Burk Declaration
- Date
- 2021-12-17
Summary
Exhibit 10 to the Burk Declaration, filed December 17, 2021 as Document 40-10 in Case 2:21-cv-00702-CLM in the U.S. District Court, N.D. of Alabama. The 33-page exhibit is an FDA Emergency Use Authorization review memorandum for EUA 27034 Amendment 305, submitted by Pfizer, Inc., on behalf of Pfizer and BioNTech on September 21, 2021 and completed September 22, 2021. It reviews clinical data from study C4591001 on a single booster dose of the Pfizer-BioNTech COVID-19 Vaccine given at least 6 months after the primary series. The memorandum reports that VRBPAC members voted 16-2 against approval of a booster for the general population and 18-0 in favor of an EUA for individuals 65 years and older and those at high risk. The review team recommends authorization for three populations, including individuals 18 through 64 years of age at high risk of severe COVID-19.
Summary drafted by a model from the document's text below and checked by script against that text before publication. It is a navigation aid, not a reading of what the document proves. Where AI is used
Full text
Case 2:21-cv-00702-CLM Document 40-10 Filed 12/17/21 Page 1 of 33 FILED
2021 Dec-17 PM 01:27
U.S. DISTRICT COURT
N.D. OF ALABAMA
Burk Declaration
Exhibit 10
Case 2:21-cv-00702-CLM Document 40-10 Filed 12/17/21 Page 2 of 33
Emergency Use Authorization (EUA) for an Unapproved Product
Review Memorandum
Identifying Information
Application Type EUA (Event-driven EUA request) Amendment
Application Number EUA 27034 Amendment 305
Sponsor Pf izer, Inc., on behalf of Pfizer and BioNTech
Submission Date September 21, 2021
Receipt Date September 21, 2021
Signatory Authority Marion F. Gruber, Ph.D., Director, CBER/OVRR
Review Team Ramachandra Naik, Ph.D., Chair, OVRR/DVRPA
CAPT Michael Smith, Ph.D., Regulatory Project Manager, OVRR/DVRPA
Laura Gottschalk, PhD., Regulatory Project Manager, OVRR/DVRPA
Joohee Lee, M.D., Clinical reviewer, OVRR/DVRPA
Lei Huang, Ph.D., Biostatistics reviewer, OBE/DB
Ye Yang, Ph.D., Biostatistics reviewer, OBE/DB
Xiao Wang, Ph.D., CMC/Product reviewer, OVRR/DVP
Brenda Baldwin, Ph.D., Data Integrity reviewer, OVRR/DVRPA
CAPT Oluchi Elekwachi, Ph.D., Labeling reviewer, OCBQ/DCM/APLB
Deborah Thompson, MD, MSPH, PVP reviewer, OBE/DE
Haecin Chun, MS, BIMO reviewer, OCBQ/DIS
Review Completion Date September 22, 2021
Established Name/Other Pf izer-BioNTech COVID-19 Vaccine/ BNT162b2
names used during
development
Dosage Forms/Strengths and A 0.3 mL suspension for intramuscular injection
Route of Administration
Intended Use for EUA Active immunization to prevent coronavirus disease 2019 (COVID-19)
caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-
CoV-2)
Use: A single booster dose administered at least 6 months after
completing a Pfizer-BioNTech COVID-19 Vaccine primary series.
Intended Population for Booster
dose • individuals 65 years of age and older
• individuals 18 through 64 years of age at high risk of severe COVID-19
• individuals 18 through 64 years of age whose frequent institutional or
occupational exposure to SARS-CoV-2 puts them at high risk of
serious complications of COVID-19 including severe COVID-19
Case 2:21-cv-00702-CLM Document 40-10 Filed 12/17/21 Page 3 of 33
Table of Contents
1. EXECUTIVE SUMMARY ..................................................................................................... 4
2. BACKGROUND .................................................................................................................. 6
2.1.SARS-CoV-2 Virus and COVID-19 Disease.................................................................. 6
2.2.Vaccines for SARS-CoV-2............................................................................................ 7
3. RATIONALE FOR BOOSTER DOSES FOR COVID-19 VACCINES .................................... 9
4. EUA REQUIREMENTS, GUIDANCE AND CONSIDERATIONS PERTAINING
TO COVID-19 VACCINES ................................................................................................. 10
4.1.US requirements to support issuance of an EUA for a biological product..................... 10
4.2.FDA guidance for industry related to COVID-19 vaccines ........................................... 10
4.3.Regulatory considerations for a booster dose for COVID-19 vaccines ......................... 11
4.4.Data to support safety and effectiveness of a booster dose of COVID-19 vaccines...... 11
5. FDA REVIEW OF CLINICAL DATA FROM STUDY C4591001 .......................................... 12
5.1.Design....................................................................................................................... 12
5.2.Demographics and disposition.................................................................................... 14
5.3.Timing of BNT162b2 booster administration ............................................................... 16
5.4.Immunogenicity evaluation......................................................................................... 16
5.5.Safety evaluation ....................................................................................................... 20
5.6.COVID-19 cases among C4591001 study participants during the Delta variant surge.. 23
5.7.Summary of booster dose safety and immunogenicity data from study C4591001 ....... 24
6. FDA REVIEW OF OTHER INFORMATION SUBMITTED................................................... 25
6.1.Pharmacovigilance Activities ...................................................................................... 25
6.2.Clinical Assay Information .......................................................................................... 27
6.3.Inspection of Clinical Study Sites................................................................................ 27
6.4.EUA Prescribing Information and Fact Sheets ............................................................ 28
7. BENEFIT / RISK ASSSESSMENT IN THE CONTEXT OF THE PROPOSED
USE UNDER EUA ............................................................................................................. 28
7.1.Known and Potential Benefits..................................................................................... 28
7.2.Uncertain Benefits/Data Gaps .................................................................................... 29
7.3.Known and Potential Risks......................................................................................... 29
7.4.Uncertain Risks/Data Gaps ........................................................................................ 30
2
Case 2:21-cv-00702-CLM Document 40-10 Filed 12/17/21 Page 4 of 33
8. VRBPAC SUMMARY ........................................................................................................ 30
9. OVERALL SUMMARY AND RECOMMENDATIONS ......................................................... 31
10.REFERENCES................................................................................................................. 32
List of Tables
Table 1. Emergency Use Authorizations of COVID-19 Vaccines ............................................... 9
Table 2. Demographics and Baseline Characteristics, Phase 1 and Phase 2/3 Recipients of
BNT162b2 (30 µg) Booster Dose, Safety Population ...................................................... 14
Table 3. Disposition of Phase 2/3 Recipients of BNT162b2 (30 µg) Booster Dose................... 15
Table 4. Protocol Specified Immunobridging Analysis of SARS-CoV-2 Neutralizing GMTs at 1
Month Post-Booster and 1 Month Post-Primary Series in Phase 2/3 BNT162b2
Participantsa Without Evidence of SARS-CoV-2 Infection up to 1 Month After Booster,
Based on SARS-CoV-2 Microneutralization Assay-NT50 with Reference Strain, Booster
Evaluable Immunogenicity Population ............................................................................ 17
Table 5. Protocol Specified Analysis of Seroresponse Rates at 1 Month Post-Booster Dosea and
1 Month Post-Primary Seriesb in Phase 2/3 BNT162b2 Participantsc Without Evidence of
SARS-CoV-2 Infection up to 1 Month After Booster, Based on SARS-CoV-2 Virus
Microneutralization Assay NT50 with Reference Strain, Booster Evaluable Immunogenicity
Population ..................................................................................................................... 18
Table 6. Post hoc Analysis of Seroresponse Rates at 1 Month Post-Booster Dosea and 1 Month
Post-Primary Seriesb in Phase 2/3 BNT162b2 Participantsc Without Evidence of SARS-
CoV-2 Infection up to 1 Month After Booster, Based on SARS-CoV-2 Virus
Microneutralization Assay-NT50 with Reference Strain, Booster Evaluable Immunogenicity
Population ..................................................................................................................... 18
Table 7. SARS-CoV-2 Neutralizing GMTs and Seroresponsea, by Comorbidity Statusb, at 1
Month Post-Booster and 1 Month Post-Primary Series in Phase 2/3 BNT162b2
Participantsc Without Evidence of SARS-CoV-2 Infection up to 1 Month After Booster –
Booster Evaluable Immunogenicity Population ............................................................... 19
Table 8. SARS-CoV-2 Neutralizing GMTs at 1 Month Post-Booster and 1 Month Post-Primary
Series, Phase 1 Recipients of BNT162b2 (30 µg) Booster a Without Evidence of SARS-
CoV-2 Infection Up to 1 Month After Booster, Based on SARS-CoV-2 Plaque Reduction
Neutralization Assay with Reference and Delta Variant Strains ....................................... 19
Table 9. Frequency of Solicited Local Reactions by Severity, Within 7 Days After Dose 2
Compared to After Booster Dose of BNT162b2 30 µg Among Participants in Phase 1/2/3
Study C4591001............................................................................................................ 21
Table 10. Frequency of Solicited Systemic Reactions, by Severity, Within 7 Days After Dose 2
Compared to After Booster Dose of BNT162b2 30 µg Among Participants in Phase 1/2/3
Study C4591001............................................................................................................ 21
Table 11. Unsolicited Adverse Events Reported by ≥2 Phase 2/3 Participants from Booster
Dose to 1 Month After Booster Dose, Phase 2/3 Booster Safety Population (N=306)....... 23
3
Case 2:21-cv-00702-CLM Document 40-10 Filed 12/17/21 Page 5 of 33
1. EXECUTIVE SUMMARY
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic continues to
present an extraordinary challenge to global health and, as of September 2021, has caused 222
million cases of COVID-19, including 4.5 million deaths worldwide. In the United States, more
than 42 million cases have been reported to the Centers for Disease Control and Prevention
(CDC), of which 89% were among individuals 16 years and older.
On August 23, 2021, FDA approved COMIRNATY (COVID-19 Vaccine, mRNA) for active
immunization to prevent coronavirus disease 2019 (COVID-19) caused by severe acute
respiratory syndrome coronavirus 2 (SARS-CoV-2) in individuals 16 years of age and older. The
vaccine is based on the SARS-CoV-2-spike glycoprotein antigen encoded by modified mRNA
and formulated in lipid particles (LPs). The approved regimen is a 2-dose primary vaccination
series administered 3 weeks apart, with each dose containing 30 µg mRNA. The vaccine is also
authorized under EUA for use as a 2-dose primary series in individuals 12 years of age and
older and for use as a third dose of the primary series in individuals 12 years of age and older
with certain immunocompromising conditions. The vaccine authorized under EUA is also known
as the Pfizer-BioNTech COVID-19 Vaccine. During clinical development, the vaccine was called
BNT162b2.
On August 25, 2021, Pfizer submitted a supplemental Biologics License Application (sBLA) for
COMIRNATY seeking approval for use of a booster dose administered at least 6 months after
the primary series in individuals 16 years of age and older. To support the need for a booster
dose, the submission referenced several observational studies that suggest waning of
protection in the setting of the current Delta variant surge among individuals who previously
received the 2-dose primary series.
The sBLA included safety data and immunogenicity data assessed against the reference strain
(USA_WA1/2020, Wuhan-like) from approximately 300 immunocompetent adults 18 through 55
years of age who completed the primary vaccination series and who received a BNT162b2
booster dose approximately 6 months after completion of the 2-dose primary series in the
Phase 2/3 portion of an ongoing study (C4591001). Efficacy against COVID-19 was not
evaluated following the booster dose. Supportive data from the Phase 1 portion of this study in
participants 18 through 55 years of age (N=11) and 65 through 85 years of age (N=12) who had
received a BNT162b2 booster dose approximately 7 to 9 months after their primary series were
also included and consisted of safety data and exploratory immunogenicity data evaluating
neutralizing antibody titers elicited by the booster dose against the reference strain (wild-type) of
SARS-CoV-2 and variants of concern (VOCs).
The effectiveness of the booster dose is based on immunobridging analyses from the Phase 2/3
group of participants 18 through 55 years of age comparing 50% neutralizing antibody titers
against the reference strain at 1 month after the booster dose to those observed at 1 month
post-primary series among participants without evidence of prior SARS-CoV-2 infection.
Immunobridging analyses included hypothesis testing for:
• geometric mean titers (GMTs) of SARS-CoV-2 neutralizing antibodies at 1 month after the
booster dose vs. those values 1 month after the primary series, using a 1.5-fold non-
inferiority margin as the success criterion for the lower bound of the confidence interval
around the GMT ratio, and
• percentage of participants with seroresponse (≥4-fold rise from baseline at 1 month after the
booster dose vs. 1 month after primary series), using a -10% non-inferiority margin as the
4
Case 2:21-cv-00702-CLM Document 40-10 Filed 12/17/21 Page 6 of 33
success criterion for the lower bound of the confidence interval around the difference
between seroresponse rates.
Immunobridging analyses against the reference strain met the pre-specified success criteria for
GMT ratio and difference in seroresponse rates for the booster dose compared to the 2-dose
primary series. Additionally, the geometric mean-fold rise (GMFR) from before the booster dose
to 1 month after the booster dose was analyzed descriptively. Pfizer proposed to infer
effectiveness of the booster dose against the Delta variant from exploratory descriptive analyses
of 50% neutralizing antibody titers (using a non-validated assay) against this variant evaluated
among subjects from the Phase 1 portion of the study.
Solicited and unsolicited safety data from booster recipients (12 Phase 1 participants 65 through
85 years of age and 306 Phase 2/3 participants 18 through 55 years of age) were reviewed and
compared to labeled safety data from the reactogenicity subset (N=~2700) of recipients of the 2-
dose primary series. Safety following the booster dose was assessed for a median of 2.6
months among both Phase 1 and Phase 2/3 study participants. Reported frequencies and
severities of local and systemic solicited adverse reactions following the booster dose were not
substantially different from those following Dose 2 of the primary series. Reported frequencies
and severities of solicited adverse reactions following the booster dose were lower among the
12 Phase 1 participants 65 through 85 years of age compared with the 289 Phase 2/3
participants 18 through 55 years of age who provided e-diary data, similar to age group-related
differences in reactogenicity associated with the primary series. Lymphadenopathy (16/306;
5.2%) affecting axillary (n=15) and cervical chain lymph nodes (n=1) was the most common
unsolicited adverse event (AE); all events of lymphadenopathy occurred within 3 days of
vaccination. The incidence post-booster dose was substantially higher than the rate reported
among adults after any of the 2 doses of the primary series (83/21,926; 0.4%). No other adverse
events of clinical interest (i.e., myocarditis, pericarditis, Bell’s palsy, appendicitis) were reported
following the booster dose. However, most (n=15) were mild to moderate in severity and lasted
2 to 8 days. One case of mild lymphadenopathy was reported as ongoing and resolving at the
time of last assessment. No deaths were reported following the booster dose, and one nonfatal
serious adverse event (acute myocardial infarction 2 months after the booster dose, assessed
as unrelated to study vaccination) was reported.
On September 17, 2021, a VRBPAC meeting was held to discuss if the data Pfizer submitted
were sufficient to support licensure of a booster dose of COMIRNATY administered
approximately 6 months after the primary series in individuals 16 years of age and older.
VRBPAC members voted 16-2 against approval of the booster dose in this general population,
citing concerns about insufficient data to support a favorable benefit/risk determination in this
general population. Considering the committee’s feedback, the FDA then asked the committee
members to vote on whether the available data would support an Emergency Use Authorization
(EUA) of a booster dose for use in individuals 65 years and older and individuals at high risk of
severe COVID-19, and VRBPAC members voted 18-0 in favor of this EUA. VRBPAC members
also expressed support for inclusion of individuals at increased risk of occupational exposure to
SARS-CoV-2 in the EUA.
On September 21, 2021, Pfizer submitted an amendment to their EUA, containing the same
information submitted previously to the sBLA, requesting authorization of the Pfizer-BioNTech
COVID-19 vaccine for use as a booster dose at least 6 months after the primary series. Based
on a declaration by the Secretary of Health and Human Services (HHS) that the COVID-19
pandemic constitutes a public health emergency with a significant potential to affect national
security or the health and security of United States citizens living abroad, FDA may issue an
5
Case 2:21-cv-00702-CLM Document 40-10 Filed 12/17/21 Page 7 of 33
EUA for a COVID-19 vaccine after determining that certain statutory requirements are met.
Considering the statutory requirements and the totality of data available at this time to support
effectiveness of a Pfizer-BioNTech COVID-19 vaccine booster dose and to inform known and
potential benefits and known and potential risks associated with the booster dose, the review
team recommends authorization of the Pfizer-BioNTech COVID-19 vaccine under EUA for use
as a booster dose administered at least 6 months after the primary series in the following
populations:
• individuals 65 years of age and older,
• individuals 18 through 64 years of age at high risk of severe COVID-19, and
• individuals 18 through 64 years of age whose frequent institutional or occupational
exposure to SARS-CoV-2 puts them at high risk of serious complications of COVID-19
including severe COVID-19.
2. BACKGROUND
2.1. SARS-CoV-2 Virus and COVID-19 Disease
SARS-CoV-2 is a zoonotic coronavirus that emerged in late 2019 and was identified in patients
with pneumonia of unknown cause. The virus was named SARS-CoV-2 because of its similarity
to the coronavirus responsible for severe acute respiratory syndrome (SARS-CoV, a lineage B
betacoronavirus). SARS-CoV-2 is an enveloped, positive-sense, single-stranded RNA virus
sharing more than 70% of its sequence with SARS-CoV, and ~50% with the coronavirus
responsible for Middle Eastern respiratory syndrome (MERS-CoV). 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.
The SARS-CoV-2 pandemic continues to present a challenge to global health and, as of
September 7, 2021, has caused approximately 222 million cases of COVID-19, including 4.5
million deaths worldwide. In the United States, more than 42 million cases have been reported
to the Centers for Disease Control and Prevention (CDC), of which 89% have occurred in
individuals 16 years of age or older. While the pandemic has caused morbidity and mortality on
an individual level, the continuing spread of SARS-CoV-2, and emerging variants (such as the
highly transmissible Delta variant that is now predominant in the US) have caused significant
challenges and disruptions in worldwide healthcare systems, economies, and many aspects of
human activity (travel, employment, education).
Following emergency use authorization of COVID-19 vaccines in December 2020, COVID-19
cases and deaths in the United States 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 unvaccinated individuals are major factors in
the recent resurgence of COVID-19. While recently reported cases appear to be declining
relative to the Delta variant-associated peak globally and in the US, the future course of the
pandemic is uncertain.
6
Case 2:21-cv-00702-CLM Document 40-10 Filed 12/17/21 Page 8 of 33
2.2. Vaccines for SARS-CoV-2
2.2.1. COMIRNATY (COVID-19 Vaccine, mRNA)
On August 23, 2021, FDA approved COMIRNATY (COVID-19 Vaccine, mRNA) made by
BioNTech Manufacturing GmbH (in partnership with Pfizer, Inc.). COMIRNATY is a vaccine
indicated for active immunization to prevent coronavirus disease 2019 (COVID-19) caused by
severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in individuals 16 years of age
and older. The vaccine is administered IM as a series of two doses (0.3 mL each) 3 weeks
apart, with each dose containing 30 μg mRNA. COMIRNATY contains a nucleoside-modified
messenger RNA (mRNA) encoding the viral spike glycoprotein of SARS-CoV-2 that is
formulated in lipid particles. COMIRNATY is the only vaccine or medical product that is FDA
approved for prevention of COVID-19. The vaccine is also authorized under EUA for use as a 2-
dose primary series in individuals 12 years of age and older and for use as a third dose of the
primary series in individuals 12 years of age and older with certain immunocompromising
conditions. The vaccine authorized under EUA is also known as the Pfizer-BioNTech COVID-19
Vaccine. During clinical development, the vaccine was called BNT162b2.
COMIRNATY is supplied as a concentrated multi-dose liquid formulation (0.45 mL volume)
stored frozen at -90°C to -60°C in a 2 mL Type 1 glass vial. A sterile diluent, 0.9% Sodium
Chloride Injection, USP, is supplied separately and is stored at 20°C to 25°C. The COMIRNATY
Multiple Dose Vial is thawed in a refrigerator (2°C to 8°C) for 2 to 3 hours or at room
temperature (up to 25°C) for 30 minutes. Once at room temperature, the COMIRNATY Multiple
Dose Vial is diluted with 1.8 mL of the diluent. After dilution, each vial of COMIRNATY contains
six doses of 0.3 mL of vaccine. COMIRNATY does not contain preservative.
2.2.2. Efficacy of a 2-dose primary series of COMIRNATY
Efficacy of BNT162b2 for the prevention of COVID-19 occurring at least 7 days after the second
dose of vaccine was evaluated in an ongoing Phase 3 study in approximately 44,000
participants randomized 1:1 to receive two doses of either BNT162b2 or placebo, 3 weeks
apart. Participants were enrolled with stratification by age (younger adults: 18 through 55 years
of age; older adults: over 55 years of age). The population for the vaccine efficacy analysis that
supported approval of COMIRNATY included participants 16 years of age and older who had
been enrolled from July 27, 2020, and who were followed for the development of COVID-19
during blinded placebo-controlled follow-up through as late as March 13, 2021. Overall, 60.8%
of participants in the BNT162b2 group and 58.7% of participants in the placebo group had ≥4
months of follow-up time after the primary series in the blinded placebo-controlled follow-up
period. The overall VE against COVID-19 in subjects without evidence of prior SARS-CoV-2
infection was 91.1% (95% CI: 88.8 to 93.1). The overall VE against COVID-19 in subjects with
or without evidence of prior SARS-CoV-2 infection was 90.9% (95% CI: 88.5 to 92.8).
2.2.3. Safety of a 2-dose primary series of COMIRNATY
The most commonly reported solicited adverse reactions (occurring in ≥10% of participants)
among BNT162b2 vaccine recipients 16 through 55 years of age following any dose were pain
at the injection site (88.6%), fatigue (70.1%), headache (64.9%), muscle pain (45.5%), chills
(41.5%), joint pain (27.5%), fever (17.8%), and injection site swelling (10.6%). The most
commonly reported solicited adverse reactions in BNT162b2 vaccine recipients 56 years of age
and older following any dose were pain at the injection site (78.2%), fatigue (56.9%), headache,
(45.9%), muscle pain (32.5%), chills (24.8%), joint pain (21.5%), injection site swelling (11.8%),
fever (11.5%), and injection site redness (10.4%).
7
Case 2:21-cv-00702-CLM Document 40-10 Filed 12/17/21 Page 9 of 33
Among participants 16 through 55 years of age, serious adverse events from Dose 1 up to the
participant unblinding date in ongoing follow-up were reported by 0.8% of BNT162b2 recipients
and 0.9% placebo recipients. In a similar analysis, in participants 56 years of age and older
serious adverse events were reported by 1.8% of BNT162b2 recipients and 1.7% of placebo
recipients who received at least 1 dose of BNT162b2 or placebo, respectively. In these
analyses, 58.2% of study participants had at least 4 months of follow-up after the primary series.
There were no notable patterns between treatment groups for specific categories of serious
adverse events (including neurologic, neuro-inflammatory, and thrombotic events) that would
suggest a causal relationship to BNT162b2. From Dose 1 through the March 13, 2021 data
cutoff date, there were a total of 38 deaths, 21 in the BNT162b2 group and 17 in the placebo
group. None of the deaths were considered related to vaccination.
2.2.3.1. Myocarditis/pericarditis
During the time from Dose 1 to unblinding in Study C4591001, one report of pericarditis was
identified in the vaccine group, occurring in a male participant ≥55 years of age, with no medical
history, 28 days after a primary series of BNT162b2; the event was assessed by the investigator
as not related to the study intervention and was ongoing at the time of the data cutoff. One
report of myocarditis was identified in a male participant <55 years of age in the placebo group,
occurring 5 days after his second placebo dose.
Post-EUA safety surveillance reports received by FDA and CDC identified serious risks for
myocarditis and pericarditis following administration of the primary series (Dose 1 and Dose 2)
of BNT162b2. Reporting rates for medical chart-confirmed myocarditis/pericarditis in VAERS
have been higher among males under 40 years of age than among females and older males
and have been highest in males 16-17 years of age (~75 cases per million doses administered
as per CDC presentation to the ACIP on August 30, 2021), particularly following the second
dose, with onset of symptoms occurring within 7 days following vaccination. In an FDA analysis
of the Optum database, the estimated excess risk of myocarditis/pericarditis approached 200
cases per million among vaccinated males 16-17 years of age. 1 Although some cases of
vaccine-associated myocarditis/pericarditis 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
and outcomes in affected individuals, or whether the vaccine might be associated with initially
subclinical myocarditis (and if it is what are the long-term sequelae). A mechanism of action by
which the vaccine could cause myocarditis and pericarditis has not been established. FDA
determined that the benefits of the 2-dose primary series outweighed the risks of myocarditis
and pericarditis, including for males ages 16-17 years of age, and the increased risk of
myocarditis/pericarditis is described in section 5.2 Warnings and Precautions of the prescribing
information for COMIRNATY.
2.2.4. Vaccines authorized under EUA for SARS-CoV-2
FDA has issued EUAs for three COVID-19 vaccines as shown in Table 1 below.
8
Case 2:21-cv-00702-CLM Document 40-10 Filed 12/17/21 Page 10 of 33
Table 1. Emergency Use Authorizations of COVID-19 Vaccines
Sponsor Regimen Indicated Population Date of EUA
Pf izer 2 doses 3 weeks apart • Individuals ≥16 years of age December 11, 2020
• Individuals ≥12 years of age May 10, 2021
• 3rd dose for individuals ≥12 years August 12, 2021
and who have undergone solid
organ transplantation, or diagnosed
with conditions considered to have
an equivalent level of
immunocompromise
Moderna 2 doses 1 month apart • Individuals ≥18 years of age December 18, 2020
• 3rd dose for individuals ≥18 years of August 12, 2021
age who have undergone solid
organ transplantation, or diagnosed
with conditions considered to have
an equivalent level of
immunocompromise
Janssen Single dose • Adults ≥18 years of age February 27, 2021
3. RATIONALE FOR BOOSTER DOSES FOR COVID-19 VACCINES
Concerns have been raised that declining neutralizing antibody titers or reduced effectiveness
against symptomatic disease may herald significant declines in effectiveness against severe
disease. The recent emergence of the highly transmissible Delta variant of SARS-CoV-2
resulted in a new wave of COVID-19 cases in many parts of the world and has led to
considerations for administration of booster doses to individuals who received primary series of
vaccines in an effort to enhance immunity, and thus sustain protection from COVID-19.
The expected benefit of booster vaccination will depend on the impact that booster vaccination
has in reducing disease relative to the primary series. If the primary series of COMIRNATY is
still effective in preventing important COVID-19-related outcomes, then the benefit of booster
vaccination is likely to be more limited than if effectiveness following the primary series has
waned substantially. Factors supporting licensure of a booster dose should consider the
effectiveness of primary vaccination with COMIRNATY over time and against circulating
variants, the effectiveness (and its duration) of booster vaccination in preventing important
COVID-19-related outcomes in individuals who have already received a primary vaccination
series, the dynamics of the pandemic in the United States, and the risks of booster vaccination
in the general population or in certain subpopulations.
Some observational studies have suggested declining efficacy of COMIRNATY over time
against symptomatic infection or against the Delta variant, while others have not. However,
overall, data indicate that currently US-licensed or authorized COVID-19 vaccines still afford
protection against severe COVID-19 disease and death in the United States. There are many
potentially relevant studies, but FDA has not independently reviewed or verified the underlying
data or their conclusions. Some of these studies, including data from the vaccination program in
Israel, were summarized during the September 17, 2021 VRBPAC meeting. 2
It should be recognized that while observational studies can enable understanding of real-world
effectiveness, known and unknown biases potentially associated with such studies (also
summarized during the September 17, 2021 VRBPAC meeting) can affect their reliability. Due
to these biases some studies may be more reliable than others. Furthermore, US-based studies
9
Case 2:21-cv-00702-CLM Document 40-10 Filed 12/17/21 Page 11 of 33
of post-authorization effectiveness of BNT162b2 may most accurately represent vaccine
effectiveness in the US population.
4. EUA REQUIREMENTS, GUIDANCE AND CONSIDERATIONS PERTAINING TO COVID-
19 VACCINES
4.1. US requirements to support issuance of an EUA for a biological product
Based on the declaration by the Secretary of the US Department of Health and Human Services
(HHS) that the COVID-19 pandemic constitutes a public health emergency with a significant
potential to affect national security or the health and security of United States citizens living
abroad, FDA may issue an EUA after determining that certain statutory requirements are met
(section 564 of the FD&C Act (21 U.S.C. 360bbb-3)).
• The chemical, biological, radiological, or nuclear (CBRN) agent referred to in the March 27,
2020 EUA declaration by the Secretary of HHS (SARS-CoV-2) can cause a serious or life-
threatening disease or condition.
• Based on the totality of scientific evidence available, including data from adequate and well-
controlled trials, if available, it is reasonable to believe that the product may be effective to
prevent, diagnose, or treat such serious or life-threatening disease or condition that can be
caused by SARS-CoV-2, or to mitigate a serious or life-threatening disease or condition
caused by an FDA-regulated product used to diagnose, treat, or prevent a disease or
condition caused by SARS-CoV-2.
• The known and potential benefits of the product, when used to diagnose, prevent, or treat
the identified serious or life-threatening disease or condition, outweigh the known and
potential risks of the product.
• There is no adequate, approved, and available alternative to the product for diagnosing,
preventing, or treating the disease or condition.
If these criteria are met, under an EUA, FDA can authorize unapproved medical products (or
unapproved uses of approved medical products) to be used in an emergency to diagnose, treat,
or prevent serious or life-threatening diseases or conditions caused by threat agents. FDA has
been providing regulatory advice to COVID-19 vaccine manufacturers regarding the data
needed to determine that the known and potential benefits of a booster dose outweigh the
known and potential risks (see Sections 4.2-4.4 below).
In the event an EUA is issued for a booster dose of this vaccine, it would be considered
unapproved and further investigation (under an Investigational New Drug Application) would
continue.
4.2. FDA guidance for industry related to COVID-19 vaccines
To facilitate the manufacturing, clinical development, and licensure of COVID-19 vaccines, FDA
published the guidance for industry entitled Development and Licensure of Vaccines to Prevent
COVID-19 (June 2020) describing FDA’s current recommendations regarding the data needed
to facilitate clinical development and licensure of vaccines to prevent COVID-19.3 This guidance
provides an overview of key considerations to satisfy regulatory requirements set forth in the
investigational new drug application (IND) regulations in 21 CFR Part 312 and licensing
regulations in 21 CFR Part 601 for chemistry, manufacturing, and controls (CMC), and
nonclinical and clinical data through development and licensure, and for post-licensure safety
evaluation of COVID-19 preventive vaccines. The guidance notes that the efficacy of COVID-19
10
Case 2:21-cv-00702-CLM Document 40-10 Filed 12/17/21 Page 12 of 33
vaccines should be demonstrated in adequate and well controlled clinical trials that directly
evaluate the ability of the vaccine to protect humans from SARS-CoV-2 infection and/or
disease. The guidance notes further that safety evaluations including the size of the database
required to support licensure should be no different than for other preventive vaccines for
infectious diseases. Of note, this guidance does not address immunogenicity studies to infer
effectiveness of booster doses for COVID-19 vaccines. However, the guidance for industry
document Emergency Use Authorization for Vaccines to Prevent COVID-19 (May 2021,
February 2021, originally issued October 2020) describes data needed to support the
effectiveness of a modified COVID-19 vaccine against variants of concern (VOCs). 4 FDA has
applied these concepts to effectiveness evaluations of booster doses afforded by the prototype
vaccine (refer to Section 4.4 below).
4.3. Regulatory considerations for a booster dose for COVID-19 vaccines
The benefit of a booster dose must be weighed against potential risk. Available data should
support the effectiveness of the booster dose, particularly against currently circulating SARS-
CoV-2 variants, and benefit should be considered relative to the benefit provided by completion
of the primary series. Safety data should be available to identify the most frequently reported
adverse reactions associated with the booster dose. Pre-authorization clinical trials may not be
adequately powered to characterize uncommon but potentially serious adverse reactions, such
as myocarditis/pericarditis (see Section 3.1.2.1). It is currently not known if there will be an
increased risk of myocarditis/pericarditis or other adverse reactions after a booster dose of the
Pfizer-BioNTech COVID-19 vaccine. These risks and associated uncertainties have to be
considered in when assessing benefit and risk.
4.4. Data to support safety and effectiveness of a booster dose of COVID-19 vaccines
As noted above, the Guidance for Industry Emergency Use Authorization for Vaccines to
Prevent COVID-19 (May 2021) describes data that could support the effectiveness of modified
COVID-19 vaccines directed against a VOC. While the current supplement is not for a booster
dose targeted to a VOC, the intended use in the current pandemic situation is analogous, and
corresponding recommendations have been conveyed to product sponsors seeking discussions
on booster dosing with the prototype vaccine, as summarized below.
Effectiveness of a booster dose with a COVID-19 vaccine can be evaluated based on the
efficacy of the manufacturer’s authorized prototype vaccine made by the same manufacturing
process and for which a clinical disease endpoint efficacy study has been conducted that met
FDA’s pre-specified success criteria. A determination of effectiveness of a booster dose should
be supported by conducting clinical immunogenicity studies. The following considerations apply
to homologous booster doses for COVID-19 vaccines that have already been licensed or
received emergency use authorization for use in adults. As described in the EUA Guidance, a
safety and immunogenicity study conducted in a single age group (e.g., adults 18-55 years of
age) could potentially provide data to extrapolate safety and effectiveness of a booster dose for
use in all age groups for which the primary series has been approved or authorized. As a
scientific consideration, extrapolation of booster dose data across age groups presumes that no
age group-specific safety or effectiveness considerations would preclude such extrapolation.
A favorable benefit-risk assessment to support authorization or approval of a booster dose
would depend on evidence (e.g., longer term efficacy data and or data from post-authorization
effectiveness studies) that a booster dose is needed and evidence (i.e., immunogenicity data)
that the booster dose would be effective not only against the original reference or prototype
11
Case 2:21-cv-00702-CLM Document 40-10 Filed 12/17/21 Page 13 of 33
SARS-CoV-2 strain but also against circulating variants. Furthermore, it is expected that
justification for the interval chosen for the booster dose is provided taking into account both
safety and effectiveness considerations. Clinical non-inferiority immunogenicity studies should
be conducted in which the prototype COVID-19 vaccine is administered to persons who
previously received the prototype COVID-19 vaccine according to the authorized or licensed
dose and dose regimen. The immune response induced by the booster dose should be
compared to the immune response induced by the primary series, as assessed by neutralizing
antibody seroresponse rates and GMTs against the original virus (reference strain) upon which
the prototype vaccine was based. It is expected that the booster would induce an immune
response against the reference strain and clinically relevant variants of concern at levels that
meet or exceed those elicited by the primary series against the reference strain. The study
should be adequately powered for primary immunogenicity analyses to demonstrate statistical
non-inferiority of seroresponse rate and GMT elicited by the booster dose compared to the
primary series using non-inferiority margins of -10% for seroresponse rates and 1.5-fold for
GMTs, respectively. Alternative non-inferiority margins may be considered, with adequate
justification, on a case-by-case basis.
Conducting immunobridging analyses and evaluating neutralization against clinically relevant
variant viruses will require development of the appropriate neutralization assays specific for the
purpose. These assays would need to be sufficiently characterized (e.g., sensitivity, specificity)
as part of the qualification/validation process to understand and account for differences in
behavior of the different input viruses (e.g., as a result of expressing different spike protein
antigens) that could confound the ability to compare measured neutralization titers.
Safety assessments, including solicited and local and systemic adverse events assessed daily
for at least 7 days after each study vaccination as well as serious and other unsolicited adverse
events assessed during the immunogenicity evaluation period, may be sufficient to support
emergency use authorization or licensure of a booster dose. Evaluation in a larger safety
database than initially planned for immunogenicity analysis may be warranted if safety signals
that can be reasonably evaluated in pre-licensure/pre-authorization studies arise during clinical
evaluation of the booster dose. Post-licensure/post-authorization studies should be conducted
to assess longer-term safety for serious and other medically important adverse events.
The proposed use is for a booster dose of the Pfizer-BioNTech COVID-19 Vaccine administered
at least 6 months following a primary vaccination series in individuals 65 years of age and older,
individuals 18 through 64 years of age at high risk of severe COVID-19, and individuals 18
through 64 years of age whose frequent institutional or occupational exposure to SARS-CoV-2
puts them at high risk of serious complications of COVID-19 including severe COVID-19.
5. FDA REVIEW OF CLINICAL DATA FROM STUDY C4591001
5.1. Design
Study C4591001 is ongoing. The study was initially designed to evaluate two vaccine
candidates and several dosages in healthy adults in the United States (Phase 1), of which 24
participants (n=12 per age group: 18-55 years and 65-85 years) received a 2-dose primary
series of BNT162b2 (30 µg); the study population included healthy men and women and
excluded participants at high risk of SARS-CoV-2 infection or with serological evidence of prior
or current SARS-CoV-2 infection.
12
Case 2:21-cv-00702-CLM Document 40-10 Filed 12/17/21 Page 14 of 33
The Phase 2/3 portion of the study is being conducted in the United States, Argentina, Brazil,
Germany, South Africa and Turkey. Please see the Summary Basis for Regulatory Action for
the approval of a 2-dose primary series of COMIRNATY for study design details.1 Enrolled
Phase 2/3 participants were initially stratified by age (18-55 years and >55 years), with the goal
of older adults (>55 years of age) comprising 40% of the total study population. The protocol
was later amended to include adolescents 16 and 17 years of age. The study population
included participants at higher risk for acquiring COVID-19 and at higher risk of severe COVID-
19, such as health care workers, participants with autoimmune disease, and participants with
chronic but stable medical conditions such as hypertension, asthma, diabetes, and infection with
HIV, hepatitis B or hepatitis C. Participants were randomized 1:1 to receive two doses of either
BNT162b2 or saline placebo 3 weeks apart. Per protocol, since December 14, 2020, following
issuance of the Emergency Use Authorization for the Pfizer-BioNTech COVID-19 Vaccine,
Phase 2/3 participants ≥16 years of age in the vaccine and placebo groups were progressively
unblinded to their treatment assignment (when eligible for vaccination per local
recommendations), and participants originally randomized to placebo were offered vaccination
with BNT162b2 under the study protocol with continuing follow-up for safety and COVID-19-
related outcomes.
In February and March 2021, the protocol was amended to evaluate the safety and
immunogenicity of booster dose of BNT162b2 in Phase 1 participants (N=12 per age cohort: 18-
55 years and 65-85 years) and a subset of Phase 2/3 adults (N=300, ages 18-55 years), who
completed the 2-dose primary vaccination series with 30 µg BNT162b2. A booster dose of 30
µg BNT162b2 was administered approximately 7 to 9 months after a primary series for Phase 1
participants and approximately 6 months after a primary series for Phase 2/3 participants.
5.1.1. Immunogenicity evaluation
The effectiveness of the booster dose is based on an immunobridging analysis from the Phase
2/3 booster participants comparing 50% neutralizing antibody titers against the reference strain
(recombinant USA-WA1/2020) at 1 month after the booster dose to those observed at 1 month
post-primary series among subjects without evidence of prior SARS-CoV-2 infection.
Immunobridging analyses included hypothesis testing for:
• GMTs of SARS-CoV-2 neutralizing antibodies at 1 month after the booster dose vs. those
values 1 month after a primary series, using a 1.5-fold non-inferiority margin as the success
criterion for the lower bound of the confidence interval around the geometric mean ratio
(GMR), and
• percentage of participants with seroresponse (≥4-fold rise from baseline) at 1 month after
the booster dose vs. 1 month after a primary series, using a -10% non-inferiority margin as
the success criterion for the lower bound of the confidence interval around the difference
between seroresponse rates.
In the protocol-specified analysis of seroresponse, the baseline neutralizing antibody titer for
determining seroresponse to the booster dose was the pre-Dose 1 titer (same baseline titer as
used for determining seroresponse to the primary series). However, FDA also asked Pfizer to
conduct a post hoc seroresponse analysis using the pre-booster dose titer as the baseline for
determining the booster dose seroresponse (defined as ≥4-fold increase from the pre-booster
dose baseline titer).
Exploratory analyses of neutralizing antibody titers elicited by the BNT162b2 primary series and
a 30 µg BNT162b2 booster dose against the reference strain (Wuhan-like USA_WA1/2020) of
13
Case 2:21-cv-00702-CLM Document 40-10 Filed 12/17/21 Page 15 of 33
SARS-CoV-2 and the Beta and Delta variants were performed using samples from the Phase 1
study population. Discussion of these exploratory analyses in this briefing document is focused
on the Delta variant, since it is currently the predominant circulating variant in the US.
5.1.2. Safety evaluation
Phase 1 participants and Phase 2/3 participants recorded reactogenicity assessments and
antipyretic/pain medication use from Day 1 through Day 7 after booster in an e-diary.
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). Other safety assessments included: AEs occurring within
30 minutes after each dose, non-serious unsolicited AEs from Dose 1 through 1 month after the
booster dose, and serious AEs (SAEs) from the booster dose to the data cut-off date of June
17, 2021 (Phase 2/3) or May 13, 2021 (Phase 1).
Analysis populations pertaining to the 30 µg BNT162b2 booster dose
• Safety: All randomized participants who received a booster dose of 30 µg BNT162b2.
Analyses of reactogenicity endpoints were based on a subset of the safety population that
included participants with any e-diary data reported after vaccination.
• All-available immunogenicity: All participants who received a primary series of 30 µg
BNT162b2 at initial randomization, received a booster dose of 30 µg BNT162b2, and had at
least 1 valid and determinate immunogenicity result after the booster dose.
• Evaluable immunogenicity: All eligible participants who received a primary series of 30 µg
BNT162b2 as initially randomized, with Dose 2 received within 19-42 days after Dose 1,
received a booster dose of 30 µg BNT162b2, had at least 1 valid and determinate
immunogenicity result after the booster dose from a blood collection within 28-42 days after
the booster dose, and had no other important protocol deviations as determined by the
clinician.
5.2. Demographics and disposition
Demographic characteristics of the Phase 1 and Phase 2/3 study participants who received a
BNT162b2 (30 µg) booster dose are summarized in Table 2 below. Booster recipients were
predominantly White. Phase 1 excluded individuals with comorbidities that confer risk for severe
COVID-19 (i.e., obesity, diabetes with or without complications, chronic pulmonary disease,
cardiovascular conditions such as hypertension, congestive heart failure, ischemic heart
disease, HIV). Approximately 20% of booster recipients in Phase 2/3 had such comorbidities.
Table 2. Demographics and Baseline Characteristics, Phase 1 and Phase 2/3 Recipients of
BNT162b2 (30 µg) Booster Dose, Safety Population
Phase 1 Phase 1 Phase 2/3
18-55 Years 65-85 Years 18-55 Years
N=11 N=12 N=306
Characteristic n (%) n (%) n (%)
Sex: Female 9 (81.8) 6 (50.0) 166 (54.2)
Sex: Male 2 (18.2) 6 (50.0) 140 (45.8)
Age: Mean (years) 38.3 69.3 41.2
Age: Median (years) 39.0 69.0 42.0
Age: Min, max (years) 24, 55 65, 75 19, 55
Race: American Indian or Alaska Native 0 0 2 (0.7)
Race: Asian 2 (18.2) 0 16 (5.2)
14
Case 2:21-cv-00702-CLM Document 40-10 Filed 12/17/21 Page 16 of 33
Phase 1 Phase 1 Phase 2/3
18-55 Years 65-85 Years 18-55 Years
N=11 N=12 N=306
Characteristic n (%) n (%) n (%)
Race: Black or African American 1 (9.1) 0 28 (9.2)
Race: Native Hawaiian or other Pacific Islander 0 0 1 (0.3)
Race: White 8 (72.7) 12 (100.0) 249 (81.4)
Race: Multiracial 0 0 4 (1.3)
Race: Not reported 0 0 6 (2.0)
Ethnicity: Hispanic or Latino 0 0 85 (27.8)
Ethnicity: Not Hispanic or Latino 11 (100.0) 12 (100.0) 219 (71.6)
Ethnicity: Not reported 0 0 2 (0.7)
History of SARS-CoV-2 exposure pre-Dose 1a 0 0 11 (3.6)
Comorbiditiesb: Yes 0 0 56 (18.3)
Obesec 0 0 122 (39.9)
a
Missing data for 7 of the 306 (2.3%) Phase 2/3 participants.
b
Number of participants who have 1 or more comorbidities that increase the risk of severe COVID-19 disease, characterized from
medical conditions included in the Charlson comorbidity index. Phase 1: Co-morbidities that constituted risk factors for severe
COVID-19 were exclusion criteria.
c
Defined as BMI greater than 30 kg/m²
Among the 24 Phase 1 study participants randomized to the BNT162b2 primary series, 23
participants received a BNT162b2 (30 µg) booster dose (11 adults in the 18 to 55-year-old
cohort [range: 24 to 55 years] and 12 adults in the 65 to 85-year-old cohort [range: 65 to 75
years]). One participant in the 18 to 55-year-old cohort declined to receive a BNT162b2 booster
dose. All 23 Phase 1 participants who received the booster dose were included in the safety
analyses and the booster dose evaluable immunogenicity population. The disposition of Phase
2/3 study participants who received a BNT162b2 (30 µg) booster dose is summarized in Table 3
below.
Table 3. Disposition of Phase 2/3 Recipients of BNT162b2 (30 µg) Booster Dose
BNT162b2
(30 µg)
Disposition na (%)
Selected to receive BNT162b2 312 (100.0)
Saf ety population 306 (98.1)
Excluded because did not receive BNT162b2 6 (1.9)
Booster all-available immunogenicity population 306 (98.1)
Excluded because they did not have at least 1 valid and determinate
6 (1.9)
immunogenicity result after booster vaccination
Booster evaluable immunogenicity population 268 (85.9)
Without evidence of infection up to 1 month after booster dosec 234 (75.0)
Subjects excluded from booster evaluable immunogenicity population 44 (14.1)
15
Case 2:21-cv-00702-CLM Document 40-10 Filed 12/17/21 Page 17 of 33
BNT162b2
(30 µg)
Disposition na (%)
Reason f or exclusion (subjects may have been excluded for >1 reason)
Did not receive Dose 2 within 19 to 42 days after Dose 1 1 (0.3)
Did not receive BNT162b2 6 (1.9)
Did not have at least 1 valid and determinate immunogenicity result within 28 to 42
15 (4.8)
days after booster dose
Had protocol deviation(s) before the 1 month post-booster evaluation deemed to
30 (9.6)
be important by the cliniciand
a
n = Number of subjects with specified characteristic
b
Denominator for percentage calculations
c
Subjects who had no serological or virological evidence (up to 1 month after receipt of booster vaccination) of past SARS-CoV-2
infection (i.e., N-binding antibody [serum] negative at Visits pre-Dose 1 and 1 month post-Dose 2 of primary series, on the day of
booster dose, and 1 month after booster dose, and SARS-CoV-2 not detected by NAAT [nasal swab] at vaccination visits for the
primary series and booster dose) and had a negative NAAT (nasal swab) at any unscheduled visit up to 1 month after booster dose.
d
Received booster dose outside protocol-specified window of 150 to 210 days after completing the primary series (n=15); had
investigational product protocol deviations (n=13); received the booster dose outside the protocol-specified window of 150 to 210
days after a primary series & had an investigational product protocol deviation (n=1); had 6 months post-primary series/pre-booster
blood draw after receiving booster dose (n=1).
5.3. Timing of BNT162b2 booster administration
The median interval between the booster dose and completion of a BNT162b2 primary series
was 6.8 months (range 4.8 to 8.0 months) for Phase 2/3 participants and 8.3 months (range 7.9
to 8.5 months) for Phase 1 participants. Following the booster dose, the median follow-up time
was 2.6 months (range 2.1 to 2.9 months) for Phase 1 participants and 2.6 months (range 1.1 to
2.8 months) for Phase 2/3 participants.
5.4. Immunogenicity evaluation
5.4.1. Primary immunogenicity objective - 30 µg BNT162b2 booster dose
Immunogenicity of a booster dose of BNT162b2 was assessed based on analyses of GMT ratio
and seroresponse rates for neutralizing antibody titers to the reference strain.
GMTs of neutralizing antibody titers to the reference strain
Noninferiority was assessed based on the GMT of SARS-CoV-2 neutralizing titers 1 month after
the booster dose compared to 1 month after completion of a primary vaccination series. The
GMT ratio was calculated as the exponentiated mean of the difference of logarithmically
transformed titers for each participant (i.e., later time point minus earlier time point). The
associated 2-sided 97.5% CIs were obtained by constructing CIs using Student’s t-distribution
for the mean difference on the logarithmic scale and exponentiating the confidence limits. For
assessment of an adequate GMT booster response the criteria for success were met if the
lower bound of the 2-sided 97.5% CI for the GMT ratio was >0.67 and the point estimate of the
GMT ratio was ≥0.8.
Among Phase 2/3 participants in the booster evaluable immunogenicity population, the 50%
neutralizing GMTs at 1 month after booster dose were approximately 3-fold higher than those
observed at 1 month post-primary series and met the immunobridging success criteria for GMTs
against the reference strain, as shown in Table 4 below.
16
Case 2:21-cv-00702-CLM Document 40-10 Filed 12/17/21 Page 18 of 33
Table 4. Protocol Specified Immunobridging Analysis of SARS-CoV-2 Neutralizing GMTs at 1 Month
Post-Booster and 1 Month Post-Primary Series in Phase 2/3 BNT162b2 Participantsa Without
Evidence of SARS-CoV-2 Infection up to 1 Month After Booster, Based on SARS-CoV-2
Microneutralization Assay-NT50 with Reference Strain, Booster Evaluable Immunogenicity
Population
GMT (95% CI) GMT (95% CI) GMT Ratio (97.5% CI)
1 Month Post-Primary Series 1 Month Post-Booster Post-Booster/
Nb = 212 Nb = 212 Post-Primary Series
750.6 2466.0 3.3
(656.2, 858.6) (2202.6, 2760.8) (2.8, 3.9)
GMT: geometric mean titer.
Assay: SARS-CoV-2 mNeonGreen virus microneutralization assay (SARS-CoV-2 mNG NT), reference strain: recombinant
USA_WA1/2020. NT50= 50% neutralizing titer.
a
Booster evaluable immunogenicity population pertaining to 30 µg BNT162b2. Participants were 19 through 55 years of age.
b
N = Number of Phase 2/3 participants with valid and determinate assay results for the specified assay at the given dose/sampling
time point within specified window.
c
Noninferiority is declared if the lower limit of the 2-sided 97.5% CI for the GMT ratio is greater than 0.67 and the point estimate of
the GMT ratio is ≥0.8.
Rates of neutralizing antibody seroresponse to the reference strain
Noninferiority was assessed based on the difference in percentages of participants with
seroresponse defined as a ≥4-fold rise from baseline (before Dose 1), at 1 month after booster
dose and at 1 month after the primary series. If the baseline measurement was below the assay
lower limit of quantification (LLOQ), a postvaccination titer of ≥4 × LLOQ was considered a
seroresponse. Noninferiority was demonstrated if the lower limit of the 97.5% CI for the
difference in percentages of participants with seroresponse (1 month post-booster minus 1
month post-primary series) was greater than -10%.
Based on booster seroresponse defined as at least a 4-fold rise relative to pre-Dose 1, the
percentage of Phase 2/3 participants 18 through 55 years of age with seroresponse was 99.5%
at 1 month post-booster and 98.0% at 1 month post-primary series. As shown in Table 5, the
difference in seroresponse rates was 1.5% (97.5% CI: -0.7%, 3.7%), which met the
immunobridging success criterion for seroresponse rates against the reference strain.
17
Case 2:21-cv-00702-CLM Document 40-10 Filed 12/17/21 Page 19 of 33
Table 5. Protocol Specified Analysis of Seroresponse Rates at 1 Month Post-Booster Dosea and 1
Month Post-Primary Seriesb in Phase 2/3 BNT162b2 Participantsc Without Evidence of SARS-CoV-
2 Infection up to 1 Month After Booster, Based on SARS-CoV-2 Virus Microneutralization Assay
NT50 with Reference Strain, Booster Evaluable Immunogenicity Population
Seroresponse 1 Month After Seroresponse 1 Month After % Difference in Seroresponse
Primary Seriesd % [n] Booster % [n] Rate (1 month post-booster
(95% CI) (95% CI) minus 1 month post-primary
N=198 N=198 series)
(95% CI)
98.0 [194] 99.5 [197] 1.5
(94.9, 99.4) (97.2, 100.0) (-0.7, 3.7)
Assay: SARS-CoV-2 mNeonGreen virus microneutralization assay-NT50, reference strain: recombinant USA_WA1/2020.
a
Seroresponse defined as at least 4-fold rise relative to pre-Dose 1; if the baseline measurement was below LLOQ, a
postvaccination titer of ≥4 × LLOQ was considered a seroresponse.
b
Seroresponse defined as at least 4-fold rise relative to pre-Dose 1; if the baseline measurement was below LLOQ, a
postvaccination titer of ≥4 × LLOQ was considered a seroresponse.
c
Booster evaluable immunogenicity population pertaining to 30 µg BNT162b2
d
%: n/N. n = number of Phase 2/3 participants with seroresponse for the given assay at the given dose/sampling time point.
N = Number of subjects with valid and determinate assay results for the specified assay at baseline, pre-booster dose, 1 month after
primary series and 1 month after the booster dose within the specified window.
Additional analyses of rates of neutralizing antibody seroresponse to the reference strain
FDA requested that Pfizer perform a post hoc immunobridging analysis of seroresponse rates
against the reference strain using the pre-booster titer as the baseline to determine if there was
a booster dose seroresponse. As shown in Table 6 below, the booster dose seroresponse rate,
with seroresponse defined as at least a 4-fold rise relative to the pre-booster titer, was 93.9%.
The difference in seroresponse rates in this post hoc analysis was -3.9% (95% CI: -8.2%,
0.4%).
Table 6. Post hoc Analysis of Seroresponse Rates at 1 Month Post-Booster Dosea and 1 Month
Post-Primary Seriesb in Phase 2/3 BNT162b2 Participantsc Without Evidence of SARS-CoV-2
Infection up to 1 Month After Booster, Based on SARS-CoV-2 Virus Microneutralization Assay-
NT50 with Reference Strain, Booster Evaluable Immunogenicity Population
Seroresponse 1 Month After Seroresponse 1 Month After % Difference in Seroresponse
Primary Seriesd % [n] Booster % [n] Rate (1 month post-booster
(95% CI) (95% CI) minus 1 month post-primary
N=179 N=179 series)
(95% CI)
97.8 [175] 93.9 [168] -3.9
(94.4, 99.4) (89.3, 96.9) (-8.2, 0.4)
Assay: SARS-CoV-2 mNeonGreen virus microneutralization assay-NT50, reference strain: recombinant USA_WA1/2020.
a
Seroresponse defined as at least 4-fold rise relative to pre-booster; if the baseline measurement was below LLOQ, a
postvaccination titer of ≥4 × LLOQ was considered a seroresponse.
b
Seroresponse defined as at least 4-fold rise relative to pre-Dose 1 of the primary series; if the baseline measurement was below
LLOQ, a postvaccination titer of ≥4 × LLOQ was considered a seroresponse.
c
Booster evaluable immunogenicity population pertaining to 30 µg BNT162b2
d
%: n/N. n = number of Phase 2/3 participants with seroresponse for the given assay at the given dose/sampling time point.
N = Number of subjects with valid and determinate assay results for the specified assay at baseline, pre-booster dose, 1 month after
primary series and 1 month after the booster dose within the specified window.
18
Case 2:21-cv-00702-CLM Document 40-10 Filed 12/17/21 Page 20 of 33
In descriptive post hoc analyses of immunogenicity data based on presence or absence of
comorbidities, GMT and seroresponse rates among those with comorbidities were comparable
to those without comorbidities, as shown in Table 7. Obesity (~72%) was the most common
comorbid condition, followed by hypertension (~32%) and chronic pulmonary disease (~25%).
Table 7. SARS-CoV-2 Neutralizing GMTs and Seroresponsea, by Comorbidity Statusb, at 1 Month
Post-Booster and 1 Month Post-Primary Series in Phase 2/3 BNT162b2 Participantsc Without
Evidence of SARS-CoV-2 Infection up to 1 Month After Booster – Booster Evaluable
Immunogenicity Population
GMT 1 Month GMT Seroresponse Seroresponse
Comorbidity Post-Primary 1 Month 1 Month 1 Month
nd nd nd nd
Status Series Post-Booster Pre-Booster Post-Booster
(95% CI) (95% CI) (95% CI) (95% CI)
2763.1
With 745.1 80.0 94.3
126 132 (2369.2, 115 122
comorbiditiesb (610.9, 908.9) (71.5, 86.9) (88.5, 97.7)
3222.5)
1943.3
Without 786.9 73.2 93.3
88 100 (1699.1, 82 90
comorbidities (653.4, 947.6) (62.2, 82.4) (86.1, 97.5)
2222.6)
a Seroresponse was defined as ≥4-fold increase in 50% SARS-CoV-2 neutralizing GMT relative to pre-booster GMT.
b Comorbidities in these booster recipients include, in descending order of frequency, obesity (~72%), hypertension (~32%), chronic
pulmonary disease (~25%), any malignancy (~5%), diabetes (~4%), mild liver disease (~4%), and cardiovascular conditions (~1%).
c
Booster evaluable immunogenicity population pertaining to 30 µg BNT162b2. Participants were 18 through 55 years of age.
d
N = Number of Phase 2/3 participants with valid and determinate assay results for the specified assay at the given dose/sampling
time point within specified window.
5.4.2. Exploratory immunogenicity analyses against the Delta variant
In response to FDA’s request for immunogenicity data to support effectiveness of a BNT162b2
booster dose against the Delta variant, Pfizer submitted exploratory descriptive analyses of data
available to date from Phase 1 study participants who received a booster dose (11 adults ages
18-55 years and 12 adults ages 65-85 years). These data are summarized in Table 8 below. A
very limited number of serum samples were available for this analysis. In addition, the data were
generated using non-validated SARS-CoV-2 plaque reduction neutralization assays with the
reference strain (USA-WA1/2020) and the Delta variant; the relative sensitivity of the two assays
is not known.
Table 8. SARS-CoV-2 Neutralizing GMTs at 1 Month Post-Booster and 1 Month Post-Primary
Series, Phase 1 Recipients of BNT162b2 (30 µg) Boostera Without Evidence of SARS-CoV-2
Infection Up to 1 Month After Booster, Based on SARS-CoV-2 Plaque Reduction Neutralization
Assay with Reference and Delta Variant Strains
18-55 Years of Age 65-85 Years of Age
N=11 N=12
Assay Target Time Point
GMT GMT
(95% CI) (95% CI)
310.1 195.8
Ref erence strain 1 month post-primary series (203.3, 473.0) (114.7, 334.4)
1546.4 1612.7
1 month post-booster
(896.9, 2666.0) (875.5, 2970.8)
19
Case 2:21-cv-00702-CLM Document 40-10 Filed 12/17/21 Page 21 of 33
18-55 Years of Age 65-85 Years of Age
N=11 N=12
Assay Target Time Point
GMT GMT
(95% CI) (95% CI)
241.0 123.4
Delta variant 1 month post-primary series
(180.1, 322.4) (70.2, 216.9)
1321.0 1478.9
1 month post-booster
(698.5, 2498.3) (734.9, 2975.8)
GMT = geometric mean titer. Assay: SARS-CoV-2 neutralization assay, SARS-CoV-2 strains: recombinant USA_WA1/2020
(reference), B.1.617.2 (Delta).
a
Booster all-available immunogenicity population pertaining to 30 µg BNT162b2
b
N = number of Phase 1 participants with valid and determinate assay results for the specified assays at the given dose/sampling
time point.
5.5. Safety evaluation
5.5.1. Overview of adverse events
Of the 306 Phase 2/3 participants 18 through 55 years of age in the booster safety population,
289 (94.4%) recorded local and systemic solicited adverse reactions (ARs) in an e-diary within 7
days following vaccination. Overall, 83.0% of participants reported any local reaction and 77.2%
reported any systemic reaction. With respect to unsolicited adverse events, 44 (14.4%) reported
at least 1 AE from booster to 1 month thereafter. Events considered by the study investigator to
be related to study intervention were reported by 24 participants (7.8%). There was one serious
adverse event (SAE) of an acute myocardial infarction that occurred 2 months after booster
dose; this was characterized as unrelated. There were no events leading to withdrawal reported
through 1 month after booster dose administration. No study participants in this Phase 2/3
booster group died.
Overall, 73.9% of the 23 Phase 1 participants reported any local reaction and 78.2% reported
any systemic reaction after a booster dose. None of these 23 participants reported any AEs
from booster to 1 month thereafter. There were no SAEs, events leading to withdrawal through
1 month after booster dose administration, and no deaths.
5.5.2. Immediate AEs
None of the 329 participants reported immediate hypersensitivity or anaphylaxis after the
BNT162b2 booster dose.
5.5.3. Solicited adverse reactions
The frequencies of local and systemic adverse reactions within 7 days of booster in the 289
Phase 2/3 participants with evaluable e-diary data are summarized in Table 9 and Table 10.
These tables also include post-Dose 1 and post-Dose 2 data from the reactogenicity subset of
the blinded Phase 2/3 portion of C4591001 and post-booster safety data from a small group of
Phase 1 participants 65 through 85 years of age as points for comparison. Among the 289
Phase 2/3 booster recipients with evaluable e-diary data, injection site pain (83.0%) was the
most frequent solicited adverse reaction, following by fatigue (63.7%) and headache (48.4%).
The mean duration (not shown in tables) of pain at the injection site was 2.6 days (range 1 to 8
days), 2.2 days for redness (range 1 to 15 days), 2.2 days for swelling (range 1 to 8 days), 2.4
days for fatigue (range 1 to 30 days), and 2.1 days for headache (range 1 to 8 days). Severe
solicited ARs were uncommon following the booster dose, with the most frequently reported
severe solicited ARs being fatigue (4.5%) and muscle pain (1.4%) among participants 18
through 55 years of age. No Grade 4 local or systemic AR was reported after the booster dose.
20
Case 2:21-cv-00702-CLM Document 40-10 Filed 12/17/21 Page 22 of 33
There were no notable differences in the frequency or duration of local and systemic ARs
following the booster dose as compared to those reported following Dose 2 by the 2682
participants 16 through 55 years of age from the blinded Phase 2/3 portion of C4591001.
Table 9. Frequency of Solicited Local Reactions by Severity, Within 7 Days After Dose 2 Compared
to After Booster Dose of BNT162b2 30 µg Among Participants in Phase 1/2/3 Study C4591001
Dose 1 Dose 2 Booster Booster
16-55 Years 16-55 Years 18-55 Years 65-85 Years
Blinded Phase 2/3 Blinded Phase 2/3 Phase 2/3 Phase 1
N=2899a N=2682a N=289b N=12c
n (%) n (%) n (%) n (%)
Injection Site Pain
Any 2426 (83.7) 2101 (78.3) 240 (83.0) 8 (66.7)
Mild d 1464 (50.5) 1274 (47.5) 174 (60.2) 8 (66.7)
Moderate 923 (31.8) 788 (29.4) 65 (22.5) 0 (0.0)
Severe 39 (1.3) 39 (1.5) 1 (0.3) 0 (0.0)
Swelling
Any (>2.0 cm) 184 (6.3) 183 (6.8) 23 (8.0) 0 (0.0)
Mild e 124 (4.3) 110 (4.1) 13 (4.5) 0 (0.0)
Moderate 54 (1.9) 66 (2.5) 9 (3.1) 0 (0.0)
Severe 6 (0.2) 7 (0.3) 1 (0.3) 0 (0.0)
Redness
Any (>2.0 cm) 156 (5.4) 151 (5.6) 17 (5.9) 0 (0.0)
Mild e 113 (3.9) 90 (3.4) 10 (3.5) 0 (0.0)
Moderate 36 (1.2) 50 (1.9) 7 (2.4) 0 (0.0)
Severe 7 (0.2) 11 (0.4) 0 (0.0) 0 (0.0)
Adverse reactions were collected in the electronic diary (e-diary) from Day 1 through Day 7 after the booster dose.
N: Number of subjects reporting at least 1 yes or no response for the specified reaction after the specified dose.
n: number of subjects with the specified characteristic.
%: n/N.
a
Reactogenicity subset of participants from the blinded, placebo-controlled Phase 2/3 portion of C4591001
b
Recipients of booster dose of BNT162b2 (from P2/P3 portion of study after unblinding) with e-diary data
c
Recipients of booster dose of BNT162b2 from Phase 1 vaccine candidate and dose-ranging portion of C4591001
d
Mild: does not interfere with activity; moderate: interferes with activity; severe: prevents daily activity.
e
Mild: 2.0 to 5.0 cm; moderate: 5.0 to 10.0 cm; severe: >10.0 cm.
Table 10. Frequency of Solicited Systemic Reactions, by Severity, Within 7 Days After Dose 2
Compared to After Booster Dose of BNT162b2 30 µg Among Participants in Phase 1/2/3 Study
C4591001
Dose 1 Dose 2 Booster Booster
16-55 Years 16-55 Years 18-55 Years 65-85 Years
Blinded Phase 2/3 Blinded Phase 2/3 Phase 2/3 Phase 1
N=2899 N=2682 N=289* N=12
n (%) n (%) n (%) n (%)
Fatigue
Any 1431 (49.4) 1649 (61.5) 185 (63.8) 5 (41.7)
Mild a 760 (26.2) 558 (20.8) 69 (23.8) 2 (16.7)
Moderate 630 (21.7) 949 (35.4) 103 (35.5) 3 (25.0)
Severe 41 (1.4) 142 (5.3) 13 (4.5) 0 (0.0)
Headache
Any 1262 (43.5) 1448 (54.0) 140 (48.4) 5 (41.7)
Mild a 785 (27.1) 699 (26.1) 83 (28.7) 4 (33.3)
Moderate 444 (15.3) 469 (17.5) 54(18.7) 1 (8.3)
Severe 33 (1.1) 91 (3.4) 3 (1.0) 0 (0.0)
21
Case 2:21-cv-00702-CLM Document 40-10 Filed 12/17/21 Page 23 of 33
Dose 1 Dose 2 Booster Booster
16-55 Years 16-55 Years 18-55 Years 65-85 Years
Blinded Phase 2/3 Blinded Phase 2/3 Phase 2/3 Phase 1
N=2899 N=2682 N=289* N=12
n (%) n (%) n (%) n (%)
New/worsened muscle pain
Any 664 (22.9) 1055 (39.3) 113 (39.1) 4 (33.3)
Mild a 353 (12.2) 441 (16.4) 52 (18.0) 2 (16.7)
Moderate 296 (10.2) 552 (20.6) 57 (19.7) 2 (16.7)
Severe 15 (0.5) 62 (2.3) 4 (1.4) 0 (0.0)
Chills
Any 479 (16.5) 1015 (37.8) 84 (29.1) 2 (16.7)
Mild a 338 (11.7) 477 (17.8) 37 (12.8) 0 (0.0)
Moderate 126 (4.3) 469 (17.5) 44 (15.2) 2 (16.7)
Severe 15 (0.5) 69 (2.6) 3 (1.0) 0 (0.0)
New/worsened joint pain
Any 342 (11.8) 638 (23.8) 73 (25.3) 2 (16.7)
Mild a 200 (6.9) 291 (10.9) 36 (12.5) 0 (0.0)
Moderate 137 (4.7) 320 (11.9) 36 (12.5) 2 (16.7)
Severe 5 (0.2) 27 (1.0) 1 (0.3) 0 (0.0)
Diarrhea
Any 309 (10.7) 269 (10.0) 25 (8.7) 0 (0.0)
Mild b 251 (8.7) 219 (8.2) 21 (7.3)
Moderate 55 (1.9) 44 (1.6) 4 (1.4)
Severe 3 (0.1) 6 (0.2) 0
Vomiting 34 (1.2) 58 (2.2) 5 (1.7) 0 (0.0)
Mild c 29 (1.0) 42 (1.6) 5 (1.7)
Moderate 5 (0.2) 12 (0.4) 0 (0.0)
Severe 0 (0.0) 4 (0.1) 0 (0.0)
Fever
≥38.0°C 119 (4.1) 440 (16.4) 25 (8.7) 0 (0.0)
≥38.0 to 38.4°C 86 (3.0) 254 (9.5) 12 (4.2)
>38.4 to 38.9°C 25 (0.9) 146 (5.4) 12 (4.2)
>38.9 to 40.0°C 8 (0.3) 39 (1.5) 1 (0.3)
>40.0°C 0 (0.0) 1 (0.0) 0 (0.0)
Antipyretic or pain 805 (27.8) 1213 (45.2) 135 (46.7) 4(33.3)
medication used
N = Number of participants reporting at least 1 yes or no response for the specified reaction after the specified dose.
n = Number of participants with the specified reaction.
%: n/N
*
For fatigue, n=290 due to one participant reporting it directly rather than through e-diary
a
Mild: does not interfere with activity; Moderate: some interference with activity; Severe: prevents daily activity.
b
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.
c
Mild: 1 to 2 times in 24 hours; Moderate: >2 times in 24 hours; Severe: requires intravenous hydration
d
Severity was not collected for use of antipyretic or pain medication
5.5.4. Unsolicited Adverse Events
Table 11 presents the unsolicited AEs obtained from the 306 Phase 2/3 booster recipients
through 1 month after a booster dose. The most common unsolicited AE was lymphadenopathy
(n=16; 5.2%) affecting axillary (n=15) and cervical chain lymph nodes (n=1), which was reported
at a higher rate than following primary series doses (0.4%). Most events of lymphadenopathy
following the booster dose (n=15) were mild to moderate in severity and lasted between 2 to 8
days. Two cases of mild lymphadenopathy were reported as ongoing at the time of data cut-off;
at the time of this review, lymphadenopathy reported by one of the participants resolved 6 days
22
Case 2:21-cv-00702-CLM Document 40-10 Filed 12/17/21 Page 24 of 33
after onset and for the other participant, the event continues to be ongoing. One severe event of
lymphadenopathy was reported by one participant with an onset at 2 days post-Dose 3 and
recovered/resolved 5 days from onset. Other unsolicited AEs occurring in more than one subject
included nausea (0.7%), injection site pain (0.7%), pain (0.7%), back pain (0.7%), neck pain
(0.7%), headache (0.7%), anxiety (0.7%), and contact dermatitis (0.7%). There were no
reported AEs in the 1 month after the booster dose in the Phase 1 subjects (n=23).
Table 11. Unsolicited Adverse Events Reported by ≥2 Phase 2/3 Participants from Booster Dose to
1 Month After Booster Dose, Phase 2/3 Booster Safety Population (N=306)
System Organ Class
n (%)
Preferred Term
Blood and lymphatic system disorders 16 (5.2)
Lymphadenopathy 16 (5.2)
Gastrointestinal disorders 4 (1.3)
Nausea 2 (0.7)
General disorders and administration site conditions 8 (2.6)
Injection site pain 2 (0.7)
Pain 2 (0.7)
Musculoskeletal and connective tissue disorders 7 (2.3)
Back pain 2 (0.7)
Neck pain 2 (0.7)
Nervous system disorders 5 (1.6)
Headache 2 (0.7)
Psychiatric disorders 2 (0.7)
Anxiety 2 (0.7)
Skin and subcutaneous tissue disorders 3 (1.0)
Dermatitis contact 2 (0.7)
n = Number of Phase 2/3 participants reporting at least 1 occurrence of the specified event.
N = number of Phase 2/3 participants in the specified group. This value is the denominator for the percentage calculations.
After the 1-month post-booster monitoring period, one additional AE of acute myocardial
infarction was reported as an unrelated serious AE on Day 62 post-booster dose that was
recovered/resolved with sequelae. FDA reviewed the details of the serious AE and agrees with
Pfizer’s assessment that the event was unrelated to vaccination. No other SAEs were reported
following the booster dose, and no participants were withdrawn due to AEs.
Aside from lymphadenopathy (described in an earlier paragraph), other adverse events of
clinical interest identified from Study C4591001 and post-authorization use include
myocarditis/pericarditis, anaphylaxis, appendicitis, and Bell’s palsy. No cases of myocarditis,
pericarditis, anaphylaxis, appendicitis, or Bell’s palsy were reported by Phase 1 or Phase 3
booster dose recipients through the data cutoff dates (May 13, 2021 and June 17, 2021,
respectively).
5.6. COVID-19 cases among C4591001 study participants during the Delta variant
surge
No cases of COVID-19 occurred among the 329 BNT162b2 booster dose recipients in study
C4591001 during follow-up after the booster dose through the data cutoff date for the EUA
amendment submission.
Responding to an FDA request, Pfizer performed a post hoc analysis of protocol-specified
COVID-19 cases accrued during the period of July 1, 2021 through August 31, 2021
(corresponding to the Delta variant surge) among participants 16 years of age and older who
23
Case 2:21-cv-00702-CLM Document 40-10 Filed 12/17/21 Page 25 of 33
completed the 2-dose primary series. The analysis compared rates of COVID-19 among
participants who completed the 2-dose primary series early in the study (i.e., those who were
originally randomized to BNT162b2) vs. those who completed the 2-dose primary series later in
the study (i.e., those who were originally randomized to placebo and then crossed over to
BNT162b2). Study participants included in the analysis were those who remained at risk for first
occurrence of COVID-19 following the BNT162b2 primary series (i.e., participants who
previously reported COVID-19 or who received additional study vaccinations after the primary
series were excluded). The analysis used data extracted on September 2, 2021 from the study’s
live database; the datasets were not submitted to FDA.
Although not independently verified by FDA, the post hoc analysis appears to indicate that the
incidence of SARS-CoV-2 during the analysis period among 18,727 study participants originally
randomized to BNT162b2 (mean of 9.8 months post-Dose 2 at the beginning of the analysis
period) was 70.3 cases per 1,000 person-years, compared with an incidence of 51.6 cases per
1,000 person-years among 17,748 study participants originally randomized to placebo and
crossed over to BNT162b2 (mean of 4.7 months post-Dose 2 at the beginning of the analysis
period). An additional analysis appears to indicate that incidence of COVID-19 generally
increased in each group of study participants with increasing time post-Dose 2 at the start of the
analysis period. Only 3 severe COVID-19 cases were reported during the analysis period, all of
which occurred among study participants who were originally randomized to BNT162b2; all 3
severe COVID-19 cases were reported in individuals ≥70 years of age and with comorbid
conditions (hypertension, obesity, history of myocardial infarction).
The reported incidence of COVID-19 among study participants who completed the primary
series <4 months prior to the start of the analysis period was 43.4 cases per 1,000 person-
years. In contrast, during the blinded, placebo-controlled follow-up period of the study with data
cutoff of March 13, 2021 (prior to the Delta variant surge), the incidence of COVID-19 among
BNT162b2 recipients in the Evaluable Efficacy Population (nearly 60% of whom had 4 months
or more of blinded follow-up post-Dose 2) was 12.6 cases per 1,000 person-years.1 This
observation suggests that while waning immunity is one potential factor that may have
contributed to the higher incidence breakthrough cases during the Delta variant surge, it is
possible that other factors (e.g., dynamics of Delta variant transmission and potential
differences in vaccine effectiveness against the Delta variant vs. strains circulating during the
placebo-controlled portion of the trial) may also have contributed.
5.7. Summary of booster dose safety and immunogenicity data from study C4591001
The clinical data submitted to this EUA amendment come from an ongoing Phase 1/2/3 study
(C4591001), which is also the source of clinical data supporting the original approval of the 2-
dose primary series for use in individuals 16 years of age and older. The BNT162b2 30 µg
booster dose was initially assessed in a cohort of 23 Phase 1 study participants (11 participants
18-55 years of age and 12 participants 65-85 years of age), and then in 306 Phase 2/3 study
participants 18 through 55 years of age.
Effectiveness of the booster dose against the reference strain is being inferred based on
immunobridging to the 2-dose primary series, as assessed by SARS-CoV-2 neutralizing
antibody titers elicited by the vaccine. Immunobridging success criteria for the reference strain
(USA_WA1/2020) were met for both pre-specified co-primary immunogenicity endpoints among
study participants with no evidence of SARS-CoV-2 infection prior to 1 month after the booster
dose. Safety data from 289 Phase 2/3 booster recipients do not show evidence of increased
local or systemic reactogenicity relative to Dose 2. Most reactogenicity events after the booster
24
Case 2:21-cv-00702-CLM Document 40-10 Filed 12/17/21 Page 26 of 33
dose were of mild to moderate severity and self-limited in duration. While evaluated in only 12
Phase 1 participants 65 through 85 years of age, the booster dose appears to be less
reactogenic in older adults 65 years of age and above compared to younger adults 18 through
55 years of age. No deaths, vaccine-related serious adverse events, or events of myocarditis,
pericarditis, anaphylaxis, appendicitis, or Bell’s palsy were reported among the 329 Phase 1 and
Phase 2/3 study participants who received the BNT162b2 booster dose.
6. FDA REVIEW OF OTHER INFORMATION SUBMITTED
6.1. Pharmacovigilance Activities
Pfizer submitted a Pharmacovigilance Plan (PVP) to monitor safety concerns following
administration of a booster dose of the Pfizer-BioNTech COVID-19 Vaccine. The Sponsor
identified anaphylaxis and myocarditis and pericarditis as important identified risks and vaccine-
associated enhanced disease, including vaccine-associated enhanced respiratory disease, as
an important potential risk. Use in pregnancy and lactation, vaccine effectiveness, and use in
pediatric individuals <12 years of age are areas the Sponsor identified as missing information.
Division of Epidemiology recommendations for safety monitoring of the authorized booster dose
under this EUA are as follows:
1. Mandatory reporting by the Sponsor of the following events to Vaccine Adverse Event
Reporting System (VAERS) within 15 days:
• Serious adverse events (irrespective of attribution to vaccination)
• Cases of multisystem inflammatory syndrome in children and adults
• Cases of COVID-19 that result in hospitalization or death
Additionally, following approval of Comirnaty 125742/0, the Sponsor was also asked to
submit all reports of myocarditis and pericarditis as 15-day reports to VAERS.
2. The Sponsor will conduct periodic aggregate review of safety data and submit periodic
safety reports at monthly intervals. Each periodic safety report is required to contain
descriptive information which includes:
• A narrative summary and analysis of adverse events submitted during the reporting
interval, including interval and cumulative counts by age groups, special populations
(e.g., pregnant women), and adverse events of special interest (AESIs)
• A narrative summary and analysis of vaccine administration errors, whether or not
associated with an adverse event, that were identified since the last reporting interval
• Newly identified safety concerns in the interval
• Actions taken since the last report because of adverse experiences (e.g., changes
made to the Fact Sheet for Healthcare Providers Administering Vaccine (Vaccination
Providers), changes made to studies or studies initiated)
3. The Sponsor will conduct post-authorization observational studies to evaluate the
association between Pfizer-BioNTech COVID-19 Vaccine and a pre-specified list of AESIs,
including myocarditis and pericarditis, along with deaths and hospitalizations, and severe
COVID-19. The study population should include individuals administered the authorized
Pfizer-BioNTech COVID-19 Vaccine under this EUA in the general US population (12 years
of age and older), individuals who receive a booster dose, and populations of interest such
as healthcare workers, pregnant women, immunocompromised individuals, and
subpopulations with specific comorbidities. The studies should be conducted in large scale
databases with an active comparator.
25
Case 2:21-cv-00702-CLM Document 40-10 Filed 12/17/21 Page 27 of 33
The above condition of authorization under the EUA, to conduct post-authorization
observational studies, will encompass the evaluation of a booster dose in the following
studies, which are also existing postmarketing requirements/commitments (PMR/PMC) that
were previously identified in the August 23, 2021, approval letter for Comirnaty BL
125742/0:
a. PMR #4, C4591009: A non-interventional post-approval safety study of the Pfizer-
BioNTech COVID-19 mRNA vaccine in the United States
Objective: To assess the occurrence of safety events of interest, including myocarditis
and pericarditis, in the general US population of all ages, pregnant women, the
immunocompromised, and persons with a prior history of COVID-19 within selected data
sources participating in the US Sentinel System.
b. PMR #5, C4591021: Post-conditional approval active surveillance study among
individuals in Europe receiving the Pfizer-BioNTech Coronavirus Disease 2019
(COVID-19) Vaccine
Objective: To assess the potential increased risk of AESIs, including
myocarditis/pericarditis, after being vaccinated with at least one dose of the Pfizer-
BioNTech COVID-19 Vaccine.
c. PMR #6, C4591021: Substudy to describe the natural history of myocarditis and
pericarditis following administration of COMIRNATY
Objective: To describe the natural history of post-vaccination myocarditis/pericarditis,
including recovery status, risk factors, and/or identification of serious cardiovascular
outcomes within one year of myocarditis/pericarditis diagnosis among individuals
vaccinated with BNT162b2 as well as individuals not vaccinated with a COVID-19
vaccine.
d. PMR #7, C4591036: Prospective cohort study with at least 5 years of follow-up for
potential long-term sequelae of myocarditis after vaccination (in collaboration
with Pediatric Heart Network [PHN]). Working title: Myocarditis/pericarditis follow-
up study within the Pediatric Heart Network
Objective: To characterize the clinical course, risk factors, resolution, long-term
sequelae, and quality of life in children and young adults <21 years with acute post-
vaccine myocarditis/pericarditis.
e. PMC #10, C4591022: Pfizer-BioNTech COVID-19 Vaccine exposure during
pregnancy: A non-interventional post-approval safety study of pregnancy and
infant outcomes in the Organization of Teratology Information Specialists
(OTIS)/Mother To Baby Pregnancy Registry
Objective: To assess whether pregnant women receiving BNT162b2 experience
increased risk of pregnancy and infant safety outcomes, including major congenital
malformations, spontaneous abortion, stillbirth, preterm delivery, small for gestational
age, and small for age postnatal growth to one year of age.
f. PMC #12, C4591012: Post-emergency use authorization active safety surveillance
study among individuals in the Veteran’s Affairs Health System receiving Pfizer-
BioNTech Coronavirus Disease 2019 (COVID-19) vaccine
26
Case 2:21-cv-00702-CLM Document 40-10 Filed 12/17/21 Page 28 of 33
Objective: To assess whether individuals and sub-cohorts of interest (i.e.,
immunocompromised, elderly, individuals with specific comorbidities, individuals
receiving only one dose of the Pfizer-BioNTech COVID-19 Vaccine, and individuals with
prior SARS-CoV-2 infection) in the Veterans Health Administration (VHA) system
experience increased risk of safety events of interest following receipt of the Pfizer-
BioNTech COVID-19 Vaccine.
Additionally, the Sponsor will conduct the C4591031 Substudy, to prospectively assess the
incidence of subclinical myocarditis following administration of a third dose of COMIRNATY in a
subset of participants 16 to 30 years of age, as a PMR (PMR #9 in Comirnaty BL 125742/0
approval letter dated August 23, 2021).
The Sponsor also plans to include booster dose analyses for Study C4591014, entitled “Pfizer-
BioNTech COVID-19 BNT162b2 Vaccine Effectiveness Study Kaiser Permanente Southern
California” (PMC #13 in Comirnaty BL 125742/0 approval letter dated August 23, 2021).
4. Mandatory reporting by vaccination providers to VAERS, and to the extent feasible, to the
Sponsor, for the following events:
• Vaccine administration errors whether or not associated with an adverse event
• Serious adverse events (irrespective of attribution to vaccination)
• Cases of multisystem inflammatory syndrome in children and adults
• Cases of COVID-19 that result in hospitalization or death
5. Active surveillance of vaccine recipients via the v-safe program. V-safe is a new
smartphone-based opt-in program that uses text messaging and web surveys from CDC to
check in with vaccine recipients for health problems following COVID-19 vaccination. The
system also will provide telephone follow-up to anyone who reports medically significant
(important) adverse events.
6.2. Clinical Assay Information
The SARS-CoV-2 mNG microneutralization assay used in the Phase 2/3 clinical study
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 validation study, executed at Pfizer Hackensack
Meridian Health Center (Nutley, New Jersey), were submitted to support the suitability of the
assay for neutralizing antibody assessment against the USA_WA1/2020 strain.
For the Phase 1 booster dose study, a plaque-reduction neutralization test (PRNT) was used to
determine neutralizing titers against the reference USA_WA1/2020 strain and the SARS-CoV-2
virus Delta variant (a recombinant virus with Delta variant spike gene on the USA_WA1/2020
genetic background). The PRNT assay is a non-validated assay and was used for exploratory
purposes only.
6.3. Inspection of Clinical Study Sites
Bioresearch Monitoring (BIMO) inspections were waived for this EUA amendment.
27
Case 2:21-cv-00702-CLM Document 40-10 Filed 12/17/21 Page 29 of 33
6.4. EUA Prescribing Information and Fact Sheets
The Full EUA Prescribing Information, Fact Sheet for Health Care Providers Administering
Vaccine (Vaccination Providers), and Vaccine Information Fact Sheet for Recipients and
Caregivers were reviewed, and suggested revisions were sent to the Sponsor. The revised Fact
Sheets are accurate, not misleading, and appropriate for the proposed use of the product under
EUA.
7. BENEFIT / RISK ASSSESSMENT IN THE CONTEXT OF THE PROPOSED USE UNDER
EUA
7.1. Known and Potential Benefits
The Pfizer-BioNTech COVID-19 vaccine has been demonstrated to be highly efficacious against
COVID-19 and severe COVID-19 (~91% VE and ~95% VE, respectively, in analyses from the
ongoing Phase 3 clinical trial that supported FDA licensure). Clinical benefit of a booster dose
administered at least 6 months after completion of the primary series would be related to
restoration of high vaccine effectiveness (or more durable vaccine effectiveness) in individuals
for whom protective immunity has waned. In considering the statutory criteria for EUA, the
relevant clinical benefit would be related specifically to protection against serious outcomes of
COVID-19. The evidence for benefit of a booster dose is therefore derived from: 1) data to
support waning protection against serious outcomes of COVID-19 in those populations for which
use of a booster dose under EUA is being considered; and 2) data to support effectiveness of a
booster dose against currently circulating SARS-CoV-2 variants.
With regard to evidence to support waning protection against serious outcomes of COVID-19,
data from observational studies presented at the VRBPAC meeting (although not independently
verified by FDA) indicate such waning protection most convincingly among adults 65 years of
age and older. In FDA’s assessment, and as reflected by the VRBPAC votes and discussion,
evidence to directly support waning protection against serious outcomes of COVID-19 is much
less convincing for populations younger than 65 years of age. However, evidence from
observational studies presented at the VRBPAC meeting and from post-hoc analyses of
COVID-19 cases among BNT162b2 primary series recipients in the ongoing clinical trial
C4591001 (although not independently verified by FDA) do provide some evidence of waning
protection against SARS-CoV-2 infection and symptomatic COVID-19 over time following the
primary series in younger adults. Considering this evidence, it is reasonable to conclude that
certain subgroups at high risk of severe COVID-19 (e.g., due to underlying medical conditions),
or whose frequent institutional or occupational exposure to SARS-CoV-2 puts them at high risk
of serious complications of COVID-19 (including severe COVID-19), would be at greater risk of
these more serious outcomes than the general population. Thus, despite a lack of data at this
time directly demonstrating waning protection against serious COVID-19 outcomes in these
subgroups, it is reasonable to conclude that in these subgroups a booster dose will potentially
prevent serious COVID-19 outcomes as a result of improving protection against all symptomatic
COVID-19.
With regard to evidence to support effectiveness of a booster dose against currently circulating
SARS-CoV-2 variants, the successful booster dose immunobridging analyses from the Phase
2/3 portion of study C4591001 supports inference of effectiveness of the booster dose in
individuals 18-55 years of age against the reference strain (USA_WA1/2020). As outlined in the
FDA Guidance document, Emergency Use Authorization for Vaccines to Prevent COVID-19,
this inference of effectiveness can be extrapolated to other age groups for which the vaccine
primary series has been authorized or approved (e.g., individuals >55 years of age). Additional
28
Case 2:21-cv-00702-CLM Document 40-10 Filed 12/17/21 Page 30 of 33
exploratory immunogenicity analyses evaluating neutralization of the reference strain and the
Delta variant, although limited by small numbers of samples and use of a non-validated assay,
support the potential for the booster dose to provide additional protection against the currently
circulating Delta variant.
7.2. Uncertain Benefits/Data Gaps
Effectiveness of booster dose against SARS-CoV-2 variants of concern
As summarized above, immunogenicity data to support effectiveness of the booster dose
against the Delta variant are limited to exploratory analyses in a small number of study
participants, using non-validated assays. Additionally, data are lacking at this time to directly
demonstrate efficacy of a booster dose against clinical disease outcomes from SARS-CoV-2
Delta variant infection. Furthermore, other variants against which the BNT162b2 booster dose
may be less effective could emerge in the future.
Booster dose durability of protection
Immunogenicity analyses were conducted 1 month post-booster; therefore, it is not possible to
assess sustained effectiveness over a period of time prior longer than 1 month.
Effectiveness of booster dose against viral shedding and transmission
The effectiveness of a booster dose against transmission of SARS-CoV-2 from individuals who
are infected despite vaccination has not yet been established. Observational studies are
planned and ongoing to further evaluate this effect.
Effectiveness of booster dose against long term effects of COVID-19 disease
Prevention of cases of symptomatic COVID-19 by a booster dose will likely result in prevention
of some COVID-19 cases with long-term sequelae. However, additional studies are needed to
verify this potential benefit.
Future effectiveness of booster dose as influenced by characteristics of the pandemic,
changes in the virus, and/or potential effects of co-infections
The evolution of the pandemic characteristics, such as increased attack rates, emergence of
new variants, and/or the effect of coinfections may potentially limit the generalizability of the
efficacy conclusions over time. Continued evaluation of booster dose effectiveness following
issuance of an EUA and/or licensure will be critical to address these uncertainties.
7.3. Known and Potential Risks
In study C4591001, reported frequencies and severities of solicited adverse reactions following
the booster dose were generally similar to or lower than those following Dose 2 of the primary
series, with the exception of a slight increase in the frequency of mild injection site pain.
Lymphadenopathy, mostly axillary, mild-to-moderate in severity and transient, following a
booster dose (5.2%) occurred at over 10-fold greater frequency compared to the primary series
(0.4%). Reported frequencies and severities of solicited adverse reactions were lower among
the 12 Phase 1 participants 65 through 85 years of age compared with the 289 Phase 2/3
participants 18 through 55 years of age, similar to age group-related differences in
reactogenicity associated with the primary series. However, the small number of study
participants in this older adult age group limits any conclusions about the reactogenicity profile
of the booster dose. Nonetheless, it is reasonable to extrapolate safety of the booster dose in
adults >55 years of age from booster dose safety data in adults 18 through 55 years of age and
29
Case 2:21-cv-00702-CLM Document 40-10 Filed 12/17/21 Page 31 of 33
primary series safety data in adults >55 years of age (including an absence of specific safety
concerns for this age group). Lymphadenopathy, mostly axillary, mild-to-moderate in severity
and transient, following a booster dose (5.2%) occurred at over 10-fold greater frequency
compared to the primary series (0.4%).
Anaphylaxis and myocarditis/pericarditis are known uncommon but serious risks associated with
the BNT162b2 primary series. No cases of anaphylaxis, myocarditis, or pericarditis were
reported by Phase 1 or Phase 2/3 booster dose recipients through the data cutoff dates (May
13, 2021 and June 17, 2021, respectively), although the number of study participants exposed
to a booster dose precludes a meaningful evaluation of these risks. With regard to anaphylaxis,
individuals who experience a severe allergic reaction to a primary series dose would be
contraindicated to receive a booster dose, and it is unlikely that an individual would experience
an anaphylactic reaction to a booster dose in the absence of a prior severe allergic reaction to a
primary series dose. With regard to myocarditis/pericarditis, available data suggest that this risk
is greatest in males under the age of 40 (and specifically males 16-17 years of age) following
the second primary series dose. It is unknown whether this risk would be similar, increased, or
decreased following a booster dose as compared to following the second primary series dose.
While observational safety data from widespread use of a booster dose in the Israel were
presented at the VRBPAC meeting, these data have not been independently reviewed by FDA,
are limited in duration, and are particularly limited in number of booster dose recipients under
the age of 20 years.
7.4. Uncertain Risks/Data Gaps
Adverse reactions that are very uncommon or that require longer follow-up to be
detected
In addition to uncertainty around the risk of myocarditis/pericarditis following a booster dose as
described above, the duration of safety follow-up and the size of the available booster dose
safety database limit the ability to detect the emergence of rare adverse reactions, which may
only be identified with broader use and more prolonged safety follow up. Active and passive
safety surveillance will continue during the post-authorization period to detect new safety
signals.
Safety of booster dose in certain subpopulations
No clinical safety data for a booster dose are available at this time for certain subpopulations,
such as pediatric populations less than 18 years of age or pregnant or lactating individuals. For
pediatric populations less than 18 years of age, safety data from use of the primary series
demonstrates an increased risk of myocarditis/pericarditis, particularly in males, compared to
older age groups, and significant uncertainty exists as to whether this risk could be further
increased following a booster dose. For pregnant or lactating individuals, available safety data
from use of the primary series do not raise specific safety concerns about extrapolating safety of
a booster dose from data in non-pregnant, non-lactating individuals.
8. VRBPAC SUMMARY
The Vaccines and Related Biological Products Advisory Committee convened on September
17, 2021 in open session to discuss whether the data Pfizer has submitted are sufficient to
support approval of a booster dose of COMIRNATY when administered approximately 6 months
after the primary series to individuals 16 years of age and older.
30
Case 2:21-cv-00702-CLM Document 40-10 Filed 12/17/21 Page 32 of 33
The VRBPAC was asked to vote on the following question: Do the safety and effectiveness data
from clinical trial C4591001 support approval of a COMIRNATY booster dose administered at
least 6 months after completion of the primary series for use in individuals 16 years of age and
older? Please vote Yes or No.
The results of the vote were as follows: Yes=2, No=16.
Thus, the committee voted against approval of a booster dose for individuals 16 years of age
and older. Committee members expressed concern regarding uncertainties about the benefit
afforded by a booster dose relative to the benefit provided by previous vaccination with the
primary series in persons 16 years of age and older. Concerns were expressed about post-
authorization data demonstrating increased risks of myocarditis and pericarditis, particularly
within 7 days following the second dose of COMIRNATY with the highest risk in males 16 to 17
years of age. There is currently only limited data whether this risk may be further increased after
a booster dose of COMIRNATY. Some committee members also noted the absence of robust
data regarding the effectiveness of a booster dose against the currently circulating Delta variant
of SARS-CoV-2.
Considering the committee’s feedback, the FDA then asked the committee members to vote on
whether the available data would support an emergency use authorization of a booster dose for
individuals 65 years and older. Prior to VRBPAC members casting their vote, FDA provided
them with a brief overview of applicable EUA criteria.
The committee was presented with a second voting question: Based on the totality of scientific
evidence available, including the safety and effectiveness data from clinical trial C4591001, do
the known and potential benefits outweigh the known and potential risks of a COMIRNATY
booster dose administered at least 6 months after completion of the primary series for use in
individuals 65 years of age and older, and individuals at high risk of severe COVID-19?
Please vote Yes or No.
The results of the vote were as follows: Yes=18, No=0.
Thus, the committee voted unanimously that the known and potential benefits outweigh the
known and potential risks of a single booster dose of the Pfizer-BioNTech COVID-19 Vaccine
for individuals 65 years of age and older and individuals at high risk of severe COVID-19.
Following the vote, the committee members were polled and unanimously expressed support
that the EUA include individuals at high risk of occupational exposure to SARS-CoV-2.
9. OVERALL SUMMARY AND RECOMMENDATIONS
Following review of information submitted in support of the EUA request, the review team
concludes that:
• As summarized in Section 2 of this review, the CBRN agent referred to in the March 27,
2020 EUA declaration by the Secretary of HHS (SARS-CoV-2) can cause a serious or
life-threatening disease or condition.
• Based on the immunogenicity data summarized in Section 5 of this review, a Pfizer-
BioNTech COVID-19 Vaccine booster dose, when administered at least 6 months after
the primary series, may be effective in improving protection against serious outcomes of
COVID-19 among individuals in whom primary series immunity has waned.
31
Case 2:21-cv-00702-CLM Document 40-10 Filed 12/17/21 Page 33 of 33
• Based on the data summarized in Section 5 of this review and assessment of benefits
and risks in Section 7 of this review, the known and potential benefits of a booster dose
of the vaccine outweigh the known and potential risks of the vaccine for certain
subgroups who are at increased risk of waning protection against serious outcomes of
COVID-19. These subgroups include individuals 65 years of age and older (based on
data from observational studies), individuals 18 through 64 years of age at high risk for
severe COVID-19 (e.g., due to underlying medical conditions), and individuals 18
through 64 years of age whose frequent institutional or occupational exposure to SARS-
CoV-2 puts them at high risk of serious complications of COVID-19 including severe
COVID-19. Considering the current uncertainties around waning protection against
serious COVID-19 outcomes among younger primary series recipients without risk
factors for severe COVID-19 or frequent and unavoidable exposure to SARS-CoV-2, and
the current uncertainties around safety of a booster dose in younger adult age groups,
available data at this time do not clearly support a favorable benefit/risk determination for
use of a booster dose in the general population of adults 18 through 64 years of age.
Similarly, based on uncertainties around whether there has been any waning of
protective immunity against serious outcomes of COVID-19 in pediatric age groups for
whom the primary series is authorized (i.e., adolescents 12 through 17 years of age),
and uncertainties around risks, available data at this time are not sufficient to support a
favorable benefit/risk determination for use of a booster dose in pediatric age groups.
• COMIRNATY is the only FDA approved vaccine indicated for active immunization for
prevention of COVID-19 caused by SARS-CoV-2. It is licensed as a 2-dose primary
series given 3 weeks apart. A third dose is authorized for use in immunocompromised
individuals as part of the primary series. No COIVD-19 vaccine is currently available for
use as a booster dose.
The review team therefore recommends authorization of the Pfizer-BioNTech COVID-19
Vaccine under EUA for use as a booster dose administered at least 6 months after the primary
series in the following populations:
• individuals 65 years of age and older,
• individuals 18 through 64 years of age at high risk of severe COVID-19, and
• individuals 18 through 64 years of age whose frequent institutional or occupational
exposure to SARS-CoV-2 puts them at high risk of serious complications of COVID-19
including severe COVID-19.
10. REFERENCES
1
FDA. Vaccine approval package: COMIRNATY (COVID-19 Vaccine, mRNA) (Application No 125742).
August 23, 2021. https://www.fda.gov/media/151733/download
2
FDA. Vaccines and Related Biological Products Advisory Committee September 17, 2021 Meeting.
Event materials available at https://www.fda.gov/advisory-committees/advisory-committee-
calendar/vaccines-and-related-biological-products-advisory-committee-september-17-2021-meeting-
announcement#event-materials
3
FDA. Guidance for Industry: Development and Licensure of Vaccines to Prevent COVID-19. June 2020.
https://www.fda.gov/media/139638/download
4
FDA. Guidance for Industry: Emergency Use Authorization for Vaccines to Prevent COVID-19. February
2021. https://www.fda.gov/media/142749/download
32
File and source
- File
- gov.uscourts.alnd.177186.40.10.pdf
- Size
- 769,708 bytes
- SHA-256
- 0bb5512108aa55b3ee196c083020f2522ee6ca80a10cb9f62900318dbda46c6c
- Original
- archive.org