docs/Statistical-Review-COMIRNATY.txt

Statistical Review
STN: 125742/45
Application Type
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 Reviewers)
Susan Wollersheim
Project Manager
Michael Smith; Laura Gottschalk
Priority Review
Yes
Reviewer Name
Ye Yang, Mathematical Statistician, DB/VEB
Review Completion Date /
Stamped Date
Concurrence
Lei Huang, Concurring Reviewer, DB/VEB
Supervisory Concurrence
Tsai-Lien Lin, Branch Chief, DB/VEB
Applicant
Established Name
(Proposed) Trade Name
Dosage Form(s) and Route(s) of
Administration
Dosing Regimen
Indication(s) and Intended
Population(s)
BioNTech Manufacturing GmbH (in partnership with Pfizer, Inc.)
COVID-19 Vaccine, mRNA
COMIRNATY
Injectable Suspension, Intramuscular
Two 0.3 mL doses, three weeks apart
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 age
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Table of Contents
Glossary....
3
1. Executive Summary..
2. Clinical and Regulatory Background
5
3. Submission Ouality and Good Clinical Practices ..............
5
3.1 Submission Quality and Completeness ....
3.2 Compliance With Good Clinical Practices And Data Integrity
4. Significant Efficacy/Safety Issues Related to Other Review Disciplines............
5
5. Sources of Clinical Data and Other Information Considered in the Review...........
5
5.1 Review Strategy .........
5.2 BLA/IND Documents That Serve as the Basis for the Statistical Review ......
5.3 Table of Studies/Clinical Trials...
6. Discussion of Individual Studies/Clinical Trials ..
6.1 Study C4591001......
6.1.1 Objectives.
6.1.2 Design Overview.
6.1.3 Population
6.1.4 Study Treatments or Agents Mandated by the Protocol
6.1.6 Sites and Centers
6.1.7 Surveillance/Monitoring.
6.1.8 Endpoints and Criteria for Study Success
6.1.9 Statistical Considerations & Statistical Analysis Plan
6.1.10 Study Population and Disposition
6.1.11 Efficacy Analyses.....
6.1.12 Safety Analyses.
7. Integrated Overview of Efficacy...........
10
17
8. Integrated Overview of Safety.......
17
9. Additional Statistical Issues...........
.............. 17
10. Conclusions..........
10.1 Statistical Issues and Collective Evidence..............
10.2 Conclusions and Recommendations..
17
17
........ Id
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GLOSSARY
ADaM
AE
BIMO
BLA
BNT16262
CI
COVID-19
EUA
GMT
GMR
NAAT
RT-PCR
SAE
SAP
SARS-CoV-2
SDTM
SRR
VE
Analysis Data Model
Adverse Event
Bioresearch Monitoring
Biologics License Application
Pfizer-BioNTech COVID-19 Vaccine
Confidence Interval
Coronavirus Disease 2019
Emergency Use Authorization
Geometric Mean Titer
Geometric Mean Titer Ratio
Nucleic Acid Amplification Test
Reverse Transcription-Polymerase Chain Reaction
Serious Adverse Event
Statistical Analysis Plan
Severe Acute Respiratory Syndrome Coronavirus 2
Study Data Tabulation model
Seroresponse Rate
Vaccine Efficacy
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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 individuals ≥16 years of age. Pfizer submitted a Biologics License Application Supplement (BLA; STN 125742/45) on December 16, 2021 to seek licensure of COMIRNATY for use in individuals 12 through 15 years of age. The BLA is supported by data from Study C4591001. This statistical review focuses on the efficacy, immunogenicity, and safety data from adolescents 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, placebo-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 portion of the study under a protocol amendment, were enrolled at selected sites in the United States, where 2,264 participants were randomized 1:1 to receive two doses of BNT16262 or placebo 21 days apart.
Immunogenicity was assessed at 1 month after Dose 2. A random sample of 280 adolescents was selected to support immunobridging to a random sample of 280 young adults 16 to 25 years of age from the same study. Supplementary to immunobridging, adolescents were surveilled for 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 Population without evidence of prior SARS-CoV-2 infection starting at 7 days post Dose 2 (Vaccine 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 recipients after either dose. The most commonly reported adverse reactions were injection site pain, fatigue, and headache.
There was no notable difference in the frequency 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 intervention. 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 crossover dose of BNT162b2. One SAE of appendicitis in a
12-year-old female participant was reported 3 days after the second crossover dose and was considered by the investigator to be related to the study vaccination.
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Overall, the clinical data support the effectiveness of BNT1622. While there is some reactogenicity associated with BNT162b2, the majority of solicited adverse reactions were mild or moderate in severity and of short duration. I defer to the clinical reviewer, Dr. Susan Wollersheim, on the overall safety conclusion for BNT162b2.
2. Clinical and Regulatory Background
The Pfizer-BioNTech COVID-19 Vaccine (BNT16262, 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 individuals ≥16 years of age, which was amended to include individuals 12 through 15 years of age on May 10,
2021. COMIRNATY was licensed for use in individuals ≥16 years of age on August 23,
2021. Pfizer submitted an BLA (STN 125742/45) on December 16, 2021 to seek licensure of COMIRNATY for use in individuals 12 through 15 years of age.
3. SUBMISSION QUALITY AND GOOD CLINICAL PRACTICES
3.1 Submission Quality and Completeness
The submission was adequately organized for conducting a complete statistical review without unreasonable difficulty.
3.2 Compliance With Good Clinical Practices And Data Integrity
Please refer to Kanaeko Ravenell's Bioresearch 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 review focuses on the efficacy, immunogenicity, 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 the Basis for the Statistical Review
The following documents submitted to the BLA are reviewed:
STN 125742/45:
1. Amendment 0 (submitted on 12/16/2021)
• Module 2. Common Technical Document Summaries
• Module 5. Clinical Study Reports
2. Amendment 2 (submitted on 2/2/2022)
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• Module 1. Administrative Information and Prescribing Information
3. Amendment 4 (submitted on 3/11/2021)
• Module 1. Administrative Information and Prescribing Information
4. Amendment 7 (submitted on 3/18/2021)
• Module 1. Administrative Information and Prescribing Information
5.3 Table of Studies/Clinical Trials
Data from one ongoing clinical study 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 safety, immunogenicity, and efficacy of BNT16262.
Table 1. Clinical Study Supporting Licensure in Adolescents 12 Through 15 Years of Age
Study
Description
BNT162b2 (N)
Placebo (N)
C4591001 Phase 1/2/3, randomized, 1134 (Phase 3
1130 (Phase 3
Status
Ongoing
placebo-controlled, observer- adolescents
adolescents
blind study to evaluate the only)
only)
safety, immunogenicity, and efficacy of BNT16262
N=number of randomized participants.
Source: Summarized by the reviewer based on information provided in Clinical Overview.
6. DISCUSSION OF INDIVIDUAL STUDIES/CLINICAL TRIALS
6.1 Study C4591001 (Phase 3)
6.1.1 Obiectives
Primary Safety Objective:
• To define the safety profile of BNT16262 in participants 12 to 15 years of age.
Secondary Immunogenicity Objective:
• To demonstrate the noninferiority of the immune response to BNT1622 in participants 12 to 15 years of age compared to participants 16 to 25 years of age.
Exploratory Efficacy Obiective:
• To describe the efficacy of prophylactic BNT16262 against confirmed COVID-19 occurring from 7 days after the second dose through the blinded follow-up period in participants without, and with and without, evidence of infection before vaccination.
Reviewer comment:
• Demonstration of efficacy was listed as an exploratory objective as immunobridging was the basis for inferring effectiveness of BNT162b2 among adolescents.
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6.1.2 Design Overview
Study C4591001 is an ongoing, randomized, placebo-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 portion of the study under a protocol amendment, were enrolled at selected sites in the United States, where 2,264 participants were randomized 1:1 to receive two doses of BNT16262 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 immunobridging analyses, adolescents were surveilled for potential cases of COVID-19. Those who developed acute respiratory illness were tested for SARS-CoV-2 infection using reverse transcription-polymerase chain reaction (RT-PCR) in an illness visit. Participants originally randomized to placebo who became eligible to receive BNT1622 were offered the opportunity to receive
BNT16262 no later than 6 months post Dose 2.
All adolescents were to record local reactions, systemic events, and antipyretic/pain medication usage from Day 1 through Day 7 after each dose. Unsolicited As 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, including but not limited to use of mass transportation, relevant demographics, and frontline essential workers. The age groups considered in this review are adolescents 12 to 15 years of age and young adults 16 to 25 years of age randomly sampled to support immunobridging.
6.1.4 Study Treatments or Agents Mandated by the Protocol
The study interventions were 30ug of BNT16262 and saline placebo.
6.1.6 Sites and Centers
A total of 29 sites in the United States enrolled adolescents in the study.
6.1.7 Surveillance/Monitoring
Please refer to Dr. Susan Wollersheim's clinical review memo.
6.1.8 Endpoints and Criteria for Study Success
The immunobridging endpoint was the neutralizing antibody titer at 28 days after Dose 2.
Effectiveness of BNT1622 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 defined as GMT of adolescents divided by GMT of young adults, was >0.67. Difference in seroresponse rates (SRRs) was evaluated
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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 a ≥4-fold rise in titer from baseline when the baseline titer is ›LLOQ.
Efficacy was assessed descriptively based on cases of confirmed COVID-19, defined as having a positive nuclei acid amplification test (NAAT) plus 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 least one of the following:
• Clinical signs at rest indicative of severe systemic illness (respiratory rate >30 breaths per minute, heart rate ≥125 beats per minute, SpOz <93% on room air at sea level, or Pa02/FiO2 <300 mm Hg);
• Respiratory failure (defined as needing high-flow oxygen, noninvasive ventilation, mechanical ventilation, or CMO);
• Evidence of shock (systolic blood pressure <90 mm Hg, diastolic blood pressure <60 mm Hg, or requiring vasopressors);
• Significant acute renal, hepatic, or neurologic dysfunction;
Admission to an ICU;
• Death.
Solicited safety endpoints included the occurrence of local (redness, swelling, injection site pain) and systemic (fever, fatigue, headache, chills, vomiting, diarrhea, muscle pain, joint pain) reactions within 7 days of each dose. 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 exponentiating the difference and associated 95% CIs of the mean log-titers based on the t-distribution. The confidence interval for the SRR difference was estimated via the Miettinen-Nurminen method. The primary immunobridging analysis was based on the Evaluable Immunogenicity Population, defined as participants who: 1) received both doses of the randomized 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 analysis, 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 adiusted for surveillance time. Analysis was based on the Evaluable Efficacy Population, 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 who received at least 1 dose of the intervention. Participants were analyzed according to the intervention randomized.
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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 participants 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 Safety Population, defined as all participants who received at least 1 dose of study intervention, analyzed according 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 adolescents 12 to 15 years of age. A total of 2,264 adolescents were randomized. The percentages of participants who received each dose were similar between the vaccine and placebo 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 (68%), 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 reagent leading to a halt to laboratory testing. A total of 190 (68%) and 170 (61%) participants, respectively, were included in the Evaluable Immunogenicity Population without evidence of infection.
Table 2. Subject Disposition
BNT162b2 n (%)
Randomized
1134 (100)
Not vaccinated
3 (0.3)
Vaccinated
1131 (99.7)
Dose 1
1131 (99.7)
Dose 2
1124 (99.1)
Withdrawn from the stud
5 (0.4)
Lost to follow-up
3 (0.3)
Withdrawal by subject
1 (0.1)
Withdrawal by parent/guardian
1 (0.1)
Dose 1 All-Available Efficacy Population
1131 (99.7)
Evaluable Efficacy Population
1119 (98.7)
Without evidence of infection
1057 (93.2)
Source: Adapted from Tables 4 and 10 of Interim Clinical Study Report.
Placebo
Total
n (%)
n (%)
1130 (100)
2264 (100)
1 (0.1)
4 (0.2)
1129 (99 9)
2260 (99.8)
1129 (99 9)
2260 (99 8)
1117 (98.8)
2241 (99.0)
14 (1.2)
19 (0.8)
2 (0.2)
5 (0.2)
7 (0.6)
8 (0.4)
5 (0.4)
6 (0.3)
1129 (99 9)
2260 (99.8)
1109 (98.1)
2228 (98 4)
1030 (91.2)
2087 (92.2)
6.1.10.1.1 Demographics
Table 3 presents the demographic characteristics of the adolescent Safety Population.
Demographic characteristics were generally similar with regard to age, sex, race, ethnicity, and baseline SARS-CoV-2 serostatus between participants who received BNT16262 and those who received placebo. Among all participants who received either
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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
BNT162b2
N=1131 n (%)
Sex
-
Male
567 (50.1)
Female
564 (49.9)
Race
-
White
970 (85.8)
Black/African-American
52 (4.6)
American Indian/Alaskan Native
4 (0.4)
Asian
72 (6.4)
Native Hawaiian/Other Pacific Islander
3 (0.3)
Multiracial
24 (2.1)
Not Reported
6 (0.5)
Ethnicity
Hispanic/Latino
132 (11.7)
Non-Hispanic/Non-Latino
997 (88.2)
Not Reported
2 (0.2)
Age (years)
Mean (Standard Deviation)
13.6 (1.1)
Median (Minimum, Maximum)
14.0 (12. 15)
Baseline SARS-CoV-2 status
Positive
46 (4 1)
Negative
1083 (95.8)
Missing
2 (0.2)
Source: Table 11 of Interim Clinical Stud Report.
Placebo
N=1129 n (%)
-
585 (51.8)
544 (48.2)
-
962 (85.2)
57 (5.0)
3 (0.3)
71 (6.3)
0
29 (2.6)
7 (0.6)
-
130 (11.5)
996 (88.2)
3 (0.3)
Total
N=2260 n (%)
-
1152 (51.0)
1108 (49.0)
-
1932 (85.5)
109 (4.8)
7 (0.3)
143 (6.3)
3 (0.1)
53 (2.3)
13 (0.6)
13.6 (1.1)
14.0 (12, 15)
262 (11.6)
1993 (88.2)
5 (0.2)
-
13.6 (1.1)
14.0 (12, 15)
50 (4.4)
1078 (95.5)
1 (0.1)
96 (4.2)
2161 (95.6)
3 (0.1)
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), meeting the prespecified success criterion.
Table 4. Geometric Mean Titer Ratio - Evaluable Immunogenicity Population
Group
GMT (95% CI)
GMT (95% CI)
12-15 Years of Age
16-25 Years of Age
N=190
N=170
BNT16262
1253.6 (1117.7, 1406.1)
708.1 (625.9, 801.1)
GMR (95% CI)
12-15 Years/16-
25 Years
1.77 (1.50, 2.09)
N=number of participants with available titer at I month after Dose 2.
Source: Summarized by the reviewer based on response to March 7, 2022 information request.
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Table 5 presents descriptive analysis results for the SR difference. Overall, 97.2% and 96.8% of adolescents and young adults, respectively, in the Evaluable Immunogenicity Population without evidence of SARS-CoV-2 infection achieved seroresponse, resulting in an SRR difference of 0.4% (95% CI: -4.2% to 5.5%).
Table 5. Seroresponse Rate Difference - Evaluable Immunogenicity Population
Group
Seroresponse
Seroresponse
n (%, 95% CI)
n (%,95% CI)
12-15 Years of Age
16-25 Years of Age
N=143
N=124
BNT16262
139 (97.2)
120 (96.8)
Seroresponse %
Difference (95% CI)
12-15 Years Minus 16-25
Years
0.4(-4.2,5.5)
(93.0, 99.2)
(91.9, 99.1)
N=number of participants with available titer before vaccination and at I month after Dose 2. n=number of participants achieving seroresponse at I month after Dose 2.
Source: Summarized by the reviewer based on response to March 7, 2022 information request.
Reviewer comment:
Analyses 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 LLO9 should have been 41 instead of in the submitted datasets. The results presented in Tables 4 and 5 reflect the updated LLOQ.
6.1.11.2 Analyses of Efficacy Endpoints
In the Evaluable Efficacy Population without evidence of SARS-CoV-2 infection, 28
COVID-19 cases among placebo recipients and none among BNT16262 recipients were observed during blinded follow-up from 7 days post Dose 2 to the September 2, 2021
cutoff (Table 6), resulting in a VE point estimate of 100% (95% CI: 86.8% to 100%). A similar VE was observed among participants with or without evidence of infection (VE=100%; 95% CI: 87.5% to 100%). These analyses 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 the 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 BNT16262 recipients occurred prior to Dose 2.
No protocol-defined severe COVID-19 was observed in either group as of the cutoff.
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Table 6. Efficacy by Population and Time Period
Population/Surveillance Period
BNT162b2 n (1000-py)
N=1057
Placebo n (1000-py)
N=1030
VE (95% CI)
Evaluable Efficacy Population without evidence of infection
>7 davs after Dose 2
>7 davs to <2 months after Dose 2
>2 months to <4 months after Dose 2
>4 months after Dose 2
Evaluable Efficacy Population with or
0 (0 343)
0 (0.138)
0 (0.148)
0 (0.057)
N=1119
28 (0.322)
15 (0.133)
10 (0.139)
3 (0.050)
N=1109
100.0 (86.8, 100.0)
100.0 (73.2, 100.0)
100.0 (58.0, 100.0)
100.0 (-112.1, 100.0)
-
without evidence of infection
>7 davs after Dose 2
>7 days to <2 months after Dose 2
>2 months to <4 months after Dose 2
>4 months after Dose 2
Dose 1 All-Available Efficacy
0 (0.362)
0 (0.146)
0 (0.155)
0 (0.061)
N=1131
30 (0.345)
17 (0.142)
10 (0.148)
3 (0.055)
N=1129
100.0 (87.5, 100.0)
100.0 (76.4, 100.0)
100.0 (57.4, 100.0)
100.0 (-117.8, 100.0)
Population
After Dose 1
3 (0.450)
48 (0.434)
Dose 1 to before Dose 2
3 (0.065)
12 (0.065)
Dose 2 to <7 davs after Dose 2
0 (0.021)
5 (0.021)
≥7 days after Dose 2
0 (0.364)
31 (0.348)
94.0 (81.3, 98.8)
75.1 (7.6, 95.5)
100.0 (-8.7, 100.0)
100.0 (87.9, 100.0)
N=number of participants in the population; n=number of participants meeting the primary endpoint definition: py=person-vears of surveillance.
Source: Tables 12, 13, and 15 of Interim Clinical Study Report.
Fioure 1 Cumulative Incidence of COVTD-19 - Dose 1 All-Availahle Efficacy Penulation
060
0.055
0.050
0.045
Cumulative Incidence of COVID-19 Occ
0.030
0.020
0.010
0.005
0.000
thieere at rick
Dave After Dose 1
Cumulative Number of Events
A: BNT16262 (30 mg)
R. Parenc
Source: Figure I of Interim Clinical Study Report.
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6.1.11.3 Subpopulation Analyses
Table 7 presents the subgroup efficacy analysis results for the Dose 1 All-Available Efficacy Population. Overall, high efficacy was observed regardless of sex or ethnicity and among White participants. The limited number of cases observed among non- White participants precludes meaningful interpretation of efficacy within this subgroup.
Table 7. Efficacy Starting at Dose 1 by Subgroup - Dose 1 All-Available Efficacy Population
Population/Surveillance Period
BNT162b2
-
Male
3 (0.227)
Female
0 (0.223)
Race
-
White
2 (0.384)
Black or African American
0 (0.024)
Other
1 (0.042)
Ethnicity
-
Hispanic/Latino
1 (0.055)
Non-Hispanic/Non-Latino
2 (0 394)
Placebo
I (1000-py)
48 (0.434)
-
26 (0.223)
22 (0.211)
-
45 (0.367)
2 (0.026)
1 (0.042)
-
11 (0.051)
37 (0.382)
VE (95% CI)
n (1000-py)
Overall
3 (0.450)
Sex
94.0 (81.3, 98.8)
-
88.7 (63.0, 97.8)
100.0 (82.7. 100.0'
-
95.8 (83.8, 99.5)
100.0 (-479.7, 100.0)
1.4 (-7638.0, 98.7)
-
91.6 (42.3, 99.8)
94.8 (79.7, 99.4)
n=number of participants meeting the primary endpoint definition. py=person-vears of surveillance.
Source: Table 14.13 of Interim Clinical Study Report.
Reviewer Comment:
• The immunogenicity and efficacy data reported 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 BNT1622 recipients than among placebo recipients after either dose.
Injection site pain, fatigue, and headache were the most frequently reported solicited adverse reactions. The incidences of solicited local reactions were slightly higher after Dose 1 than after Dose 2, while the incidences of solicited systemic reactions were generally higher after Dose 2 with the exception of vomiting and diarrhea.
Among BNT162b2 recipients, the median onset day of solicited local reactions was Day 1 (i.e. day of vaccination) to Day 2 after either dose, with a median duration of 2 days.
The median onset day of solicited systemic reactions was Day 2 to Day 3 after either dose, with a median duration of 1 to 2 days.
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Table 8. Frequency of Solicited Reactions Within 7 Days of each Dose
BNT162b2
Placebo
Dose 1
Dose 1
N=1127
N=1127
n (%)
n (%)
Redness
-
-
Any (>2.0 cm)
65 (5.8)
12 (1.1)
Mild
44 (3.9)
11 (1.0)
Moderate
20 (1.8)
1 (0.1)
Severe
1 (0.1)
0 (0.0)
Swelling
Any (>2.0 cm)
78 (6.9)
11 (1.0)
Mild
55 (4.9)
9 (0.8)
Moderate
23 (2.0)
2 (0.2)
Severe
0 (0.0)
0 (0.0)
Pain at the injection site
-
-
Any
971 (86.2)
263 (23.3)
Mild
467 (41.4)
227 (20.1)
Moderate
493 (43.7)
36 (3.2)
Severe
11 (1.0)
0 (0.0)
Fever
-
>38.0°C
114 (10.1)
12 (1.1)
>38.0°C to 38.4°C
74 (6.6)
8 (0.7)
>38 4°C to 38 9°C
29 (2.6)
2 (0.2)
>38.9°C to 40.0°C
10 (0.9)
2 (0.2)
>40.0°C
1 (0.1)
0 (0.0)
Fatigue
Any
Mild
Moderate
Severe
Headache
Anv
Mild
Moderate
Severe
677(60.1)
278 (24.7)
384 (34.1)
15 (1.3)
-
623 (55.3)
361 (32.0)
251 (22.3)
11 (1.0)
457 (40.6)
250 (22.2)
199 (17.7)
8 (0.7)
396 (35.1)
256 (22.7)
131 (11.6)
9 (0.8)
Chills
Any
Mild
Moderate
Severe
Vomiting
Any
Mild
Moderate
Severe
Diarrhea
Anv
Mild
311 (27.6)
195 (17.3)
111 (9.8)
5 (0.4)
-
31 (2.8)
30 (2.7)
0 (0.0)
1 (0.1)
-
90 (8.0)
77 (6.8)
109 (9.7)
82 (7.3)
25 (2.2)
2 (0.2)
-
10 (0.9)
8 (0.7)
2 (0.2)
0 (0.0)
-
82 (7.3)
72 (6.4)
BNT162b2
Dose 2
N=1097 n (%)
-
55 (5.0)
29 (2.6)
26 (2.4)
0 (0.0)
54 (4.9)
36 (3.3)
18 (1.6)
0 (0.0)
-
866 (78.9)
466 (42.5)
393 (35.8)
7 (0.6)
-
215 (19.6)
107 (9 8)
83 (7.6)
25 (2.3)
0 (0.0)
-
726 (66.2)
232 (21.1)
468 (42.7)
26 (2.4)
-
708 (64.5)
302 (27.5)
384 (35.0)
22 (2.0)
455 (41.5)
221 (20 1)
214 (19.5)
20 (1.8)
-
29 (2.6)
25 (2.3)
4 (0.4)
0 (0 0)
-
65 (5.9)
59 (5.4)
Statistical Review
STN: 125742/45
Placebo
Dose 2
N=1078 n (%)
-
10 (0.9)
8 (0.7)
2 (0.2)
0 (0.0)
-
6 (0.6)
4 (0.4)
2 (0.2)
0 (0.0)
-
193 (17.9)
164 (15.2)
29 (2.7)
0 (0.0)
7 (0.6)
5 (0.5)
1 (0.1)
1 (0.1)
0 (0.0)
-
264 (24.5)
133 (12.3)
127 (11.8)
4 (0.4)
-
264 (24.5)
170 (15.8)
93 (8.6)
1 (0.1)
74 (6.9)
53 (4.9)
21 (1.9)
0 (0.0)
-
12 (1.1)
11 (1.0)
1 (0.1)
0 (0.0)
44(4.1)
39 (3.6)
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Statistical Review
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BNT162b2
Dose 1
N=1127 n (%)
Moderate
13 (1.2)
Severe
0 (0.0)
Placebo
Dose 1
N=1127 n (%)
10 (0.9)
0 (0.0)
BNT162b2
Dose 2
N=1097 n (%)
6 (0.5)
0 (0 0)
New or worsened muscle pain
-
-
Any
272 (24.1)
148 (13.1)
355 (32.4)
Mild
125 (11.1)
88 (7.8)
152 (13.9)
Moderate
145 (12.9)
60 (5.3)
197 (18.0)
Severe
2 (0.2)
0 (0.0)
6 (0.5)
New or worsened joint pain
-
-
-
Any
109 (9.7)
77 (6.8)
173 (15.8)
Mild
66 (5.9)
50 (4.4)
91 (8.3)
Moderate
42 (3.7)
27 (2.4)
78 (7.1)
Severe
1 (0.1)
0 (0.0)
4 (0.4)
Antipyretic use
413 (36.6)
111 (9.8)
557 (50 .8)
Placebo
Dose 2
N=1078 n (%)
5 (0.5)
0 (0.0)
-
90 (8.3)
51 (4.7)
37 (3.4)
2 (0.2)
-
51(4.7)
30 (2.8)
21 (1.9)
0 (0.0)
95 (8.8)
N=number of subjects responding yes or no for any reaction within 7 days of dosing. n=number of subiects with the specified reaction.
Source: Summarized by the reviewer based on response to March 14, 2022 information request.
Unsolicited Adverse Events
Tables 9 and 10 present the numbers and percentages 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 BNT1622 and placebo recipients from Dose 1 to 1 month after Dose 2, while a slightly higher percentage of placebo recipients reported any AE from Dose 1 to 6 months after Dose 2.
A higher percentage of BNT162b2 recipients reported any A considered by the investigator to be related to the study intervention in both risk windows. A total of 10
(0.9%) BNT16262 recipients and 2 (0.2%) placebo 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 approximately 4.4 months among all participants.
A total of 1,010 subjects who originally received placebo received at least 1 dose of BNT162b2 after unblinding prior to the September 2, 2021 cutoff. Among these subjects, 6 (0.6%) reported any SAE, of whom a 12 year-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 vaccination. The median duration of follow-up after unblinding was approximately 4 months among all unblinded participants.
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Statistical Review
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Table 9. Number of Subjects Reporting at Least 1 A by Time Period - Safety Population
BNT162b2
Placebo
BNT162b2
1 Month Post
1 Month Post
6 Months Post
Dose 2 or
Dose 2 or
Dose 2 or
Unblinding
Unblinding
Unblinding
N=1131
N=1129
N=1131
n (%)
n (%)
n (%)
Any AE
74 (6.5)
77 (6.8)
95 (8.4)
Related
36 (3.2)
24 (2.1)
36 (3.2)
Severe
7 (0.6)
2 (0.2)
13 (1.1)
Life-Threatening
1 (0.1)
1 (0.1)
2 (0.2)
Anv SAE
4 (0.4)
1 (0.1)
10 (0.9)
Related
O
O
0
Severe
2 (0.2)
O
7 (0.6)
Life-Threatening
0
1 (0.1)
1 (0.1)
Any nonserious AE
72 (6.4)
76 (6.7)
89 (7.9)
Related
36 (3.2)
24 (2.1)
36 (3.2)
Severe
5 (0.4)
2 (0.2)
6 (0.5)
Life-Threatening
1 (0.1)
O
1 (0.1)
Any AE leading to withdrawal
1 (0.1)
0
1 (0.1)
N=number of subjects who received at least I dose of the study intervention. n=number of subjects reporting at least I event.
Source: Adapted from Table P of 508 Tables and Table 18 of Interim Clinical Study Report.
Placebo
6 Months Post
Dose 2 or
Unblinding
N=1129 n (%)
113 (10.0)
24 (2.1)
5 (0.4)
1 (0.1)
2 (0.2)
O
1 (0.1)
1 (0.1)
111 (9.8)
24 (2.1)
4 (0.4)
0
O
Table 10. Number of Subjects Reporting at Least 1 A After Unblinding - Safety Population
BNT16262
Placebo - BNT162b2
Unblinding to Cutoff
Crossover to Cutoff
N=1107
N=1010
n (%)
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
Any SAE
4 (0.4)
Related
O
Severe
1 (0.1)
6 (0.6)
1 (0.1)
3 (0.3)
Life-Threatening
0
An nonserious AE
14 (1.3)
Related
4 (0.4)
Severe
2 (0.2)
Life-Threatening
0
Any AE leading to withdrawal
0
262 (25 9)
241 (23.9)
9 (0.9)
0
0
N=number of subjects who received at least I dose of the study intervention. n=number of subjects reporting at least I event.
Source: Tables 25 and 35 of Interim Clinical Study Report.
Reviewer Comments:
• The solicited and unsolicited AEs reported in the interim clinical study report were consistent with the SDTM data.
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Statistical Review
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Myocarditis and Pericarditis
No myocarditis or pericarditis was reported 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 BNT16262.
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 neutralizing 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 starting at 7 days post Dose 2 (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 observed severe COVID-19 precludes assessment of efficacy against severe disease in this population.
The frequency and severity of local and systemic reactions were generally higher among
BNT16262 recipients than among placebo recipients after either dose. The most commonly reported adverse reactions were injection site pain, fatigue, and headache.
There was no notable difference in the frequencies of any unsolicited A between arms during blinded follow-up, while a higher percentage of BNT162b2 recipients reported any 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 intervention. No participants died as of the cutoff. One SAE of myocarditis was reported in a 15-year-old male participant 2 days after receiving the second crossover vaccination dose of BNT16262. One SAE of appendicitis in a 12-year-old female participant was reported 3 days after the second crossover dose and was considered by the investigator to be related to the study vaccination.
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Statistical Review
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10.2 Conclusions and Recommendations
Overall, the clinical data support the effectiveness of BNT162b2. While there is some reactogenicity associated with BNT16262, the majority of solicited adverse reactions were mild or moderate in severity and of short duration. I defer to the clinical reviewer, Dr. Susan Wollersheim, on the overall safety conclusion for BNT162b2.
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