Document text
Statistical Review
STN: 125742/45
Page i Application T ype BLA Supplement
STN 125742/45
CBER Received Date December 16, 2021
PDUFA Goal Date June 17, 2022
Division / Office DVRPA/OVRR
Committee Chair Ramachandra Naik
Clinical Reviewer(s) Susan Wollersheim
Project Mana ger Michael Smith; Laura Gottschalk
Priorit y Review Yes
Reviewer Name Ye Yang, Mathem atical Statistician, DB/VEB
Review Completion Date /
Stamped Date
Concurrence Lei Huan g, Concurrin g Reviewer, DB/VEB
Supervisory Concurrence Tsai-Lien Lin, Branch Chief, DB/VEB
Applicant BioNTech Manufacturing GmbH (in
partnership with Pfizer, Inc.)
Established Name COVID-19 Vaccine, mRNA
(Proposed) Trade Name COMIRNATY
Dosage Form(s) and Route(s) of
Administration Injectable Suspension, Intramuscular
Dosin g Regimen Two 0.3 mL doses, three weeks apart
Indication(s) and Intended
Population(s) Active immunization to prevent coronavirus
disease 2019 (COVID-19) caused by severe
acute respiratory syndrome coronavirus 2
(SARS-CoV-2) in individuals 12 through 15
years of a ge
Statistical Review
STN: 125742/45
Page ii Table of Contents
Glossary ...................................................................................................................... ....... 3
1. Executive Summary ...................................................................................................... 4
2. Clinical and Regulatory Background ......................................................................... 5
3. Submission Quality and Good Clinical Practices ...................................................... 5
3.1 Submission Quality and Completeness ....................................................................................... ...... 5
3.2 Compliance With Good Clinical Pr actices And Data Integrity ......................................................... 5
4. Significant Efficacy/Safety Issues Rela ted to Other Review Disciplines.................. 5
5. Sources of Clinical Data and Other Information Considered in the Review .......... 5
5.1 Review Strategy ........................................................................................................... ..................... 5
5.2 BLA/IND Documents That Serve as the Ba sis for the Statistical Review ........................................ 5
5.3 Table of Studies/Cli nical Trials .......................................................................................... ............... 6
6. Discussion of Individual Studies/Clinical Trials ........................................................ 6
6.1 Study C4591001 ............................................................................................................ .................... 6
6.1.1 Objectives .............................................................................................................. .................. 6
6.1.2 Design Overview ......................................................................................................... ............ 7
6.1.3 Population .............................................................................................................. ................. 7
6.1.4 Study Treatments or Agents Ma ndated by the Protocol .......................................................... 7
6.1.6 Sites and Centers ....................................................................................................... .............. 7
6.1.7 Surveillance/Monitoring ................................................................................................. ......... 7
6.1.8 Endpoints and Criteria for Study Success ............................................................................... 7
6.1.9 Statistical Considerations & Statistical Analysis Plan ............................................................ 8
6.1.10 Study Population and Disposition ....................................................................................... .. 9
6.1.11 Efficacy Anal yses ...................................................................................................... .......... 10
6.1.12 Safety Analyses ........................................................................................................ ........... 13
7. Integrated Overview of Efficacy ................................................................................ 17
8. Integrated Overview of Safety ................................................................................... 17
9. Additional Statistical Issues ....................................................................................... 17
10. Conclusions ............................................................................................................... . 17
10.1 Statistical Issues and Collective Evidence ............................................................................... ...... 17
10.2 Conclusions and Re commendations .......................................................................................... .... 18
Statistical Review
STN: 125742/45
Page 3 GLOSSARY
ADaM Analysis Data Model AE Adverse Event BIMO Bioresearch Monitoring BLA Biologics License Application BNT162b2 Pfizer-BioNTech COVID-19 Vaccine CI Confidence Interval COVID-19 Coronavirus Disease 2019 EUA Emergency Use Authorization GMT Geometric Mean Titer GMR Geometric Mean Titer Ratio NAAT Nucleic Acid Amplification Test RT-PCR Reverse Transcription-Polymerase Chain Reaction SAE Serious Adverse Event SAP Statistical Analysis Plan SARS-CoV-2 Severe Acute Resp iratory Syndrome Coronavirus 2
SDTM Study Data Tabulation model SRR Seroresponse Rate VE Vaccine Efficacy
Statistical Review
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Page 4 1. Executive Summary
The Pfizer-BioNTech COVID-19 Vaccine (BNT162b2, COMIRNATY) was licensed on
August 23, 2021 for active immunization to prevent Coronavirus Disease 2019 (COVID-
19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 ( SARS-CoV-2) in
LQGLYLGXDOV \HDUV RI D JH 3IL]HU VXEPLWWHG D Biologics License Application
Supplement (sBLA; STN 125742/45) on Decemb er 16, 2021 to seek licensure of
COMIRNATY for use in individuals 12 through 15 years of age. The sBLA is supported
by data from Study C4591001. This statisti cal review focuses on the efficacy,
immunogenicity, and safety data from adoles cents 12 through 15 years of age in the
Phase 3 part of Study C4591001 collected up to the September 2, 2021 data cutoff.
Study C4591001 is an ongoing, randomized, plac ebo-controlled, observer-blinded Phase
1/2/3 study being conducted in the United States, Argentina, Brazil, Germany, South
Africa, and Turkey among participants 12 years of age. Adolescents 12 through 15
years of age, included in the Phase 3 porti on of the study under a pr otocol amendment,
were enrolled at selected sites in the Un ited States, where 2,264 participants were
randomized 1:1 to receive two doses of BNT162b2 or placebo 21 days apart.
Immunogenicity was assessed at 1 month after Dose 2. A random sample of 280 adolescents was selected to support imm unobridging to a random sample of 280 young
adults 16 to 25 years of age from the sa me study. Supplementary to immunobridging,
adolescents were surveilled fo r potential cases of COVID-19.
The prespecified immunobridging success criterion comparing 12 to 15 year-old
geometric mean neutralizing titers (GMTs) to 16 to 25 year-old GMTs from Study C4591001 was met (GMT ratio [GMR]=1.77; 95% Confidence Interval [CI]: 1.50 to
2.09). High efficacy against protocol-defined COVID-19 was observed among participants in the Evaluable Efficacy Popul ation without evidence of prior SARS-CoV-2
infection starting at 7 days post Dose 2 (V accine Efficacy [VE]=100%; 95% CI: 86.8% to
100%) and among participants in the Dose 1 All-Available Efficacy Population starting
after Dose 1 (VE=94.0%; 95% CI: 81.3% to 98.8 %). The lack of severe COVID-19 cases
observed precludes assessment of efficacy against severe disease in this population.
The frequency and severity of local and systemic reactions were generally higher among
BNT162b2 recipients than among placebo reci pients after either dose. The most
commonly reported adverse reactions were in jection site pain, fatigue, and headache.
There was no notable difference in the frequen cy of any unsolicited adverse event (AE)
between arms during blinded follow-up, while a higher percentage of BNT162b2
recipients reported any serious AE (SAE; 0.9 %) compared to placebo recipients (0.2%).
Of note, no SAE reported during blinded follow -up was considered by the investigator to
be related to the study interv ention. No participants died as of the September 2, 2021
cutoff. One SAE of myocarditis was reported in a 15-year-old male participant 2 days
after receiving the second cr ossover dose of BNT162b2. One SAE of appendicitis in a
12-year-old female participant was reported 3 days after the s econd crossover dose and
was considered by the investigator to be related to the study vaccination.
Statistical Review
STN: 125742/45
Page 5 Overall, the clinical data support the e ffectiveness of BNT162b2. While there is some
reactogenicity associated with BNT162b2, th e majority of solicite d adverse reactions
were mild or moderate in severity and of s hort duration. I defer to the clinical reviewer,
Dr. Susan Wollersheim, on the overal l safety conclusi on for BNT162b2.
2. Clinical and Regulatory Background
The Pfizer-BioNTech COVID-19 Vaccine (BNT162b2, COMIRNATY) was authorized
under an Emergency Use Authorization (EUA) on December 11, 2020 for active immunization to prevent COVID-19 caused by SARS-CoV-2 in LQGLYLGXDOV \HDUV RI
age, which was amended to include indivi duals 12 through 15 years of age on May 10,
2021. &20,51$7<ZDVOLFHQVHGIRU XVHLQLQGLYLGXDOV\ears of age on August 23,
2021. Pfizer submitted an sBLA (STN 125742/45) on December 16, 2021 to seek
licensure of COMIRNATY for use in i ndividuals 12 through 15 years of age.
3. SUBMISSION QUALITY AND GOOD CLINICAL PRACTICES
3.1 Submission Quality and Completeness
The submission was adequately organized fo r conducting a complete statistical review
without unreasonable difficulty.
3.2 Compliance With Good Clinical Practices And Data Integrity
Please refer to Kanaeko Ravenell’s Biores earch Monitoring inspections review memo.
4. SIGNIFICANT EFFICACY /SAFETY ISSUES RELATED TO OTHER REVIEW
DISCIPLINES
Please refer to reviews of other review disciplines.
5. SOURCES OF CLINICAL DATA AND OTHER INFORMATION CONSIDERED IN
THE REVIEW
5.1 Review Strategy
This statistical revi ew focuses on the efficacy, immunoge nicity, and safety data from
adolescents 12 to 15 years of age in the Phase 3 part of Study C4591001 collected up to
the September 2, 2021 data cutoff.
5.2 BLA/IND Documents That Serve as th e Basis for the St atistical Review
The following documents submitte d to the sBLA are reviewed:
STN 125742/45:
1. Amendment 0 (submitted on 12/16/2021)
x Module 2. Common Technical Document Summaries
x Module 5. Clinical Study Reports
2. Amendment 2 (submitted on 2/2/2022)
Statistical Review
STN: 125742/45
Page 6 x Module 1. Administrative Informatio n and Prescribing Information
3. Amendment 4 (submitted on 3/11/2021)
x Module 1. Administrative Informatio n and Prescribing Information
4. Amendment 7 (submitted on 3/18/2021)
x Module 1. Administrative Informatio n and Prescribing Information
5.3 Table of Studies/Clinical Trials
Data from one ongoing clinical st udy were submitted to support licensure in adolescents
(Table 1). Study C4591001 is a multi-center, Phase 1/2/3, randomized, double-blinded,
placebo-controlled study to evaluate safet y, immunogenicity, and ef ficacy of BNT162b2.
Table 1. Clinical Study Supporting Licensure in Adolescents 12 Through 15 Years of Age
Study Description BNT162b2 (N) Placebo (N) Status
C4591001
Phase 1/2/3, randomized,
placebo-controlled, observer-blind study to evaluate the safety, immunogenicity, and efficacy of BNT162b2 1134 (Phase 3
adolescents only) 1130 (Phase 3
adolescents only) Ongoing
N=number of randomized participants.
Source: Summarized by the reviewer based on in formation provided in Clinical Overview.
6. DISCUSSION OF INDIVIDUAL STUDIES /CLINICAL TRIALS
6.1 Study C4591001 (Phase 3)
6.1.1 Objectives
Primary Safety Objective:
x To define the safety profile of BNT162b2 in participants 12 to 15 years of age.
Secondary Immunogenicity Objective:
x To demonstrate the noninferiority of the immune response to BNT162b2 in
participants 12 to 15 years of age compared to participan ts 16 to 25 years of age.
Exploratory Efficacy Objective:
x To describe the efficacy of prophylactic BNT162b2 ag ainst confirmed COVID-19
occurring from 7 days after the second dose through the blinded follow-up period
in participants without, a nd with and without, eviden ce of infection before
vaccination.
Reviewer comment:
x Demonstration of efficacy was liste d as an exploratory objective as
immunobridging was the basis for infe rring effectiveness of BNT162b2 among
adolescents.
Statistical Review
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Page 7 6.1.2 Design Overview
Study C4591001 is an ongoing, randomized, plac ebo-controlled, observer-blinded Phase
1/2/3 study being conducted in the United States, Argentina, Brazil, Germany, South
Africa, and Turkey among participants 12 years of age. Adolescents 12 through 15
years of age, included in the Phase 3 porti on of the study under a pr otocol amendment,
were enrolled at selected sites in the United States, where 2,264 participants were randomized 1:1 to receive two doses of BNT162b2 or placebo 21 days apart.
Immunogenicity was assessed at 1 month after Dose 2. A sample of 280 participants was
randomly selected from each age group (12 to 15 years and 16 to 25 years) to support
immunobridging. Supplementary to immunobr idging analyses, adolescents were
surveilled for poten tial cases of COVID-19. Those w ho developed acute respiratory
illness were tested for SARS-CoV-2 infec tion using reverse transcription-polymerase
chain reaction (RT-PCR) in an illness visit. Pa rticipants originally randomized to placebo
who became eligible to receive BNT162b2 we re offered the opportunity to receive
BNT162b2 no later than 6 m onths post Dose 2.
All adolescents were to reco rd local reactions, systemic events, and antipyretic/pain
medication usage from Day 1 through Day 7 af ter each dose. Unsolicited AEs and SAEs
were collected starting from Dose 1.
6.1.3 Population
The study enrolled participants 12 years of age who, in the judgement of the
investigator, were at higher risk for acquiring COVID-19, in cluding but not limited to use
of mass transportation, relevant demographics, and frontline essential workers. The age
groups considered in this review are adol escents 12 to 15 years of age and young adults
16 to 25 years of age randomly sa mpled to support immunobridging.
6.1.4 Study Treatments or Agents Mandated by the Protocol
The study interventions were 30 μg of BNT162b2 and saline placebo.
6.1.6 Sites and Centers
A total of 29 sites in the United Stat es enrolled adolescents in the study.
6.1.7 Surveillance/Monitoring
Please refer to Dr. Susan Wollers heim’s clinical review memo.
6.1.8 Endpoints and Criteria for Study Success
The immunobridging endpoint was the neutralizi ng antibody titer at 28 days after Dose 2.
Effectiveness of BNT162b2 among adolescents was inferred by bridging their GMT of
neutralizing antibodies to the GMT from a random subset of young adults 16 to 25 years
of age from the same study. Success would be declared if the lower bound of the two-
sided 95% CI for the GMR, where GMR is de fined as GMT of adolescents divided by
GMT of young adults, was >0.67. Difference in seroresponse rates (SRRs) was evaluated
Statistical Review
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Page 8 descriptively. Seroresponse was defined as a change from a baseline (pre-Dose 1) titer
below the LLOQ to 4*LLOQ 28 days after Dose 2, or D -fold rise in titer from
baseline when the baseline titer is LLOQ.
Efficacy was assessed descri ptively based on cases of c onfirmed COVID-19, defined as
having a positive nucleic acid am plification test (NAAT) pl us at least one of the
following symptoms: fever, cough, shortness of breath, chills, muscle pain, new loss of
taste or smell, sore throat, diarrhea, or vomiting. Severe COVID-19 was defined as a confirmed COVID-19 plus at l east one of the following:
x Clinical signs at rest indicative of severe sys WHPLFLOOQHVV UHVSLUDWRU\ UDWH
EUHDWKV SHU PLQXWH KHDUW UD WH EHDWV SHU PLQXWH 6S2
2 RQ URRP DLU DW
sea level, or PaO 2/FiO 2 <300 mm Hg);
x Respiratory failure (defined as needing high-flow oxygen, noninvasive
ventilation, mechanical ventilation, or ECMO);
x Evidence of shock (systolic blood pressure <90 mm Hg, diastolic blood pressure
<60 mm Hg, or requiring vasopressors);
x Significant acute renal, hepati c, or neurologic dysfunction;
x Admission to an ICU;
x Death.
Solicited safety endpoints included the occurrence of local (redness, swelling, injection site pain) and systemic (fever , fatigue, headache, chills, vo miting, diarrhea, muscle pain,
joint pain) reactions within 7 days of each dos e. Unsolicited safety endpoints included the
occurrence of AEs and SAEs within three different risk windows: 1) Dose 1 to 1 month post Dose 2, 2) Dose 1 to 6 months post Dose 2, unblinding, or the September 2, 2021
data cutoff, whichever was earlier , and 3) unblinding to the cutoff.
6.1.9 Statistical Considerations & Statistical Analysis Plan
GMR and 95% CIs were obtained by exponent iating the difference and associated 95%
CIs of the mean log-titers based on the t-dist ribution. The confidence interval for the SRR
difference was estimated via the Miet tinen-Nurminen met hod. The primary
immunobridging analysis was based on the Evaluable Immunogenicity Population, defined as participants who: 1) received both doses of the ra ndomized vaccine, with Dose
2 within 19 to 42 days after Dose 1, 2) had at least 1 valid and determinate
immunogenicity result collected within 28 to 42 days after Dose 2, and 3) had no other
important protocol deviations. In addition, for the primary anal ysis, participants must not
have any evidence of SARS-CoV-2 infection up to 1 month after Dose 2. VE was estimated as 1 minus the incidence rate ratio of COVID-19 relative to placebo,
with associated 95% CI calculated by the Clopper-Pearson method adjusted for
surveillance time. Analysis was based on the Evaluable Efficacy P opulation, defined as
participants who received the randomized intervention within the predefined window and
had no major protocol deviations up to 7 days post Dose 2, and the Dose 1 All-Available
Efficacy Population, defined as all randomized participants w ho received at least 1 dose
of the intervention. Participants were analyzed according to the intervention randomized.
Statistical Review
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Page 9 VE in the Evaluable Efficacy Population was descriptively presented among participants:
1) without evidence of SARS-CoV-2 infection up to 7 days post Dose 2, and 2) with or
without evidence of prior infection.
Solicited safety analyses were based on partic ipants who received at least one dose of the
study intervention and responded yes or no to any reaction within 7 days of each dose.
Unsolicited safety analyses were based the Sa fety Population, defined as all participants
who received at least 1 dose of study intervention, analyzed ac cording to the intervention
received. Safety endpoints were summarized descriptively.
6.1.10 Study Population and Disposition
6.1.10.1 Populations Enrolled/Analyzed
Table 2 shows the disposition of randomized adol escents 12 to 15 years of age. A total of
2,264 adolescents were randomized. The percenta ges of participants who received each
dose were similar between the vaccine and pl acebo groups. In addition, 280 participants
12 to 15 years old and 280 participants 16 to 25 years old were selected for
immunobridging, of which 208 (74%) and 190 (6 8%), respectively, had a determinate
immunogenicity result available after Dose 2. The lower number of participants with an
available immunogenicity result, noted by the Applicant on March 15, 2021, was due to
an insufficient supply of a critical assay reag ent leading to a halt to laboratory testing. A
total of 190 (68%) and 170 ( 61%) participants, respective ly, were included in the
Evaluable Immunogenicity Population without evidence of infection.
Table 2. Subject Disposition
Source: Adapted from Tables 4 and 10 of Interim Clinical Study Report.
6.1.10.1.1 Demographics
Table 3 presents the demogra phic characteristics of the adolescent Safety Population.
Demographic characteristics were generally similar with regard to age, sex, race,
ethnicity, and baseline SARS-CoV-2 serost atus between participants who received
BNT162b2 and those who received placebo. Among all participants who received either - BNT162b2
n (%) Placebo
n (%) Total
n (%)
Randomized 1134 (100) 1130 (100) 2264 (100)
Not vaccinated 3 (0.3) 1 (0.1) 4 (0.2)
Vaccinated 1131 (99.7) 1129 (99.9) 2260 (99.8)
Dose 1 1131 (99.7) 1129 (99.9) 2260 (99.8)
Dose 2 1124 (99.1) 1117 (98.8) 2241 (99.0)
Withdrawn from the study 5 (0.4) 14 (1.2) 19 (0.8)
Lost to follow-up 3 (0.3) 2 (0.2) 5 (0.2)
Withdrawal by subject 1 (0.1) 7 (0.6) 8 (0.4)
Withdrawal by parent/guardian 1 (0.1) 5 (0.4) 6 (0.3)
Dose 1 All-Available Efficacy Populatio n 1131 (99.7) 1129 (99.9) 2260 (99.8)
Evaluable Efficacy Population 1119 (98.7) 1109 (98.1) 2228 (98.4)
Without evidence of infection 1057 (93.2) 1030 (91.2) 2087 (92.2)
Statistical Review
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Page 10 intervention, 51.0% were male, 85.5% were White, 4.8% were Black or African
American, 6.3% were Asian, and 0.3% were American Indian or Alaska Native.
Demographic characteristics in the Evaluable Efficacy Population were generally similar
to those in the Safety Population.
Table 3. Demographics Characteristics of the Safety Population
Source: Table 11 of Interim Clinical Study Report.
6.1.11 Efficacy Analyses
6.1.11.1 Analyses of Immunogenicity Endpoints
Table 4 presents the immunobridging analysis of GMR at 28 days after Dose 2 in the
Evaluable Immunogenicity Population without evidence of SARS-CoV-2 infection up to
1 month post Dose 2. The GMR comparing 12 to 15 year-old GMTs to 16 to 25 year-old
GMTs was 1.77 (95% CI: 1.50 to 2.09), meetin g the prespecified success criterion.
Table 4. Geometric Mean Titer Ratio – Evaluable Immunogenicity Population
Group GMT (95% CI)
12-15 Years of Age
N=190 GMT (95% CI)
16-25 Years of Age
N=170 GMR (95% CI)
12-15 Years/16-
25 Years
BNT162b2 1253.6 (1117.7, 1406.1) 708.1 (625.9, 801.1) 1.77 (1.50, 2.09)
N=number of participants with available titer at 1 month after Dose 2.
Source: Summarized by the reviewer based on re sponse to March 7, 2022 information request. - BNT162b2
N=1131
n (%) Placebo
N=1129
n (%) Total
N=2260
n (%)
Sex - - -
Male 567 (50.1) 585 (51.8) 1152 (51.0)
Female 564 (49.9) 544 (48.2) 1108 (49.0)
Race - - -
White 970 (85.8) 962 (85.2) 1932 (85.5)
Black/African-American 52 (4.6) 57 (5.0) 109 (4.8)
American Indian/Alaskan Na tive 4 (0.4) 3 (0.3) 7 (0.3)
Asian 72 (6.4) 71 (6.3) 143 (6.3)
Native Hawaiian/Other Pacific Islander 3 (0.3) 0 3 (0.1)
Multiracial 24 (2.1) 29 (2.6) 53 (2.3)
Not Reported 6 (0.5) 7 (0.6) 13 (0.6)
Ethnicity - - -
Hispanic/Latino 132 (11.7) 130 (11.5) 262 (11.6)
Non-Hispanic/Non-Latino 997 (88.2) 996 (88.2) 1993 (88.2)
Not Reported 2 (0.2) 3 (0.3) 5 (0.2)
Age (years) - - -
Mean (Standard Deviation) 13.6 (1.1) 13.6 (1.1) 13.6 (1.1)
Median (Minimum, Maximum) 14.0 (12, 15) 14.0 (12, 15) 14.0 (12, 15)
Baseline SARS-CoV-2 status - - -
Positive 46 (4.1) 50 (4.4) 96 (4.2)
Negative 1083 (95.8) 1078 (95.5) 2161 (95.6)
Missing 2 (0.2) 1 (0.1) 3 (0.1)
Statistical Review
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Page 11 Table 5 presents descriptive analysis result s for the SRR difference. Overall, 97.2% and
96.8% of adolescents and young adults, respec tively, in the Evaluable Immunogenicity
Population without evidence of SARS-CoV-2 infection achie ved seroresponse, resulting
in an SRR difference of 0.4% (95% CI: -4.2% to 5.5%).
Table 5. Seroresponse Rate Differen ce – Evaluable Immunogenicity Population
Group Seroresponse
n (%, 95% CI)
12-15 Years of Age
N=143 Seroresponse
n (%, 95% CI)
16-25 Years of Age
N=124 Seroresponse %
Difference (95% CI)
12-15 Years Minus 16-25
Years
BNT162b2 139 (97.2)
(93.0, 99.2) 120 (96.8)
(91.9, 99.1) 0.4 (-4.2, 5.5)
N=number of participants with available titer befo re vaccination and at 1 month after Dose 2.
n=number of participants achieving sero response at 1 month after Dose 2.
Source: Summarized by the reviewer based on re sponse to March 7, 2022 information request.
Reviewer comment:
xAnalyses of GMR and SRR difference based on the same population were used to
support the May 10, 2021 EUA. Of note, the applicant discovered that the assay
LLOQ should have been 41 instead of in the submitted datasets. The resultspresented in Tables 4 an d 5 reflect the updated LLOQ.
6.1.11.2 Analyses of Efficacy Endpoints
In the Evaluable Efficacy Population wit hout evidence of SARS-CoV-2 infection, 28
COVID-19 cases among placebo recipients and none among BNT162b2 recipients were
observed during blinded follow-up from 7 days post Dose 2 to the September 2, 2021
cutoff (Table 6), resu lting in a VE point estimate of 100% (95% CI: 86.8% to 100%). A
similar VE was observed among participants with or wit hout evidence of infection
(VE=100%; 95% CI: 87.5% to 100%). These an alyses were based on a median follow-up
of 4.4 months post Dose 2.
Figure 1 shows the cumulative incidence of COVID-19 in the Dose 1 All-Available
Efficacy Population, where 48 cases in th e placebo group and 3 cases in the BNT162b2
group were observed during blinded follow- up starting after Dose 1 (VE=94.0%; 95%
CI: 81.3% to 98.8%). All 3 cases from BNT162b2 recipients occurred prior to Dose 2.
No protocol-defined severe COVID-19 was obs erved in either group as of the cutoff. (b) (4)
Statistical Review
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Page 12Table 6. Efficacy by Population and Time Period
Population/Surveillance Period BNT162b2
n (1000-py)Placebo
n (1000-py)VE (95% CI)
Evaluable Efficacy Population without
evidence of infectionN=1057 N=1030 -
GD\V DIWHU 'RVH 0 (0.343) 28 (0.322) 100.0 (86.8, 100.0)
GD\V WR PRQWKV DIWHU Dose 2 0 (0.138) 15 (0.133) 100.0 (73.2, 100.0)
PRQWKV WR PRQWKV DIWHU 'RVH 0 (0.148) 10 (0.139) 100.0 (58.0, 100.0)
PRQWKV DIWHU 'RVH 0 (0.057) 3 (0.050) 100.0 (-112.1, 100.0)
Evaluable Efficacy Population with or without evidence of infectionN=1119 N=1109 -
GD\V DIWHU 'RVH 0 (0.362) 30 (0.345) 100.0 (87.5, 100.0)
GD\V WR PRQWKV DIWHU 'RVH 0 (0.146) 17 (0.142) 100.0 (76.4, 100.0)
PRQWKV WR PRQWKV DIWHU 'RVH 0 (0.155) 10 (0.148) 100.0 (57.4, 100.0)
months after Dose 2 0 (0.061) 3 (0.055) 100.0 (-117.8, 100.0)
Dose 1 All-Available EfficacyPopulationN=1131 N=1129 -
After Dose 1 3 (0.450) 48 (0.434) 94.0 (81.3, 98.8)
Dose 1 to before Dose 2 3 (0.065) 12 (0.065) 75.1 (7.6, 95.5)
Dose 2 to <7 days after Dose 2 0 (0.021) 5 (0.021) 100.0 (-8.7, 100.0)
GD\V DIWHU 'RVH 0 (0.364) 31 (0.348) 100.0 (87.9, 100.0)
N=number of participants in the population; n= number of participants meeting the primary
endpoint definition; py=person-years of surveillance.
Source: Tables 12, 13, and 15 of Interim Clinical Study Report.
Figure 1 Cumulative Incidence of COVID- 19 – Dose 1 All-Available Effic opulation
Source: Figure 1 of Interim Clinical Study Report.
igure 1 Cumulative Incidence of COVID
19
Dose 1 All
Available Efficacy Population
Statistical Review
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Page 13 6.1.11.3 Subpopulation Analyses
Table 7 presents the subgroup efficacy anal ysis results for the Dose 1 All-Available
Efficacy Population. Overall, hi gh efficacy was observed rega rdless of sex or ethnicity
and among White participants. The limited number of cases observed among non-White
participants precludes meani ngful interpretation of efficacy within this subgroup.
Table 7. Efficacy Starting at Dose 1 by Subgro up – Dose 1 All-Available Efficacy Population
Population/Surveillance Period BNT162b2
n (1000-py) Placebo
n (1000-py) VE (95% CI)
Overall 3 (0.450) 48 (0.434) 94.0 (81.3, 98.8)
Sex - - -
Male 3 (0.227) 26 (0.223) 88.7 (63.0, 97.8)
Female 0 (0.223) 22 (0.211) 100.0 (82.7, 100.0)
Race - - -
White 2 (0.384) 45 (0.367) 95.8 (83.8, 99.5)
Black or African American 0 (0.024) 2 (0.026) 100.0 (-479.7, 100.0)
Other 1 (0.042) 1 (0.042) 1.4 (-7638.0, 98.7)
Ethnicity - - -
Hispanic/Latino 1 (0.055) 11 (0.051) 91.6 (42.3, 99.8)
Non-Hispanic/Non-Latino 2 (0.394) 37 (0.382) 94.8 (79.7, 99.4)
n=number of participants meeting the primary endpoint definition.
py=person-years of surveillance.
Source: Table 14.13 of Interi m Clinical Study Report.
Reviewer Comment:
xThe immunogenicity and efficacy data re ported by the applicant were consistent
with the Study Data Tabulation Model (SDTM) data.
6.1.12 Safety Analyses
Solicited Local and Systemic Reactions
Table 8 shows the frequency by severity of each solicited local and systemic reaction
within 7 days of each dose among adolescents. In general, incidence of any redness, swelling, injection site pain, fever, fatigue, headache, chills, vomiting, new or worsened
muscle pain, and new or worsened joint pain was higher among BNT162b2 recipients
than among placebo recipients after either dose.
Injection site pain, fatigue, and headache were the most frequently reported solicited
adverse reactions. The incidenc es of solicited local reactions were slightly higher after
Dose 1 than after Dose 2, while the incide nces of solicited systemic reactions were
generally higher after Dose 2 with th e exception of vomiting and diarrhea.
Among BNT162b2 recipients, the me dian onset day of solicite d local reactions was Day
1 (i.e. day of vaccination) to Day 2 after eith er dose, with a median duration of 2 days.
The median onset day of soli cited systemic reac tions was Day 2 to Day 3 after either
dose, with a median du ration of 1 to 2 days.
Statistical Review
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Page 14 Table 8. Frequency of Solicited Reac tions Within 7 Days of each Dose
- BNT162b2
Dose 1
N=1127
n (%) Placebo
Dose 1
N=1127
n (%) BNT162b2
Dose 2
N=1097
n (%) Placebo
Dose 2
N=1078
n (%)
Redness - - - -
Any (>2.0 cm) 65 (5.8) 12 (1.1) 55 (5.0) 10 (0.9)
Mild 44 (3.9) 11 (1.0) 29 (2.6) 8 (0.7)
Moderate 20 (1.8) 1 (0.1) 26 (2.4) 2 (0.2)
Severe 1 (0.1) 0 (0.0) 0 (0.0) 0 (0.0)
Swelling - - - -
Any (>2.0 cm) 78 (6.9) 11 (1.0) 54 (4.9) 6 (0.6)
Mild 55 (4.9) 9 (0.8) 36 (3.3) 4 (0.4)
Moderate 23 (2.0) 2 (0.2) 18 (1.6) 2 (0.2)
Severe 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
Pain at the injection site - - - -
Any 971 (86.2) 263 (23.3) 866 (78.9) 193 (17.9)
Mild 467 (41.4) 227 (20.1) 466 (42.5) 164 (15.2)
Moderate 493 (43.7) 36 (3.2) 393 (35.8) 29 (2.7)
Severe 11 (1.0) 0 (0.0) 7 (0.6) 0 (0.0)
Fever - - - -
ႏ 114 (10.1) 12 (1.1) 215 (19.6) 7 (0.6)
ႏWR ႏ 74 (6.6) 8 (0.7) 107 (9.8) 5 (0.5)
>ႏ WR ႏ 29 (2.6) 2 (0.2) 83 (7.6) 1 (0.1)
> ႏ WR ႏ 10 (0.9) 2 (0.2) 25 (2.3) 1 (0.1)
!ႏ 1 (0.1) 0 (0.0) 0 (0.0) 0 (0.0)
Fatigue - - - -
Any 677 (60.1) 457 (40.6) 726 (66.2) 264 (24.5)
Mild 278 (24.7) 250 (22.2) 232 (21.1) 133 (12.3)
Moderate 384 (34.1) 199 (17.7) 468 (42.7) 127 (11.8)
Severe 15 (1.3) 8 (0.7) 26 (2.4) 4 (0.4)
Headache - - - -
Any 623 (55.3) 396 (35.1) 708 (64.5) 264 (24.5)
Mild 361 (32.0) 256 (22.7) 302 (27.5) 170 (15.8)
Moderate 251 (22.3) 131 (11.6) 384 (35.0) 93 (8.6)
Severe 11 (1.0) 9 (0.8) 22 (2.0) 1 (0.1)
Chills - - - -
Any 311 (27.6) 109 (9.7) 455 (41.5) 74 (6.9)
Mild 195 (17.3) 82 (7.3) 221 (20.1) 53 (4.9)
Moderate 111 (9.8) 25 (2.2) 214 (19.5) 21 (1.9)
Severe 5 (0.4) 2 (0.2) 20 (1.8) 0 (0.0)
Vomiting - - - -
Any 31 (2.8) 10 (0.9) 29 (2.6) 12 (1.1)
Mild 30 (2.7) 8 (0.7) 25 (2.3) 11 (1.0)
Moderate 0 (0.0) 2 (0.2) 4 (0.4) 1 (0.1)
Severe 1 (0.1) 0 (0.0) 0 (0.0) 0 (0.0)
Diarrhea - - - -
Any 90 (8.0) 82 (7.3) 65 (5.9) 44 (4.1)
Mild 77 (6.8) 72 (6.4) 59 (5.4) 39 (3.6)
Statistical Review
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Page 15 - BNT162b2
Dose 1
N=1127
n (%) Placebo
Dose 1
N=1127
n (%) BNT162b2
Dose 2
N=1097
n (%) Placebo
Dose 2
N=1078
n (%)
Moderate 13 (1.2) 10 (0.9) 6 (0.5) 5 (0.5)
Severe 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
New or worsened muscle pain - - - -
Any 272 (24.1) 148 (13.1) 355 (32.4) 90 (8.3)
Mild 125 (11.1) 88 (7.8) 152 (13.9) 51 (4.7)
Moderate 145 (12.9) 60 (5.3) 197 (18.0) 37 (3.4)
Severe 2 (0.2) 0 (0.0) 6 (0.5) 2 (0.2)
New or worsened joint pain - - - -
Any 109 (9.7) 77 (6.8) 173 (15.8) 51 (4.7)
Mild 66 (5.9) 50 (4.4) 91 (8.3) 30 (2.8)
Moderate 42 (3.7) 27 (2.4) 78 (7.1) 21 (1.9)
Severe 1 (0.1) 0 (0.0) 4 (0.4) 0 (0.0)
Antipyretic use 413 (36.6) 111 (9.8) 557 (50.8) 95 (8.8)
N=number of subjects responding yes or no for any reaction within 7 days of dosing.
n=number of subjects with the specified reaction. Source: Summarized by the reviewer based on re sponse to March 14, 2022 information request.
Unsolicited Adverse Events
Tables 9 and 10 present the numbers and per centages of adolescent participants who
reported any unsolicited AE, SAE, nonserious AE, or AE leading to withdrawal after
Dose 1. These numbers are reported for three separate risk windows: 1) Dose 1 to 1
month post Dose 2, 2) Dose 1 to 6 months post Dose 2, unblinding, or the September 2,
2021 data cutoff, whichever was earlier , and 3) unblinding to the cutoff.
The percentages of subjects who reported any AE were similar between BNT162b2 and
placebo recipients from Dose 1 to 1 mont h after Dose 2, while a slightly higher
percentage of placebo recipients reported a ny AE from Dose 1 to 6 months after Dose 2.
A higher percentage of BNT162b2 recipients reported any AE considered by the investigator to be related to the study inte rvention in both risk windows. A total of 10
(0.9%) BNT162b2 recipients and 2 (0.2%) plac ebo recipients reported any SAE up to 6
months post Dose 2, none of which was considered by the investigator to be related to the
study intervention. No participants died as of the cutoff. The median duration of blinded
follow-up after Dose 2 was approximate ly 4.4 months among all participants.
A total of 1,010 subjects who originally r eceived placebo received at least 1 dose of
BNT162b2 after unblinding prior to the September 2, 2021 cu toff. Among these subjects,
6 (0.6%) reported any SAE, of whom a 12 ye ar-old female participant reported an SAE
of appendicitis 3 days after the second crossover dose that was considered by the
investigator to be related to vaccinati on. The median duration of follow-up after
unblinding was approximately 4 months among all unblinde d participants.
Statistical Review
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Page 16 Table 9. Number of Subjects Reporting at L east 1 AE by Time Period – Safety Population
- BNT162b2
1 Month Post
Dose 2 or
Unblinding
N=1131
n (%) Placebo
1 Month Post
Dose 2 or
Unblinding
N=1129
n (%) BNT162b2
6 Months Post
Dose 2 or
Unblinding
N=1131
n (%) Placebo
6 Months Post
Dose 2 or
Unblinding
N=1129
n (%)
Any AE 74 (6.5) 77 (6.8) 95 (8.4) 113 (10.0)
Related 36 (3.2) 24 (2.1) 36 (3.2) 24 (2.1)
Severe 7 (0.6) 2 (0.2) 13 (1.1) 5 (0.4)
Life-Threatening 1 (0.1) 1 (0.1) 2 (0.2) 1 (0.1)
Any SAE 4 (0.4) 1 (0.1) 10 (0.9) 2 (0.2)
Related 0 0 0 0
Severe 2 (0.2) 0 7 (0.6) 1 (0.1)
Life-Threatening 0 1 (0.1) 1 (0.1) 1 (0.1)
Any nonserious AE 72 (6.4) 76 (6.7) 89 (7.9) 111 (9.8)
Related 36 (3.2) 24 (2.1) 36 (3.2) 24 (2.1)
Severe 5 (0.4) 2 (0.2) 6 (0.5) 4 (0.4)
Life-Threatening 1 (0.1) 0 1 (0.1) 0
Any AE leading to withdrawal 1 (0.1) 0 1 (0.1) 0
N=number of subjects who received at le ast 1 dose of the study intervention.
n=number of subjects reporting at least 1 event. Source: Adapted from Table P of 508 Tables and Table 18 of In terim Clinical Study Report.
Table 10. Number of Subjects Reporting at Least 1 AE After Unblinding – Safety Population
- BNT162b2
Unblinding to Cutoff
N=1107
n (%) Placebo – BNT162b2
Crossover to Cutoff
N=1010
n (%)
Any AE 18 (1.6) 265 (26.2)
Related 4 (0.4) 242 (24.0)
Severe 3 (0.3) 12 (1.2)
Life-Threatening 0 0
Any SAE 4 (0.4) 6 (0.6)
Related 0 1 (0.1)
Severe 1 (0.1) 3 (0.3)
Life-Threatening 0 0
Any nonserious AE 14 (1.3) 262 (25.9)
Related 4 (0.4) 241 (23.9)
Severe 2 (0.2) 9 (0.9)
Life-Threatening 0 0
Any AE leading to withdrawal 0 0
N=number of subjects who received at le ast 1 dose of the study intervention.
n=number of subjects reporting at least 1 event. Source: Tables 25 and 35 of Interim Clinical Study Report.
Reviewer Comments:
x The solicited and unsolicited AEs reported in the interim clinical study report
were consistent with the SDTM data.
Statistical Review
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Page 17
Myocarditis and Pericarditis
No myocarditis or pericarditis was repor ted during blinded follow-up. One SAE of
myocarditis was identified in a 15-year-old male participant 2 days after receiving the
second crossover vaccination dose of BNT162b2.
7. INTEGRATED OVERVIEW OF EFFICACY
No integrated analysis of efficacy was performed.
8. INTEGRATED OVERVIEW OF SAFETY
No integrated analysis of safety was performed.
9. ADDITIONAL STATISTICAL ISSUES
There are no additional statistical issues.
10. CONCLUSIONS
10.1 Statistical Issues and Collective Evidence
No major statistical issues affecting study conclusions were identified for the
immunogenicity, efficacy and safety data. The prespecified immunobridging success
criterion comparing 12 to 15 year-old neut ralizing GMTs to 16 to 25 year-old GMTs
from Study C4591001 was met (GMR=1.77; 95% CI : 1.50 to 2.09). High efficacy against
protocol-defined COVID-19 was observed among participants in the Evaluable Efficacy
Population without evidence of prior SARS-CoV-2 infection st arting at 7 days post Dose
2 (VE=100%; 95% CI: 86.8% to 100%) and am ong participants in the Dose 1 All-
Available Efficacy Popula tion starting after Dose 1 (VE=94.0%; 95% CI: 81.3% to
98.8%). The lack of observed severe COVID- 19 precludes assessment of efficacy against
severe disease in this population. The frequency and severity of local and syst emic reactions were generally higher among
BNT162b2 recipients than among placebo reci pients after either dose. The most
commonly reported adverse reactions were in jection site pain, fatigue, and headache.
There was no notable difference in the frequ encies of any unsolicited AE between arms
during blinded follow-up, while a higher per centage of BNT162b2 recipients reported
any SAE (0.9%) compared to placebo recipi ents (0.2%). Of note, no SAE reported
during blinded follow-up was considered by the investigator to be related to the study
intervention. No participants died as of the cutoff. One SA E of myocarditis was reported
in a 15-year-old male particip ant 2 days after receiving th e second crossover vaccination
dose of BNT162b2. One SAE of appendicitis in a 12-year-old fema le participant was
reported 3 days after the second crossover dose and was considered by the investigator to
be related to th e study vaccination.
Statistical Review
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Page 18 10.2 Conclusions and Recommendations
Overall, the clinical data support the e ffectiveness of BNT162b2. While there is some
reactogenicity associated with BNT162b2, th e majority of solicite d adverse reactions
were mild or moderate in severity and of s hort duration. I defer to the clinical reviewer,
Dr. Susan Wollersheim, on the overal l safety conclu sion for BNT162b2.