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BNT162b2
BLA STN 125742/0
M 1.11.3 Response to FDA Information Request
PFIZER CONFIDENTIAL
Page 1BNT162b2 (COMIRNATY)
BLA STN 125742/0
Response to CBER22 July 2021 Information Request Regarding
ClinicalShellTablesfor Study C4591001
Follow-Up #2
August 2021
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BNT162b2
BLA STN 125742/0
M 1.11.3 Response to FDA Information Request
PFIZER CONFIDENTIAL
Page 21.INTRODUCTION
Reference is made to BLA STN 125742/0 for COVID- 19 mRNA Vaccine (COMI RNATY),
for active immunization to prevent COVID-19 caused by SARS-CoV-2 in individuals
≥16years of age and to CBER’s 22July 2021 Information Request received via email from
Laura Gottschalk, PhD, CBER, OVRR , regarding the request to provide additional sensitivity
analysisin question 5b if it was not previously provided or conducted .This request was made
initially on 22 July 2021 and Pfizer agreed to provide the results of the additional sensitivity
analysis by 02 August 2021 in the 26 July 2021 responses submitted to CBE R.
Reference is made to BLA STN 125742/0 for COVID- 19 mRNA Vaccine (COMI RNATY),
for active immunization to prevent COVID -19 caused by SARS-CoV-2 in individuals
≥16years of age and to CBER’s 22 July 2022 Information Request received via email from
Laura Go ttshalk, PhD (CBER) regarding clinical shell tables for Study C4591001.
Further reference is made to the Response to CBER 22 July 2021 Information Request
submitted to BL A 125742/0 on 26 July 2021 (Sequence Number 0018) and to the Response
to CBER 22 July 2021 Information Request Follow-up #1submitted to BLA 125549/0 on 28
July 2021 (Sequence Number 0020 )
Please note the following:
Responses to CBER 22 July 2021 Information Request I tems 3, 4, 5, 7, 8 and 9 were
submitted to BL A 125742/0 on 26 July 2021.The present submission provides
further follow -up to the information provided in this document for Item 5(b).
Response to CBER 22 July 2021 Information Request I tems 1 and 2 were submitted
to BLA 125742/0 on 28July 2021.
CBER 22 July 2021 Information Request I tem 6 will be the subject of separate,
future, follow -up Response .
CBER requests are provided below in bold italics with Sponsor responses in plain text.
2.REQUESTS
2.1. CBER Request5
In the efficacy analyses, subjects at risk were determined (in part) by the
“PDRMUPFL=’N’” condition, which would exclude all subjects who had reported COVID
symptoms but had missing or unknown PCR results at any time. It may be reasonable to
exclude subjects who had reported COVID symptoms but had missing/unknown PCR
resultsprior to 7 days after dose 2 for the efficacy analyses in subjects without evidence of
infection, as this would define a more specific group of subjects without evidence of
infection. However, based on your analyses, subjects who reported symptoms and had
missing/unknown PCR results after 7 days post dose 2 were also excluded from the
efficacy analyses, while these subjects were in fact at risk for the efficacy endpoint starting
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BLA STN 125742/0
M 1.11.3 Response to FDA Information Request
PFIZER CONFIDENTIAL
Page 3from 7 days post dose 2. For example, Subject 10011087 was excluded since he/s he
reported symptoms on 01/09/2021 without any associated PCR result, which was ~144 days
post dose 2 .
a.Please explain why these subjects were not considered at risk for the respective
efficacy endpoints, and comment on the impact of the exclusion on the VE
results.
b.In Section 6.1.3.1.2 of the SAP, it is stated that “with MAR assumption, a
missing efficacy endpoint (laboratory -confirmed COVID -19 results) may be
imputed based on predicted probability using the fully conditional specification
method.” Please c larify whether this sensitivity analysis was conducted and the
location of the sensitivity analyses if they were submitted. If not, please perform
such a sensitivity analysis for subjects who reported COVID symptoms but had
missing/unknown PCR results .
Sponsor Response
The response to Item 5(a)and an initial response to I tem 5(b) was previously submitted to
CBER on 26 July 2021 (Response to 22 July 2021 Information Request ; Sequence Number
0018).
The additional sensitivity anal ysisto respond toItem 5(b) is provided in Table 1.
A total of 648 subjects (279 in BNT162b2 group and 369 in placebo group) in the evaluable
population reported COVID -19 symptoms f rom 7 days post Dose 2 but had PCR results
missing/unknown as of data cutoff 13 Mar 2021 (Table 2of theResponse to CBER 22 July
2021 Information Request Follow-up #1submitted on 28 July 2021). Sensitivity analysis
with missing data imputation described in the SAP ,using the same methods as theoriginal
EUA database ,was performed using the updated data .
It was expected that the missing data had minimal impact on the overall result. As shown in
Table 1below, average VE after imputation was over 70% even with up to 16- fold increase
of positivity rate applied to the BNT162b2 group. With over 20- fold increase of positivity
rate applied to the BNT162b2 group, median lower bound of the 95% CI for VE is still >60%
and the percentage of times the posterior probability of VE >30% was greater than 98.6% is
100%.
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M 1.11.3 Response to FDA Information Request
PFIZER CONFIDENTIAL
Page 4Table 1. Table Sensitivity and Robustness Analysis of Missing Laboratory Results for Vaccine Efficacy
–First COVID -19 Occurrence From 7 Days After Dose 2
– Subjects Without Evidence of Infection Prior to 7 Days After Dose 2 – Evaluable Efficacy (7 Days) Population
Assumed
Missing
Data
MechanismAverage
Positive Rate (%)
Across all Imputations
(BNT162b2:Placebo)aInfection Rates Based on
Existing and
Imputed Values
(BNT162b2:Placebo)bMedian Posterior
Probability of VE
> 30%Percentage of
Posterior
Probability
of VE >30%
greater than
98.6%Median of
Lower
Limit of
95% CI for
VEMedian VE
(%)Average VE
(%)
MAR 4.0:28.5 4.21:45.31 100.00 100.00 88.56 90.78 90.76
MNAR1 10.1:28.5 5.01:45.31 100.00 100.00 86.55 88.97 88.98
MNAR2 23.3:28.5 6.76:45.31 100.00 100.00 82.30 85.12 85.14
MNAR3 45.3:28.5 9.69:45.31 100.00 100.00 75.36 78.79 78.69
MNAR4 69.1:28.5 12.85:45.31 100.00 100.00 67.71 71.78 71.75
MNAR5 85.9:28.5 15.08:45.31 100.00 100.00 62.36 66.81 66.85
Abbreviations: MAR = missing at random; MNAR = missing not at random; VE = vaccine efficacy.
Note: Each row of this table represents summary results from 500 imputations that were generated using SAS PROC MI Fully Conditiona l Specification (FCS)
method. Each imputation filled in the missing laboratory results based on a logistic regression model at the subject level, under the assumed missing data
mechanism.
a. Average positive rate for each vaccine group w as calculated as the mean of positive rates across all imputations among subjec ts with missing data after
each imputation. Under the MAR assumptio n, the imputation model assumes the probability of positive cases for each vaccine group to be the same as observed
from subjects with no missing data in that group. Under each MNAR assumption, while keeping the imputation model for placebo group unchanged , an
increase in the positive rate for the BTN162b2 group w as assumed to reflect a potential conservative and unknowable MNAR
scenario for efficacy results of the study.
b. Infection rate in each vaccine group was the number of cases divided by a total number of subjects in that vaccine group times 1000.
PFIZER CONFIDENTIAL SDTM Creation: 25MAR2021 (19:22) Source Data: adc19ef Table Generation: 30JUL2021 (12:35)
(Cutoff Date: 13MAR2021, Snapshot Date: 25MAR2021) Output File: ./nda2_unblinded/C4591001_BL A_RR/adc19ef_ve_7pd2_w o_sen1_eval_bla
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BLA STN 125742/0
M 1.11.3 Response to FDA Information Request
PFIZER CONFIDENTIAL
Page 53.REFERENCES
None
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