2 in 2260 participants 12-15 years of age . The immunobridging analysis results show that
the immune response following receipt of 2 doses of BNT162b2, given 3 weeks apart,
in participants 12-15 years of age was non-inferior to immune responses in participants
16-25 years of age (the most clinically relevant subgroup of the study population in
whom VE has been demonstrated). In updated descriptive efficacy analyses, VE after 7
days post Dose 2 was 100% (95% CI: 86.8; 100.0) in participants 12-15 years of age
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without prior evidence of SARS-CoV-2 infection and 100% (95% CI: 87.5, 100.0) in
participants with or without prior infection. Although based on a small number of cases
in descriptive analyses, the supplementary VE data provide compelling direct evidence
of clinical benefit in addition to the immunobridging data.
The clinical safety data submitted represent at least 1000 participants in the 12-15 years of age group with at least 6 months of total safety follow-up and met FDA
expectations for an acceptable pre-licensure safety database. In the clinical trial, local
and/or systemic solicited reactions following vaccination were generally of short
duration and occurred more commonly in the BNT162b2 group than the placebo group.
Overall, SAEs were infrequently reported by participants in both groups. Adverse reactions other than solicited reactogenicity events identified from the clinical trial data
include myocarditis, lymphadenopathy and nausea (the latter from a small numerical
imbalance of temporally associated events, like ly consistent with reactogenicity). These
imbalances support labeling of both lymphadenopathy and nausea as potential adverse
reactions.
Post-authorization safety surveillance has already identified additional clinically important but infrequent adverse reactions: anaphylaxis and myocarditis/pericarditis.
The risk of myocarditis, observed as highest in males 12 through 17 years of age, is
being addressed by labeling in the Warnings and Precautions Section of the US
package insert, by ongoing monitoring through active and passive surveillance, and by
postmarketing studies to be conducted by the Applicant, US Government agencies, and other healthcare stakeholders to further evaluate and understand these risks.
Data from numerous published observational studies of real-world use of the vaccine,
although not independently reviewed and confirm ed by FDA, appear to corroborate the
clinical benefit supported by th e clinical trial results, most notably against COVID-19
associated hospitalization and death. Despite mo re recent real-world evidence from the
Omicron predominant period indicating decreased vaccine effectiveness and waning
effectiveness against more mild COVID-19 compared to that demonstrated in clinical
trials during circulation of previous vari ants, available evidence indicates a 2-dose
series continues to provide substantial protection against more severe COVID-19 and its serious outcomes caused by currently circulating SARS-CoV-2 variants;
consequently, the WHO and national regulatory and public health authorities continue
to endorse use of currently available COVID-19 vaccines for use in primary vaccination.
Based on the totality of data and the benefit-risk considerations as described in Section
11 below, the clinical reviewer concludes that the clinical trial data submitted in this
application, and complemented by available post-authorization data and plans for post-
licensure studies, support approval of BNT162b2 for the indication of active
immunization to prevent symptomatic coronavirus disease 2019 (COVID 19) caused by
severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in individuals 12-15
years of age.
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11. RISK-BENEFIT CONSIDERATIONS AND RECOMMENDATIONS
11.1 Risk-Benefit Considerations
Table 18. STN125742: Risk-Benefit Considerations
Decision Factor Evidence and Uncertainties Conclusions and Reasons
Analysis of
Condition x SARS CoV-2, a novel respiratory coronavirus causing COVID-19, is
currently responsible for a global pandemic that has significantly
disrupted human activity on a global scale.
x COVID-19 is associated with significant morbidity, mortality (>6.3 million
deaths worldwide to date) and long-term sequelae among survivors. In
the US, COVID-19 has been responsible for >4.9 million hospitalizations and >1 million deaths to date.
x Multiple variants of the virus are circulating and continue to emerge.
Evidence of an increase in transmissibility, shorter incubation periods
and/or more severe disease (e.g., increased hospitalizations or deaths) has been associated with some of these variants.
x Uncertainties include: lack of complete understanding of mechanisms of
pathogenesis and individual risk for severe disease; evolving
epidemiology of the pandemic; and potential for emergence of SARS-CoV-2 variants with altered infectivity, virulence, and/or capacity to
evade immunity from natural infection or vaccination. x Since the beginning of the COVID-19 pandemic in
early 2020, SARS-CoV-2 remains a cause of
significant morbidity and mortality in the US and worldwide.
Unmet Medical
Need x Remdesivir is the only drug approved for the treatment of COVID-19, and
approved use is limited to hospitalized adults and pediatric patients [12
years of age and older and weighing at least 40 kilograms (about 88 pounds)].
x Paxlovid is authorized for the treatment of mild-moderate COVID-19 in
adults and children 12 years of age and older, weighing at least 40
kilograms, with positive results of direct SARS-CoV-2 testing and who are
at high risk for progression to severe COVID-19.
x Monoclonal antibodies are available under EUA for treatment and post-
exposure prophylaxis but not for pre-exposure prophylaxis.
x Comirnaty is one of two COVID-19 vaccines approved for the prevention
of COVID-19. Currently, no vaccines are FDA-approved for the prevention of COVID-19 in individuals <16 years of age. This has been
cited as a reason for vaccine hesitancy and refusal of some individuals
to receive approved and/or EUA vaccines. x Public health measures of social distancing and
masking are helpful but do not prevent all
transmission of the virus.
x There is an unmet medical need in individuals <16
years of age for an FDA-approved vaccine to prevent
COVID-19 caused by SARS-CoV-2.
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Decision Factor Evidence and Uncertainties Conclusions and Reasons
x Non-pharmacologic measures to prevent transmission of SARS-CoV-2
include masks, social distancing, and avoidance of high-risk situations.
These actions do not prevent all infections.
x Uncertainties include to what extent the recent increased incidence of
new infections in the US is due to waning immunity from natural infection or vaccination, the emergence of new variants, or a combination of these
factors.
Clinical Benefit x The immunobridging analysis results from Study C4591001 show that the
immune response following receipt of 2 doses of BNT162b2, given 3
weeks apart, in participants 12-15 years of age is comparable to immune
response in participants 16-25 years of age, for whom efficacy of the vaccine was previously demonstrated.
x In descriptive efficacy analyses, vaccine efficacy after 7 days post Dose
2 was 100% (95% CI: 86.8; 100.0) in participants 12-15 years of age without prior evidence of SARS-CoV-2 infection. However, COVID-19
cases included in this efficacy analyses were accrued prior to emergence
of currently circulating variants whose spike protein mutations are known
to adversely impact effectiveness of the vaccine.
x Uncertainties in clinical benefit include longer-term duration of protection;
effectiveness in certain populations (e.g., significantly
immunocompromised) not well represented in the clinical trial; and
effectiveness against SARS-CoV-2 variants that may emerge in the future. x The evidence for clinical benefit meets the evidentiary
standards (i.e., substantial evidence of effectiveness)
for approval of Comirnaty for use in individuals 12-15 years of age.
x Despite real-world evidence indicating decreased
vaccine effectiveness and waning effectiveness
against more mild COVID-19 compared to that demonstrated in clinical trials, available evidence indicates a 2-dose series continues to provide
substantial protection against more severe COVID-19
and its serious outcomes caused by currently circulating SARS-CoV-2 variants; consequently, the WHO and national regulatory and public health
authorities continue to endorse use of currently
available COVID-19 vaccines for use in primary vaccination.
x Additional data from post-approval studies are
needed to further address uncertainties in clinical
benefit.
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Decision Factor Evidence and Uncertainties Conclusions and Reasons
Risk x The most frequently reported adverse reactions in the ongoing placebo-
controlled trial were solicited injection site reactions (redness, swelling,
and pain) and systemic adverse reactions (fever, fatigue, headache,
chills, vomiting, diarrhea, muscle pain, and joint pain).
x Among unsolicited adverse events reported in the trial, an imbalance in
self-limited lymphadenopathy (9 events in vaccine recipients, mostly
ipsilateral and regional to the injection site, vs. 2 events in placebo
recipients) and nausea (5 events in vaccine recipients and 2 event in a
placebo recipient) supports a causal association with the vaccine,
consistent with events observed in older age groups.
x Similar to other preventive vaccines, hypersensitivity reactions, including
anaphylaxis rarely, are a known risk associated with Comirnaty.
x One case of myocarditis occurred on Day 3 post Dose 2 in an adolescent
participant in this trial, with resolution of symptoms with conservative
management. Myocarditis and pericarditis are known to be risks
associated with Comirnaty, with most cases characterized by resolution of symptoms with conservative management and return to normal activities among individuals with at least 90 days of follow-up. The risk of
myocarditis/pericarditis is greatest following Dose 2 of the vaccine series
and is greatest among males 12-17 years of age compared to females
and compared to older and younger males.
x Uncertainties related to risks of myocarditis and pericarditis include lack
of precise estimates for excess risk across various age and gender
subgroups (accounting for background cases of COVID-19-associated myocarditis and pericarditis that would be prevented by vaccination), whether and how frequently subclinical cases occur, and longer-term
outcomes and prognoses.
x The risk profile of Comirnaty is now informed by intensive post-
authorization and post-approval safety surveillance following hundreds of millions of doses, including post-authorization safety surveillance in
millions of adolescents 12-15 years of age. While this safety surveillance
has not identified risks other than those summarized above, it is possible that additional rare but clinically important risks could be identified in the
future. x The most commonly manifested risks are mild to
moderate, self-limited injection site and systemic
adverse reactions.
x Less commonly manifested but potentially serious
risks include severe allergic reactions and myocarditis/pericarditis. Additional data are needed to
better quantify the risks of myocarditis and
pericarditis and to more fully understand long-term prognoses for vaccine-associated myocarditis and pericarditis.
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Decision Factor Evidence and Uncertainties Conclusions and Reasons
Risk Management x Labeling for Comirnaty describes the common and uncommon (but
potentially serious) risks associated with the vaccine. The labeling
includes warning statements for severe allergic reactions and
myocarditis/pericarditis.
x Safety surveillance efforts by the Applicant and led by US public health
agencies (FDA and CDC) will continue following approval of Comirnaty
for use in adolescents 12-15 years of age.
x The Applicant will be required to conduct post-approval studies to further
evaluate vaccine safety and effectiveness, and specifically to better understand the identified risks of vaccine-associated myocarditis and
pericarditis and their long-term sequelae. x Risk mitigation strategies for Comirnaty for use in
individuals 12 years of age and older include
communication of risks and benefits through labeling,
directed counseling prior to vaccination according to individual risks and benefits, and a pharmacovigilance plan to further evaluate risks.
x Ongoing monitoring of COVID-19 epidemiology
(including emergence of variants) and vaccine effectiveness will also be critical to updating benefit risk assessments and risk mitigation strategies as the
pandemic evolves over time.
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11.2 Risk-Benefit Summary and Assessment
COVID-19 caused by SARS-CoV-2 is associated with a wide spectrum of
manifestations, including mild illness in some individuals but severe morbidity (in some
cases with long-term sequelae) and/or mortality in others. Over 6.3 million deaths
attributable to COVID-19 have been reported worldwide since the beginning of the
pandemic in late 2019, with >1 million US deaths since the beginning of the pandemic and >4.9 million US hospitalizations from August 2020 to the week ending on July 2,
2022. Currently, the surge of COVID-19 associated with widespread transmission of the
SARS-CoV-2 Omicron variant has reached a plateau phase. While the greatest risk of
severe or fatal COVID-19 is in individuals >65 years of age and those with comorbid
conditions (e.g., obesity, diabetes, immunocompromising conditions), significant morbidity and mortality and long-term sequelae from COVID-19 has occurred in healthy
individuals of all ages, including adolescents 12-15 years of age. In addition to
individual-level morbidity and mortality, the COVID-19 pandemic has overwhelmed
healthcare systems during periods of high incidence, and the effects of SARS-CoV-2
infection, COVID-19 disease, and the necessary public health measures implemented to
prevent infection and illness have severely disrupted human activities on a global scale.
While two COVID-19 vaccines have been approved for the prevention of COVID-19 caused by SARS-CoV-2, and emergency use authorization of the Pfizer-BioNTech
COVID-19 Vaccine is available for individual s 6 months of age and older, full approval of
a COVID-19 vaccine in the adolescent age group represents an important step in
addressing the unmet need for approved pharmacologic interventions for the prevention
of COVID-19 in pediatric age groups.
A randomized, blinded, multinational placebo-controlled trial (C4591001) that enrolled
2260 participants 12-15 years of age demonstrated the clinical benefit of Comirnaty in
this age group by successful immunobridging analyses based on a comparison of
SARS-CoV-2 50% neutralization antibody titers at 1 month after Dose 2 in participants
12-15 years of age with those of young adults 16-25 years of age (the most clinically
relevant subgroup of the study population in whom vaccine efficacy has been
demonstrated). Additionally, descriptive VE analyses, the VE after 7 days post Dose 2
was 100% (95% CI: 86.8; 100.0) in participants 12-15 years of age without prior
evidence of SARS-CoV-2 infection and provided compelling direct evidence of clinical
benefit in addition to the immunobridging results.
Data from numerous published observational studies of real-world use of the vaccine,
although not independently reviewed and confirm ed by FDA, appear to corroborate the
clinical benefit supported by the clinical trial results, most notably against COVID-19
associated hospitalization and death. Despite more recent real-world evidence from the
Omicron predominant period indicating decreased vaccine effectiveness and waning
effectiveness against more mild COVID-19 compared to that demonstrated in clinical
trials during circulation of previous variants, available evidence indicates a 2-dose series
continues to provide substantial protection against more severe COVID-19 and its
serious outcomes caused by currently circ ulating SARS-CoV-2 variants; consequently,
the WHO and national regulatory and public health authorities continue to endorse use of currently available COVID-19 vaccines for use in primary vaccination. Remaining
uncertainties regarding the clinical benefits of Comirnaty in individuals 12-15 years of
age include effectiveness against asymptomatic infection and transmission of SARS-
CoV-2, confirmation of more robust estimates of effectiveness in certain populations not
Clinical Reviewer: Susan K. Wollersheim, MD
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well represented in the clinical trial, and vaccine effectiveness against future emerging
variants.
Risks associated with Comirnaty in individua ls 12-15 years of age include common self-
limited local and systemic adverse reactions char acterized in the clinical trial, which are
mostly mild to moderate and short-lived, and rare but more serious risks of anaphylaxis and myocarditis/pericarditis as detected through post-authorization safety surveillance.
Although some cases of vaccine-associated myocarditis/pericarditis required intensive
care support (with several suspected fatal cases under CDC investigation but not
confirmed to be vaccine-associated myocarditis at the time of this review), available data
from short-term follow-up suggest that most individuals affected by vaccine-associated
myocarditis/pericarditis have had resolution of symptoms with conservative management
and return to normal activities among indi viduals with at least 90 days of follow-up.
Information is not yet available to further evaluate potential long-term sequelae and
outcomes in affected individuals, and additi onal uncertainties regarding the risk of
myocarditis/pericarditis include: whether and to what extent subclinical cases might
occur, and if they do what are the long-term outcomes; the mechanism of pathogenesis;
and individual factors conferring increas ed risk for vaccine-associated
myocarditis/pericarditis. Based on evidence from passive surveillance and observational
studies, the risk of myocarditis/pericarditis is greatest following Dose 2 of the vaccine
series and is greatest among males 12-17 years of age compared to females and
compared to older and younger males. Despite adolescent males 12-15 years of age
being included in the age group at greatest risk for vaccine-associated myocarditis, the risk and consequences of vaccine-associated myocarditis appear to be less than the risk
and consequences of cardiac complications associated with COVID-19, and the risk of
vaccine-associated myocarditis is clearly offset by the benefits of the vaccine.
The risk profile of Comirnaty is now informed by intensive post-authorization and post-approval safety surveillance following hundreds of millions of doses, including post-
authorization safety surveillance in millions of adolescents 12-15 years of age. While this
safety surveillance has not identified risks other than those summarized above, it is
possible that additional rare but clinically im portant risks could be identified in the future.
More robust characterization of the safety profile through active safety surveillance and/or controlled observational studies shoul d include specific populations (e.g.,
individuals with prior COVID-19, pregnant women, and significantly
immunocompromised individuals). Nonetheless, currently available data support a
benefit-risk balance that is clearly favorable for approving Comirnaty for use in
individuals 12-15 years of age. Mitigation of the observed risks and associated uncertainties will be accomplished through labeling (including warning statements
regarding risks of allergic reactions and vaccine-associated myocarditis/pericarditis) and
through continued safety surveillance and postmarketing studies to further assess and
understand these risks.
11.3 Discussion of Regulatory Options
The Pfizer-BioNTech COVID-19 Vaccine is autho rized for use in individuals 6 months of
age and older; Comirnaty is approved for use in individuals 16 years of age and older.
Approval of Comirnaty for use in individual s as young as 12 years of age would enable
this vaccine to be used under non-emergency conditions.
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11.4 Recommendations on Regulatory Actions
This clinical reviewer recommends approval of Comirnaty for the prevention of COVID-
19 caused by SARS-CoV-2 in individuals 12 years of age and older.
11.5 Labeling Review and Recommendations
The information in the package insert was reviewed, and requested revisions were
communicated to the Applicant. The revised label is accurate, not misleading, and
appropriate for the proposed use of the vaccine. The WARNINGS AND PRECAUTIONS
section describes the occurrence of myocarditis and pericarditis in subjects who receive
Comirnaty, and the increased risk observed for adolescents and young adult males.
11.6 Recommendations on Postmarketing Actions
There is no change to the currently required post-marketing studies as outlined in the
Comirnaty Approval Letter from August 23, 2021.
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, Chroni c Pulmonary Disease, Diabetes without
Complications, Congestive Heart Failure, Ce rebrovascular 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 Dis ease, 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]
A
PPENDIX B COVID-19 AND SEVERE COVID-19 CASE DEFINITIONS
The case definition for a confirmed case of COVID-19 for the primary efficacy endpoint,
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:
x Fever
x New or increased cough
x New or increased shortness of breath
x Chills
x New or increased muscle pain
x New loss of taste or smell
x Sore throat
x Diarrhea
x Vomiting
Clinical Reviewer: Susan K. Wollersheim, MD
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The case definition for severe COVID-19 case included a confirmed COVID-19 case with
at least one of the following:
x &OLQLFDO VLJQV DW UHVW LQGLFDWLYH RI VHYHUH V\VWHPLF LOOQHVV 5 5 EUHDWKV SHU
PLQXWH +5 EHDWV SHU PLQXWH 6S2 2 RQ room air at sea level, or
PaO2/FiO 2<300 mm Hg)
x Respiratory failure (defined as needing high-flow oxygen, noninvasive ventilation,
mechanical ventilation, or extracorporeal membrane oxygenation)
x Evidence of shock (systolic blood pressure <90 mm Hg, diastolic blood pressure <60
mm Hg, or requiring vasopressors)
x Significant acute renal, hepatic, or neurologic dysfunction
x Admission to an ICU
x Death
APPENDIX C COMIRNATY -ATTRIBUTABLE MYOCARDITIS /PERICARDITIS RISKS
Table 19. International and US Data on Comirnaty-Attributable Myocarditis/Pericarditis
Risks
Study Age
group Risk of myocarditis/pericarditis
(cases per 1 million doses
administered) Notes Reference
US,
VAERS 12-15 45.7 post Dose 2 Male only,
7-Day risk window,
Not background rate
adjusted Su
US, VSD 12-17 70.8 post Dose 2 Male and Female,
7-day risk window,
Background rate adjusted Klein
US, BEST
Data
Partner 12-15 32 combined doses, females
179 combined doses, males 7-day risk window,
Background rate adjusted Unpublished
data.
Israel
Ministry of
Health 12-15 59 post Dose 2 Male only,
21/30-Day risk window,
Not background rate
adjusted Milo
South
Korea ~16-18 18 [95% CI: 8,35] in one dose
recipients
43 [95% CI: 26,67] in two dose
recipients 12th graders (age is not
accurate)
Risk window- days between
dose 1 and 2 and 30-days
post second dose Choe et al.
Su, John R. “COVID-19 vaccine safety updates: Primary series in children and adolescents ages 5–11 and 12–15 years,
and booster doses in adolescents ages 16–24 years” Advisory Committee on Immunization Practices. January 5, 2022.
https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2022-01-05/02-COVID-Su-508.pdf
Klein, Nicola. “Vaccine Safety Datalink Rapid Cycle Analyses: Uptake and Safety of COVID-19 Vaccines in 5–11 and 12–
17-Year-Olds". Advisory Committee on Immunization Practices. January 5, 2022.
https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2022-01-05/04-COVID-Klein-508.pdf
Milo, Ron, “Protection by 4th dose of BNT162b2 against Omicron in Israel”, April 6th, FDA Vaccines and Related Biological
Products Advisory Committee Meeting, Retrieved from https://www.fda.gov/media/157492/download on May 4, 2022.
Choe, Young June, et al. "Safety and effectiveness of BNT162b2 mRNA Covid-19 vaccine in adolescents." Vaccine 40.5
(2022): 691-694.