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BNT162b2
BLASTN 125742/0
M 1.11.3 Response to FDA Information Request
PFIZER CONFIDENTIAL
Page 1BNT162b2 (COMIRNATY)
BLA STN 125742/0
Response to 27 July 2021 CBER Information Request Regarding
Assessment of Vaccine Effectiveness
30July 2021
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FDA-CBER-2021-5683-0950154
FDA-CBER-2021-5683-0950155
BNT162b2
BLASTN 125742/0
M 1.11.3 Response to FDA Information Request
PFIZER CONFIDENTIAL
Page 3LIST OF ABBREVIATIONS
Abbreviation Term
BLA Biologics License Application
CBER Center for Biologics Evaluation and Research
CI confidence interval
COVID-19 coronavirus disease 2019
FDA United StatesFood and Drug Administration
IR Information Request
SARS-CoV-2 severe acute respiratory syndrome coronavirus 2
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BLASTN 125742/0
M 1.11.3 Response to FDA Information Request
PFIZER CONFIDENTIAL
Page 41.INTRODUCTION
Reference is made to BLA STN 125742/0 for the Pfizer-BioNTech COVID -19 Vaccine for
active immunization to prevent COVID -19 caused by SARS-CoV-2 in individuals ≥16 y ears
of age.
The purpose of this document is to respond to CBER’s Information R equest (IR)
communicated from Captain Michael Smith,PhD (CBER) to Elisa Harkins Tull (Pfizer Inc.)
via email on 27July2021, requesting information regarding the assessment of vaccine
effectiveness.
CBER’s comments/requests in bold italics are followed b y the Sponsor’s responses below.
2.CBER REQUEST S
2.1. CBER Request1
1. Regarding the cumulative incidence rates, please calculate vaccine effectiveness with
confidence intervals during the two intervals of interest separately from days 35 -91 (i.e., 8
weeks of observation after dose 2) and from days 91 -224 (more prolonged foll ow up post
vaccination series).
Response
Additional feedback from CBER clarified that the two interval periods were 35 -90 and 91 -
224 days. The requested vaccine effectiveness data for days 35-90and days 91- 224 is
included below in Table1.
Subjects enrolled in the study were to receive two doses of BNT162b2 or placebo
approximately
21 days apart. The timing of
second vaccination varied across subjects , and
some subjects did not receiv e the second dose. Therefore, using days relative to Dose 1 to
approximate time after Dose 2 is not as precise as using days relative to Dose 2, a s
presented in Table 18 of the Interim Clinical Study Report Body for Study C4591001 (the
table is also included below as
Table 2).
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BLASTN 125742/0
M 1.11.3 Response to FDA Information Request
PFIZER CONFIDENTIAL
Page 5Table1. Vaccine Efficacy –First COVID -19 Occurrence After Dose 1 and Within
Specific Time Interval –Blinded Placebo -Controlled Follow -up Period –
Dose 1 All -Available Efficacy Population
Vaccine Group (as Rando mized)
BNT162b2 (30 μg)
(Na=23040)Placebo
(Na=23037)
Efficacy Endpoint
Subgroup n1bSurveillance
Timec(n2d)n1bSurveillance
Timec(n2d)VE (%) (95% CIe)
First COVID -19 occurrence after
Dose 11318.412 (22505) 10348.124 (22434) 87.8 (85.3,
89.9)
Day 35 to Day 90 253.305 (22290) 3923.249 (22117) 93.7 (90.6,
96.0)
Day 91 to Day 224 593.023 (19854) 4672.798 (19268) 88.3 (84.6,
91.2)
Abbreviation: VE = vaccine efficacy.
a. N = number of subjects in the specified group.
b. n1 = Number of subjects meeting the endpoint definition.
c. Total surveillance time in 1000 person -years for the given endpoint across all subjects within each group
at risk for the endpoint . Time period for COVID -19 case accrual is from Dose 1 to the end of the surveillance
period for the overall row and from start to the end of the range stated for each time interval.
d. n2 = Number of subjects at risk for the endpoint.
e. Confidenc e interval (CI) for VE is derived based on the Clopper and Pearson method adjusted for
surveillance time.
PFIZER CONFIDENTIAL SDTM Creation: 25MAR2021 (19:19) Source Data: adc19ef Table Generation:
29JUL2021 (16:56)
(Cutoff Date: 13MAR2021, Snapshot Date: 25MAR2021) Output File:
./nda2_unblinded/C4591001_BLA_RR/adc19ef_ve_cov_cber_pd1_aai
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M 1.11.3 Response to FDA Information Request
PFIZER CONFIDENTIAL
Page 62.2.CBER Request 2
2. We also request assessment of vaccine effectiveness during a time period that is entirely
further out from vaccination (e.g., starting at 4 months post -dose 2). We acknowledge
though that at some point unblinding and placebo cross -over started, and there m ay have
been differential loss between the two groups from blinded follow -up that could introduce
bias and/or confound the analyses.
Response
As communicated via email by Elisa Harkins Tull on 27 July 2021, the requested information
isincluded in Table 18 of the Interim Clinical Study Report Body for Study C4591001 in
Module 5.3.5.1 submitted to BLA 1257 42, which provides efficacy data from a placebo
controlled, randomized, blinded trial, not real world effectiveness data. This table is also
included belo w asTable 2.
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M 1.11.3 Response to FDA Information Request
PFIZER CONFIDENTIAL
Page 7Table 2.Vaccine Efficacy – First COVID -19 Occurrence After Dose 1 –Blinded
Placebo-Controlled Follow -up Period –Dose 1 All-Available Efficacy
Population
Vaccine Group (as Rando mized)
BNT162b2 (30 μg)
(Na=23040)Placebo
(Na=23037)
Efficacy Endpoint
Subgroup n1bSurveillance
Timec(n2d)n1bSurveillance
Timec(n2d)VE
(%)(95% CIe)
First COVID -19 occurrence after
Dose 11318.412 (22505) 10348.124 (22434) 87.8(85.3, 89.9)
After Dose 1 to before Dose 2 461.339 (22505) 1101.331 (22434) 58.4(40.8, 71.2)
After Dose 1 to <11 days after
Dose 1410.677 (22505) 500.675 (22434) 18.2(-26.1, 47.3)
≥11 Days after Dose 1 to before
Dose 250.662 (22399) 600.656 (22369) 91.7(79.6, 97.4)
Dose 2 to 7 days after Dose 2 30.424 (22163) 350.422 (22057) 91.5(72.9, 98.3)
≥7 Days after Dose 2 826.649 (22132) 8896.371 (22001) 91.2(88.9, 93.0)
≥7 days after Dose 2 to <2
Months after Dose 2122.923 (22132) 3122.884 (22001) 96.2(93.3, 98.1)
≥2 Months after Dose 2 to <4
Months after Dose 2462.696 (20814) 4492.593 (20344) 90.1(86.6, 92.9)
≥4 Months after Dose 2 241.030 (12670) 1280.895 (11802) 83.7(74.7, 89.9)
Abbreviation: VE = vaccine efficacy.
a. N = number of subjects in the specified group.
b. n1 = Number of subjects meeting the endpoint definition.
c. Total surveillance time in 1000 person -years for the given endpoint across all subjects w ithin each group
at risk for the endpoint. Time period for COVID -19 case accrual is from Dose 1 to the end of the surveillance
period.
d. n2 = Number of subjects at risk for the endpoint.
e. Confidence interval (CI) for VE is derived based on the Clopper and Pearson method adjusted for
surveillance time.
PFIZER CONFIDENTIAL SDTM Creation: 25MAR2021 (19:19) Source Data: adc19ef Table Generation:
19APR2021 (17:34)
(Cutoff Date: 13MAR2021, Snapsh ot Date: 25MAR2021) Output File:
./nda2_unblinded/C4591001_BLA/adc19ef_ve_cov_pd1_aai
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BLASTN 125742/0
M 1.11.3 Response to FDA Information Request
PFIZER CONFIDENTIAL
Page 82.3.CBER Request 3
3. Sorry, but the below question was inadvertently omitted from the earlier IR.
Additionally, the review team has requested a response to this question by Friday, July 30,
2021.
Please calculate the cumulative incidence rates of vaccine and placebo arms at Day 57 and
Day 224 and estimate the Risk Difference and Risk Ratio with their 95% CI.
Response
The incidence rates, Risk Ratio, and Risk Difference of the vaccine and placebo arms at Day
57 and Day 224 are provided below in Table 3and Table 4.
Also included in this response is Table 18 of the Interim Clinical Study Report Body ,
included above ( Table 2). As shown in Table 2, during the period of ‘after Dose 1 to <11
days after Dose 1’, the observed vaccine efficacy is very low (18.2%),as the most of the
vaccine effect has not been achieved. Therefore, the cumulative incidence after Dose 1 to
Day 57 and Day 224 requested (as shown in Table 3and Table 4) is a combination of periods
before and after meaningful vaccine effectiveness is observed and should be interpreted with
caution.
In particular, estimates of vaccine efficacy corresponding to the risk ratios in Table 3are
82.7% for Day 1 to Day 57 and 87.8% for Day 1 to Day 224. The apparent increase in
vaccine efficacy over the much longer time interval compared to the earlytimeinterval is an
artifact of the inclusion of the first 10 day s (where there is minimal efficacy)in these
calculations, as 10 days represents 17.5% of the interval from Day 1 to Day 57, but only
4.5% of the interval from Day 1 to Day 224.
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BLASTN 125742/0
M 1.11.3 Response to FDA Information Request
PFIZER CONFIDENTIAL
Page 9Table 3. Incidence Rates and Risk Ratio of First COVID -19 Occurrence After Dose
1–Blinded Placebo -Controlled Follow -up Period – Dose 1 All -Available
Efficacy Population
Vaccine Group (as Rando mized)
BNT162b2 (30 μg)
(Na=23040)Placebo
(Na=23037) Risk Ratio
Efficacy
Endpoint
Subgroup n1bSurveillance
Timec(n2d)IR (/1000
PY)en1bSurveillance
Timec(n2d)IR (/1000
PY)eIRR
(/1000
PY)f(95% CIg)
First COVID -19
occurrence after
Dose 11318.412
(22505)15.573 1034 8.124
(22434)127.279 0.122(0.101, 0.147)
After Dose 1 to
Day 57553.482
(22505)15.796 3153.459
(22434)91.073 0.173(0.128, 0.232)
After Dose 1 to
Day 2241318.412
(22505)15.573 1034 8.124
(22434)127.280 0.122(0.101, 0.147)
a. N = number of subjects in the specified group.
b. n1 = Number of subjects meeting the endpoint definition.
c. Total surveillance time in 1000 person -years for the given endpoint across all subjects w ithin each group
at risk for the endpoint. Time per iod for COVID- 19 case accrual is from Dose 1 to the end of the surveillance
period for the overall row and from start to the end of the range stated for each time interval.
d. n2 = Number of subjects at risk for the endpoint.
e. Incidence rate (IR) is calculated as number of subjects meeting the endpoint definition/total surveillance
time across all subjects at risk for the endpoint within the specific group.
f. Ratio of incidence rates (BNT162b2 [30 μg]/placebo).
g. 2-sided CI for the incid ence rate difference based on the Clopper and Pearson method adjusted for
surveillance time.
PFIZER CONFIDENTIAL SDTM Creation: 25MAR2021 (19:19) Source Data: adc19ef Table Generation:
28JUL2021 (15:13)
(Cutoff Date: 13MAR2021, Snapshot Date: 25MAR2021) Ou tput File:
./nda2_unblinded/C4591001_BLA_RR/adc19ef_ve_cov_irr_pd1_aai
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BLASTN 125742/0
M 1.11.3 Response to FDA Information Request
PFIZER CONFIDENTIAL
Page 10Table 4. Incidence Rates and Risk Difference of First COVID- 19 Occurrence After Dose 1 –Blinded Placebo -Controlled
Follow-up Period – Dose 1 All- Available Efficacy Population
Vaccine Group (as Rando mized)
BNT162b2 (30 μg)
(Na=23040)Placebo
(Na=23037) Difference
Efficacy Endpoint
Subgroup n1bSurveillance
Timec(n2d)IR (/1000
PY)en1bSurveillance
Timec(n2d)IR (/1000 PY)eIRD(/1000 PY)f(95% CIg)
First COVID -19 occurrence after
Dose 11318.412 (22505) 15.573 10348.124 (22434) 127.279 -111.707 (-119.910, -
103.503)
After Dose 1 to Day 57 553.482 (22505) 15.796 3153.459 (22434) 91.073 -75.277 (-86.166, -64.388)
After Dose 1 to Day 224 1318.412 (22505) 15.573 10348.124 (22434) 127.280 -111.707 (-119.910, -
103.503)
a. N = number of subjects in the specified group.
b. n1 = Number of subjects meeting the endpoint definition.
c. Total surveillance time in 1000 person -years for the given endpoint across all subjects w ithin each group at risk for the endpoint. Time period for COVID -
19 case accrual is from Dose 1 to the end of the surveillance period for the overall row and from start to the end of the range stated for each time interval.
d. n2 = Number of subjects at risk for the endpoint.
e. Incidence rate (IR) is calculated as number of subjects meeting the endpoint definition/total surveillance time across all su bjects at risk for the endpoi nt
within the specific group.
f. Difference in incidence rate (BNT162b2 [30 μg] -placebo).
g. 2-sided Wald CI for the incidence rate difference.
PFIZER CONFIDENTIAL SDTM Creation: 25MAR2021 (19:19) Source Data: adc19ef Table Generation: 28JUL2021 (15:14)
(Cutoff Date: 13MAR2021, Snapshot Date: 25MAR2021) Output File: ./nda2_unblinded/C4591001_BLA_RR/adc19ef_ve_cov_ird_pd1_aai
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Document Approval Record
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