Statistical Review
STN: 125742/0
Application Type
BLA, Original Application
STN
125742/0
CBER Received Date
May 18, 2021
PDUFA Goal Date
January 16, 2022
Division/ Office
DVRPA/OVRR
Committee Chair
Ramachandra Naik
Clinical Reviewers)
Ann Schwartz; 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
Supervisory Concurrence
John Scott, Director, DB
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 16 years of age and older
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Table of Contents
Glossary....
3
1. Executive Summary..
2. Clinical and Regulatory Background
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...........
8
9
9
.. 15
8. Integrated Overview of Safety.......
........ 15
9. Additional Statistical Issues...........
........... 15
10. Conclusions..........
10.1 Statistical Issues and Collective Evidence..............
10.2 Conclusions and Recommendations..
............. 15
15
........... C
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GLOSSARY
ADaM
AE
BIMO
BLA
BNT16262
COVID-19
EUA
HIV
RT-PCR
SAE
SAP
SARS-CoV-2
SDTM
Analysis Data Model
Adverse Event
Bioresearch Monitoring
Biologics License Application
Pfizer-BioNTech COVID-19 Vaccine
Coronavirus Disease 2019
Emergency Use Authorization
Human Immunodeficiency Virus
Reverse Transcription-Polymerase Chain Reaction
Serious Adverse Event
Statistical Analysis Plan
Severe Acute Respiratory Syndrome Coronavirus 2
Study Data Tabulation model
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1. Executive Summary
Pfizer submitted a Biologics License Application (BLA 125742.0) on May 18, 2021 to seek licensure of the Pfizer-BioNTech COVID-19 Vaccine (BNT162b2) 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 BLA is supported by safety, efficacy, and immunogenicity data from two ongoing studies (C4591001 and BNT-162-01). This statistical review focuses on safety data from subjects aged 16 years and above in the Phase 2/3 part of Study C4591001 collected up to the March 13, 2021 data cut-off.
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. In the Phase 2/3 portion of the study, 44,165 subjects aged 16 and above were randomized 1:1 to receive two doses of BNT16262 or placebo 21 days apart.
Randomization was stratified by age group (younger adults 18 through 55 years of age and older adults >55 years of age; adolescents 16 to 17 were later added via a protocol amendment) with 40.6% of the final study population being older adults. Since December 14, 2020, following issuance of the EUA, participants 16 years of age and older were systematically unblinded when eligible per local recommendations and offered
BNT1622 vaccination if they had been randomized to placebo.
For all 44,047 randomized participants who received at least one dose of the study intervention, unsolicited adverse events (AEs) and serious AEs (SAEs) were collected from Dose 1 up to the March 13, 2021 data cut-off. A reactogenicity subset of approximately 4,900 participants per arm who received at least one dose of the study intervention recorded local reactions, systemic events, and antipyretic/pain medication usage from Day 1 through Day 7 after each dose.
No major statistical issues were identified for the safety data during review. A higher percentage of subjects in the BNT16262 group reported solicited local and systemic reactions than placebo recipients in both the younger (16 to 55 years) and older (>55 years) adult age groups after both doses. There was an imbalance in the frequencies of unsolicited AEs in the vaccine group, driven largely by increased reactogenicity. In addition, one report of pericarditis was identified in a 66-year-old male participant 28 days after receiving Dose 2 of BNT16262. There were no reports of myocarditis in the vaccine arm up to the data cut-off. There were no major imbalances in reported SAEs, AEs leading to withdrawal, or deaths between the treatment groups at one month and up to six months after the second dose or unblinding/data cut-off.
2. Clinical and Regulatory Background
The Pfizer-BioNTech COVID-19 Vaccine (BNT1622) was granted Fast Track
Designation for individuals ≥18 years of age on July 7, 2020, and was authorized under an Emergency Use Authorization (EUA) on December 11, 2020 for individuals ≥16 years of age. The EUA was amended to include individuals ≥12 years of age on May 10, 2021.
Pfizer submitted a BLA on May 18, 2021 to seek licensure of the vaccine for active
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immunization to prevent COVID-19 caused by SARS-CoV-2 in individuals 16 years of age and older.
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 Haecin Chun'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 safety data from subiects aged 16 years and above in the Phase 2/3 part of Study C4591001 collected up to the March 13, 2021 data cut-off.
5.2 BLA/IND Documents That Serve as the Basis for the Statistical Review
The following documents submitted to the BLA are reviewed:
125742/0 (submitted on 5/6/2021)
Module 2. Common Technical Document Summaries
• Clinical Overview
• Summary of Clinical Safety
Module 5. Clinical Study Reports
125742/0/1 (submitted on 5/18/2021)
Module 1. Administrative Information and Prescribing Information
125742/0/3 (submitted on 5/19/2021)
Module 1. Administrative Information and Prescribing Information
• Response to May 18, 2021 Information Request
125742/0/26 (submitted on 8/2/2021)
Module 1. Administrative Information and Prescribing Information
• Response to July 29, 2021 Information Request
125742/0/37 (submitted on 8/9/2021)
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Module 5. Clinical Study Reports
• C4591001 - 508 Safety Tables
5.3 Table of Studies/Clinical Trials
Data from two ongoing clinical studies were submitted to support the BLA for BNT162b2 and are summarized in Table 1 below. Study C4591001 is a multi-center, Phase 1/2/3, randomized, double-blinded, placebo-controlled safety, immunogenicity, and efficacy study and Study BNT162-01 is a Phase 1 safety and immunogenicity study evaluating various vaccine candidates and dose levels.
Table 1. Clinical Trials Supporting Licensure of the Pfizer-BioNTech COVID-19 Vaccine
Study Number/ Country
Description
BNT162b2 (30 Mg)
participants (N)
Placebo participants (N)
C4591001
Argentina, Brazil, Germany, S.
Africa, Turkey, U.S.A.
Phase 1/2/3 randomized, placebo-controlled, observer-blind; to evaluate safety, immunogenicity and efficacy of COVID-19 vaccine
Phase 1: 24 (U.S.A.)
Phase 2/3: 22085
Argentina: 2887
Brazil: 1452
Germany: 250
South Africa: 401
Turkey: 251
U.S.A: 16844
Phase 1: 24 (Germany)
Phase 1: 6 (U.S.A.)
Phase 2/3: 22080
Argentina: 2889
Brazil: 1448
Germany: 250
South Africa: 399
Turkey: 249
U.S.A.: 16845
0
BNT162-01
Germany
Phase 1/2 randomized, open-label: to evaluate safety and immunogenicity,
Source: Summarized by the reviewer based on information provided in Module 2. Clinical Overview.
6. DISCUSSION OF INDIVIDUAL STUDIES/CLINICAL TRIALS
Study
Status
Ongoing
Ongoing
6.1 Study C4591001
Title of Study: A Phase 1/2/3, Placebo-Controlled, Randomized, Observer-Blind, Dose-Finding Study to Evaluate the Safety, Tolerability, Immunogenicity, and Efficacy of SARS-COV-2 RNA Vaccine Candidates Against COVID-19 in Healthy Individuals
First Subject First Visit: April 29, 2020
Data Cut-off: Mach 13, 2021
6.1.1 Obiectives
Primary Safety Objective (Phase 2/3):
• To characterize the safety profile of prophylactic BNT16262 in all participants randomized in Phase 2/3
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. In the Phase 2/3 portion of the study, 43,998 subjects were planned
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to be randomized 1:1 to receive two doses of BNT162b2 or placebo 21 days apart.
Randomization was stratified by age group (younger adults 18 through 55 years of age, older adults >55 years of age) with a goal of 40% enrollment among older adults.
Eligibility was later expanded to include adolescents 16 to 17 years of age.
Efficacy was assessed throughout the study via surveillance for potential cases of
COVID-19. Participants who developed acute respiratory illness were tested for SARS-CoV-2 infection using reverse transcription-polymerase chain reaction (RT-PCR) in an illness visit. The study included planned interim analyses of the primary efficacy endpoint at 62, 92, and 120 cases, and a final analysis of all primary and secondary efficacy endpoints after at least 164 COVID-19 cases were accrued. Participants were to be followed for a maximum of 26 months. Efficacy assessments and results are covered in detail in Dr. Lei Huang's statistical review memo.
Since December 14, 2020 following issuance of the EUA, participants 16 years of age and older were systematically unblinded and, when eligible per local recommendations, offered BNT1622 vaccination no later than the 6-month timepoint after the second study vaccination if they had been randomized to placebo.
A subset of at least 6,000 participants (the reactogenicity subset, planned to be the first 6,000 or more patients randomized) were to record local reactions, systemic events, and antipyretic/pain medication usage from Day 1 through Day 7 after each dose. For all participants, unsolicited adverse events (AEs) and serious AEs (SAEs) were collected from Dose 1 up to the March 13, 2021 data cut-off.
6.1.3 Population
The Phase 2/3 study population consisted of participants 12 years of age and older at higher risk for acquiring COVID-19 (including, but not limited to, use of mass transportation, relevant demographics, and frontline essential workers).
6.1.4 Study Treatments or Agents Mandated by the Protocol
The study interventions were 30ug of BNT1622 and saline placebo.
6.1.6 Sites and Centers
A total of 153 sites across the United States (131), Turkey (9), Germany (6), South Africa, (4), Brazil (2) and Argentina (1) participated in the study.
6.1.7 Surveillance/Monitoring
Please refer to Drs. Susan Wollersheim and Ann Schwartz's clinical review memo.
6.1.8 Endpoints and Criteria for Study Success
The safety endpoints for all subiects include the occurrence of As and SAEs from Dose 1 up to one month post Dose 2 or unblinding (whichever is earlier), and from Dose 1 up to six months post Dose 2 or unblinding. For the reactogenicity subset, safety endpoints additionally include the occurrence of local reactions (redness, swelling, and injection
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site pain) and systemic reactions (fever, fatigue, headache, chills, vomiting, diarrhea, and muscle and joint pain) within seven days of each dose.
6.1.9 Statistical Considerations & Statistical Analysis Plan
Solicited safety analyses were based on subiects in the reactogenicity subset who received at least one dose of the study intervention and responded yes or no to any reaction within seven days of each dose. Unsolicited safety analyses were based the Safety Population, which consisted of all subjects randomized in the Phase 2/3 study who received at least one dose of study intervention, analyzed according to the intervention received. Safety endpoints were summarized descriptively by computing the number and percentage of participants within the analysis set who reported at least one event
6.1.10 Study Population and Disposition
6.1.10.1 Populations Enrolled/Analyzed
Table 2 shows the disposition of randomized subjects >16 years of age in the Phase 2/3 portion of the study. A total of 44,165 subjects were randomized. The percentages of subiects who received each dose were similar between the vaccine and placebo groups.
More subjects withdrew from the study in the placebo group than in the vaccine group.
Table 2. Subiect Disposition
BNT162b2
Placebo
Total
N=22085
N=22080
N=44165
n (%)
n (%)
n (%)
Randomized
Not vaccinated
Vaccinated
Dose 1
Dose 2
Withdrawn from the study
Lost to follow-up
Withdrawal by subiect
Protocol deviation
Death
Adverse event
Physician decision
No longer meets eligibility criteria
Pregnancy
Medication error without AE
Withdrawal by parent/guardian
Other
22085 (100.0) 22080 (100.0) 44165 (100.0)
55 (0 2)
50 (0 2)
105 (0 2)
22030 (99.8)
22030 (99.8)
44060 (99.8)
22030 (99.8)
22030 (99.8)
44060 (99.8)
21675 (98.1)
21650 (98.1)
43325 (98.1)
343 (1.6)
484 (2.2)
827 (1.9)
174 (0.8)
191 (0 9)
365 (0 8)
122 (0.6)
226 (1.0)
348 (0.8)
11(<0.1)
24 (0.1)
35 (0.1)
16 (0.1)
15 (0.1)
31 (0.1)
9 (<0.1)
8 (<0.1)
17(<0.1)
3 (<0.1)
6 (<0.1)
9 (<0.1)
1 (<0 1)
4 (<0.1)
5 (<0.11
0
1 (<0.1)
1 (<0.1)
1 (<0.1)
1<0.1)
1 (<0.1)
1 (<0.1)
5 (<0.1)
9 (<0.1)
14(<0.1)
Source: Adapted from Table 31 of Summary of Clinical Safetv.
6.1.10.1.1 Demographics
Table 3 presents demographic characteristics for the Safety Population. Demographic characteristics were generally similar with regard to age, gender, race, and ethnicity
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among participants who received BNT162b2 and those who received placebo. Overall, among all the participants who received either BNT162b2 or placebo, 50.9% were male and 49.1% were female, 82.0% were White, 9.6% were Black or African American, 4.3% were Asian, and 1.0% were American Indian or Alaska Native.
Table 3. Demographics Characteristics of the Safety Population
BNT162b2
N=22026 n (%)
Placebo
N=22021 n (%)
Total
N=44047 n (%)
Sex
Male
Female
Race
White
Black/African-American
American Indian/Alaskan Native
Asian
Native Hawaiian/Other Pacific Islander
Multiracial
Not Reported
Ethnicity
Hispanic/Latino
Non-Hispanic/Non-Latino
Not Reported
Country
Argentina
Brazil
Germany
South Africa
Turkey
USA
Age Group
16-55 Years
>55 Years
Age
Mean (Standard Deviation)
Median
Minimum. Maximum
Source: Table 4 of Summary of Clinical Safetv.
11322 (51.4)
11098 (50.4)
22420 (50.9)
10704 (48.6)
10923 (49.6)
21627 (49.1'
18056 (82.0)
18064 (82.0)
36120 (82.0)
2098 (9.5)
2118 (9.6)
4216 (9.6)
221 (1.0)
217 (1.0)
438 (1.0)
952 (4.3)
942 (4.3)
1894 (4.3)
58 (0.3)
32 (0.1)
90 (0.2)
550 (2.5)
533 (2.4)
1083 (2.5)
91 (0.4)
115 (0.5)
206 (0.5)
5704 (25.9)
5695 (25.9)
11399 (25.9)
16211 (73.6) 16212 (73.6)
32423 (73.6)
111 (0.5)
114 (0.5)
225 (0.5)
2883 (13.1)
2881 (13.1)
1452 (6.6)
1448 (6.6)
249 (1.1)
250 (1.1)
401 (1.8)
399 (1.8)
249 (1.1)
249 (1_1)
16792 (76.2)
16794 (76.3)
5764 (13.1)
2900 (6.6)
499 (1.1)
800 (1.8)
498 (1.1)
33586 (76.3)
13069 (59.3)
8957 (40.7)
13095 (59.5)
8926 (40.5)
26164 (59.4)
17883 (40.6)
49.7 (16.0)
51.0
(16, 89)
49.6 (16.1)
51.0
(16, 91)
49.7 (16.0)
51.0
(16, 91)
6.1.11 Efficacy Analyses
Please refer to Dr. Lei Huang's statistical review memo.
6.1.12 Safety Analyses
Solicited Local and Systemic Reactions
Tables 4 and 5 present the frequency by severity of each solicited local and systemic reaction within seven days of each dose for the 16-to-55 and 56-and-above vear-old age
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groups, respectively. In general, incidence of any redness, swelling, injection site pain, fever, fatigue, headache, chills, new or worse muscle pain, and new or worse joint pain was higher among vaccine recipients than among placebo recipients. There were no notable differences between vaccine and placebo recipients or between vaccine Dose 1 and Dose 2 for vomiting or diarrhea.
For both age groups, injection site pain was the most frequent solicited local adverse reaction. After Dose 2, the younger age group reported any pain more frequently than the older age group (78.3% vs 66.1%). A similar pattern was observed after Dose 1.
Frequencies of any injection site redness and swelling were generally similar after each dose and for both age groups.
Among BNT16262 recipients 16 to 55 years of age, the mean duration (not shown in tables) of pain at the injection site after Dose 2 was 2.5 days (range 1 to 70 days), 2.2 days for redness (range 1 to 9 days), and 2.1 days for swelling (range 1 to 8 days).
Among BNT16262 recipients 56 years of age and older the mean duration of pain at the injection site after Dose 2 was 2.4 days (range 1 to 36 days), 3.0 days for redness (range 1 to 34 days), and 2.6 days for swelling (range 1 to 34 days).
The frequency and severity of systemic AEs were generally higher in the younger age group. Within each age group, the frequency and severity of systemic AEs were higher after Dose 2 than Dose 1, except for vomiting and diarrhea, which were generally similar regardless of dose. For both age groups, fatigue, headache and new/worsened muscle pain were the most common reactions after Dose 2.
Table 4. Frequency of Solicited Reactions Within Seven Days of each Dose (16 to 55 Years)
BNT162b2
Placebo
BNT162b2
Dose 1
Dose 1
Dose 2
N=2899
N=2908
N=2682
n (%)
n (%)
n (%)
Placebo
Dose 2
N=2684 n (%)
Redness
Any (>2.0 cm)
Mild
Moderate
Severe
Swelling
Anv (>2.0 cm)
Mild
Moderate
Severe
Pain at the iniection site
Anv
Mild
Moderate
Severe
156 (5.4)
113 (3.9)
36 (1.2)
7 (0.2)
-
184 (6.3)
124(4.3)
54(1.9)
6 (0.2)
28 (1.0)
19 (0.7)
6 (0.2)
3 (0.1)
-
16 (0.6)
6 (0.2)
8 (0.3)
2 (0.1)
Fever
>38.0°C
>38 0°C to 38 4°C
2426 (83.7)
1464 (50.5)
923 (31.8)
39 (1.3)
-
119 (4.1)
86 (3.0)
414(14.2)
391 (13.4)
20 (0.7)
3 (0.1)
-
25 (0.9)
16 (0.6)
151 (5.6)
90 (3.4)
50 (1.9)
11 (0 4)
-
183 (6.8)
110 (4.1)
66 (2.5)
7 (0.3)
-
2101 (78.3)
1274 (47.5)
788 (29.4)
39 (1.5)
-
440 (16.4)
254 (9.5)
18 (0.7)
12 (0.4)
6 (0.2)
0
5 (0.2)
3 (0.1)
2 (0.1)
312 (11.6)
284 (10.6)
28 (1.0)
0
11 (0.4)
5 (0.2)
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>38.4°C to 38.9°C
>38 9°C to 40 0°C
>40 0°C
BNT162b2
Dose 1
N=2899 n (%)
25 (0.9)
8 (0.3)
0
Placebo
Dose 1
N=2908 n (%)
5 (0.2)
4 (0.1)
Fatigue
Any
Mild
Moderate
Severe
BNT162b2
Dose 2
N=2682 n (%)
146 (5.4)
39 (1.5)
1 (0.0)
-
1649 (61.5)
558 (20.8)
949 (35.4)
142 (5.3)
Headache
Anv
Mild
Moderate
Severe
1431 (49.4)
760 (26.2)
630 (21.7)
41(1.4)
-
1262 (43.5)
785 (27.1)
444(15.3)
33(1.1)
960 (33.0)
570 (19.6)
372 (12.8)
18 (0.6)
-
975 (33.5)
633 (21.8)
318 (10.9)
24 (0.8)
1448 (54.0)
699 (26.1)
658 (24.5)
91 (3.4)
Chills
Any
Mild
Moderate
Severe
479 (16.5)
338 (11.7)
126 (4.3)
15 (0.5)
Vomiting
Any
Mild
Moderate
34 (1.2)
29 (1.0)
5 (0.2)
Severe
199 (6.8)
148 (5.1)
49 (1.7)
2 (0.1)
-
36 (1.2)
30 (1.0)
5 (0.2)
1 (0.0)
Placebo
Dose 2
N=2684 n (%)
4 (0.1)
2 (0.1)
0
-
614 (22.9)
317 (11.8)
283 (10.5)
14 (0.5)
-
652 (24.3)
404 (15.1)
230 (8.6)
18 (0.7)
-
114 (4.2)
89 (3 3)
23 (0.9)
2 (0.1)
-
30 (1.1)
20 (0.7)
10 (0.4)
0
Diarrhea
Any
Mild
Moderate
Severe
New or worsened muscle vain
Anv
Mild
Moderate
Severe
309 (10.7)
251 (8.7)
55 (1.9)
3 (0.1)
-
664 (22.9)
353 (12.2)
296 (10.2)
15 (0.5)
323 (11.1)
264 (9.1)
58 (2.0)
1 (0.0)
-
329 (11.3)
231 (7.9)
96 (3.3)
2 (0.1)
1015 (37.8)
477 (17 8)
469 (17.5)
69 (2.6)
-
58 (2.2)
42 (1 6)
12 (0.4)
4 (0.1)
-
269 (10.0)
219 (8.2)
44 (1.6)
6 (0.2)
-
1055 (39.3)
441 (16.4)
552 (20.6)
62 (2.3)
205 (7.6)
169 (6.3)
35 (1.3)
1 (0.0)
-
237 (8.8)
150 (5.6)
84 (3.1)
3 (0.1)
New or worsened joint pain
Anv
Mild
Moderate
Severe
342 (11.8)
200 (6.9)
137 (4.7)
5 (0.2)
168 (5.8)
112 (3.9)
55 (1.9)
1 (0.0)
638 (23.8)
291 (10 9)
320 (11.9)
27 (1.0)
147 (5.5)
82 (3.1)
61 (2.3)
4 (0.1)
Use of antipvretic or pain medication
805 (27.8)
398 (13.7)
1213 (45.2)
320 (11.9)
N=number of subjects responding yes or no for any reaction within seven days of dosing. n=number of subiects with the specified reaction.
Source: Adapted from Table 14.68 of C4591001 Interim Clinical Study Report.
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Table 5. Frequency of Solicited Reactions Within Seven Days of each Dose (>55 Years)
BNT162b2
Placebo
BNT162b2
Placebo
Dose 1
Dose 1
Dose 2
Dose 2
N=2008
N=1989
N=1860
N=1833
n (%)
n (%)
n (%)
n (%)
Redness
-
-
-
-
Any (>2.0 cm)
106 (5.3)
20 (1.0)
133 (7.2)
14 (0.8)
Mild
71 (3.5)
13 (0.7)
65 (3.5)
10 (0.5)
Moderate
30 (1.5)
5 (0.3)
58 (3.1)
3 (0.2)
Severe
5 (0.2)
2 (0.1)
10 (0.5)
1 (0.1)
Swelling
-
-
-
Any (>2.0 cm)
141 (7.0)
23 (1.2)
145 (7.8)
13 (0.7)
Mild
87 (4.3)
11 (0.6)
80 (4.3)
5 (0.3)
Moderate
52 (2.6)
12 (0.6)
61 (3.3)
7 (0.4)
Severe
2 (0.1)
0
4 (0.2)
1 (0.1)
Pain at the injection site
-
-
-
Any
1408 (70.1)
185 (9.3)
1230 (66.1)
143 (7.8)
Mild
1108 (55.2)
177 (8.9)
873 (46.9)
138 (7.5)
Moderate
296 (14.7)
8 (0.4)
347 (18.7)
5 (0.3)
Severe
4 (0.2)
10 (0.5)
O
Fever
>38.0°C
26 (1.3)
8 (0.4)
219 (11.8)
4 (0.2)
>38.0°C to 38.4°C
23 (1.1)
3 (0.2)
158 (8.5)
2 (0.1)
>38.4°C to 38.9°C
2 (0.1)
3 (0.2)
54 (2.9)
1 (0.1)
>38.9°C to 40.0°C
1 (0.0)
2 (0.1)
7 (0.4)
1 (0.1)
>40.0°C
0
0
Fatigue
Any
Mild
Moderate
Severe
677 (33.7)
415 (20.7)
259 (12.9)
3 (0.1)
Grade 4
Headache
Anv
Mild
Moderate
Severe
-
503 (25.0)
381 (19.0)
120 (6.0)
2 (0.1)
447 (22.5)
281 (14.1)
163 (8.2)
3 (0.2)
-
363 (18.3)
267 (13.4)
93 (4.7)
3 (0.2)
Chills
Anv
Mild
Moderate
Severe
Vomiting
Any
Mild
Moderate
130 (6.5)
102 (5.1)
28 (1.4)
0
-
10 (0.5)
9 (0.4)
1 (0.0)
69 (3.5)
49 (2.5)
19 (1.0)
1 (0.1)
9 (0.5)
9 (0.5)
0
Severe
-
949 (51.0)
391 (21.0)
497 (26.7)
60 (3.2)
1 (0.1)
-
733 (39.4)
464 (24.9)
256 (13.8)
13 (0 7\
-
435 (23 4)
229 (12.3)
185 (9.9)
21 (1.1)
-
13 (0.7)
10 (0.5)
1 (0.1)
2 (0.1)
306 (16.7)
183 (10.0)
121 (6.6)
2 (0.1)
259 (14.1)
189 (10.3)
65 (3.5)
5 (0.3)
57 (3.1)
45 (2.5)
12 (0.7)
0
5 (0.3)
5 (0.3)
0
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Statistical Review
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Diarrhea
Anv
Mild
Moderate
Severe
BNT162b2
Dose 1
N=2008 n (%)
-
168 (8.4)
137 (6.8)
27 (1.3)
4 (0.2)
Placebo
Dose 1
N=1989 n (%)
BNT162b2
Dose 2
N=1860 n (%)
Placebo
Dose 2
N=1833 n (%)
130 (6 5)
109 (5.5)
20 (1.0)
1 (0.1)
152 (8.2)
125 (6.7)
25 (1.3)
2 (0.1)
102 (5.6)
76 (4.1)
22 (1.2)
4 (0.2)
New or worsened muscle pain
Any
Mild
Moderate
Severe
New or worsened joint pain
Anv
Mild
Moderate
Severe
274 (13.6)
183 (9.1)
90 (4.5)
1 (0.0)
-
175 (8.7)
119 (5.9)
53 (2.6)
3 (0.1)
165 (8.3)
111 (5.6)
51 (2.6)
3 (0.2)
124 (6.2)
78 (3.9)
45 (2.3)
1 (0.1)
537 (28.9)
229 (12.3)
288 (15.5)
20 (1.1)
-
353 (19.0)
183 (9.8)
161 (8.7)
9 (0.5)
99 (5.4)
65 (3.5)
33 (1.8)
1 (0.1)
-
72 (3.9)
44 (2.4)
27 (1.5)
1 (0.1)
Use of antipyretic or pain medication
382 (19.0)
224 (11.3)
688 (37.0)
170 (9 3)
N=number of subjects responding yes or no for any reaction within seven days of dosing. n=number of subjects with the specified reaction.
Source: Adapted from Table 14.68 of C4591001 Interim Clinical Study Report.
Reviewer Comment:
• Three placebo recipients 16 to 55 years of age who reported fever of >42°C within seven days of the first or second dose were excluded from the analysis. As the subjects received placebo and these measurements were likely due to error, this is unlikely to affect safety conclusions.
Unsolicited Safety
Table 6 presents the numbers and percentages of subjects ≥16 years of age who reported any unsolicited AE, SAE, AE leading to withdrawal, or death after the first dose. These numbers are reported for three separate risk windows: a) Dose 1 to one month post Dose 2 or unblinding (whichever is first), b) Dose 1 to six months post Dose 2 or unblinding (whichever is first), and c (for placebo patients who received crossover vaccination) from crossover to March 13, 2021. The percentages of subjects reporting any SAE, AE leading to withdrawal, or death were generally similar between the vaccine and placebo groups from Dose 1 to one month after Dose 2 and from Dose 1 to six months after Dose 2 regardless of severity. A higher percentage of vaccine recipients reported any unsolicited AE after Dose 1 than placebo recipients. Four vaccine recipients reported SAEs up to six months post Dose 2 that were considered by the investigator to be related to the study intervention. In these analyses, 58.2% of study participants had at least four months of blinded follow-up after Dose 2.
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Statistical Review
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A total of 19,525 subiects originally randomized to placebo received at least one dose of
BNT1622 after unblinding (Dose 3 and Dose 4) and before the March 13, 2021 data cutoff. Among these subjects, one (<0.1%) subject reported an SAE of anaphylactoid reaction after Dose 3 that was considered by the investigator to be related to the study intervention. Two subjects (<0.1%) died after receiving Dose 3, but neither were considered by the investigator to be related to the intervention.
Table 6. Number of Subjects ≥16 Years of Age Reporting at Least One AE by Time Period
BNT162b2
Placebo
BNT16262
1MPD2a
1MPD2a
6MPD2®
N=21926
N=21921
N=21926
n (%)
n (%)
n (%)
Anv AE
6617 (30.2)
3048 (13.9)
6947 (31.7)
Related
5241 (23.9)
1311 (6.0)
5246 (23.9)
Severe
262 (1.2)
150 (0.7)
356 (1.6)
Life-Threatening
21 (0.1)
26 (0.1)
48 (0.2)
Any SAE
127 (0.6)
116 (0.5)
268 (1.2)
Related
3 (<0.1)
4 (<0 1)
Severe
71 (0.3)
66 (0 3)
148(0.7)
Life-Threatening
21 (0.1)
26 (0.1)
48 (0.2)
Any AE leading to withdrawal
32 (0.1)
36 (0.2)
45 (0.2)
Related
13 (0.1)
11 (0.1)
13 (0.1)
Severe
10 (<0.1)
10 (<0.1)
10 (<0.1)
Life-Threatening
3 (<0.1)
7 (<0.1)
15 (0.1)
Death
3 (<0 1)
5 (<0.1)
15 (0.1)
N=number of subjects who received at least one dose of the study intervention. n=number of subjects reporting at least one event.
"Includes all events from Dose I up to the earlier of one month post Dose 2 or unblinding.
Includes all events from Dose I up to the earlier of six months post Dose 2 or unblinding.
Includes all events from crossover vaccination (Dose 3) to March 13, 2021.
Includes all subiects randomized to placebo who received BNT1622 after unblinding.
Source: Adapted from Tables 5, 7, and 14 of Summary of Clinical Safety.
Placebo
BNT162b2
6MPD2b
PD3C
N=21921
N=19525d
n (%)
_n (%)
3568 (16.3) 4885 (25.0)
1313 (6.0)
4508 (23.1)
256 (1.2)
142 (0.7)
54 (0.2)
11 (0.1)
268 (1.2)
65 (0.3)
1 (<0 1)
1 (<0.1)
156 (0.7)
37 (0.2)
54 (0.2)
11 (0.1)
51 (0.2)
19(0.1)
12 (0.1)
12 (0.1)
12 (0.1)
2 (<0.1)
16 (0.1)
4 (<0.1)
14 (0.1)
2 (<0.1)
Reviewer Comments:
• The solicited and unsolicited AEs reported in the clinical study report were consistent with the Study Data Tabulation Model (SDTM) data.
• The solicited and unsolicited AE analyses presented do not include the 200
Human Immunodeficiency Virus (HIV)-positive participants. Similar safety results were observed in HIV-positive subjects.
• The imbalance in the frequencies of unsolicited AEs is driven largely by increased reactogenicity in the vaccine arm, in that many events associated with reactogenicity (e.g. injection site pain, fatigue, etc.) occurring within days of vaccination were reported as unsolicited AEs.
• Two subjects who received BNT162b2 and experienced an AE or SAE were not reported in the blinded follow-up safety analysis:
1. One subject (C4591001 (b) (6)
) received two doses of BNTI62b2
and reported an SAE of acute hepatic failure on Day 100 that was not considered by the investigator to be related to the study intervention. The
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Statistical Review
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subject was unblinded and withdrew from the study on the same day that the SAE was reported. As the safety analyses included only events up to the day before unblinding (regardless of the reason for unblinding), this event was not considered to have occurred during blinded follow-up.
2. One subject (C4591001 (b) (6)
) received one dose of BNT162b2
and reported a case of tinnitus with unknown start and end dates.
I defer to the clinical reviewer regarding the interpretation of these events.
• The applicant stated that 58.2% of subjects in the unsolicited safety analysis completed at least four months of follow-up post Dose 2. Of note, it appears that the applicant considered a month to be equivalent to 28 days. The median follow-up from Dose 2 to six months post Dose 2 or unblinding among ≥16-year-old participants in the Safety Population was approximately 120 days.
Ten subjects (six vaccine and four placebo) who received at least one dose of the study intervention were excluded from the Safety Set due to "lack of PI [Principal Investigator] oversight," which was not documented in the Statistical Analvsis
Plan. Among the six vaccine recipients, one non-serious AE of "excessive cerumen production" was reported that was not considered by the investigator to be related to the study intervention, and no SAEs were reported.
Myocarditis and Pericarditis
One report of pericarditis was identified in a 66-year-old male participant 28 days after receiving Dose 2 of BNT1622. One report of myocarditis was identified in a 25-year-old male participant in the placebo group five days after the second placebo dose.
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 were identified for the safety data during review. A higher percentage of subiects in the BNT16262 group reported solicited local and systemic reactions than placebo recipients in both the younger (16 to 55 years) and older (>55 years) adult age groups after each dose. There were no major imbalances in reported SAEs, AEs leading to withdrawal, or deaths between the treatment groups at one month and up to six months after the second dose or unblinding/data cut-off.
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Statistical Review
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10.2 Conclusions and Recommendations
There is evidence of reactogenicity associated with BNT162b2; the overwhelming majority of events were of mild or moderate severity and short duration. There was no evidence of increased risk of unsolicited SAE or death associated with BNT162b2 in Study C4591001. I defer to Drs. Susan Wollersheim and Ann Schwartz's clinical review memo on the overall safety conclusion for BNT16262.
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