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BNT162b2
BLA STN 125742/0
M 1.11.3 Response to FDA Information Request
PFIZER CONFIDENTIAL
1BNT162b2 (COMIRNATY)
BLASTN 125742/0
Response to CBER 22 July2021Information Request Regardin g
ClinicalShellTablesfor Study C4591001
July2021
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FDA-CBER-2021-5683-0950123
BNT162b2
BLA STN 125742/0
M 1.11.3 Response to FDA Information Request
PFIZER CONFIDENTIAL
2TABLE OF CONTENTS
1. INTRODUCTION ................................ ................................ ................................ ................. 3
2. CBER INFORMATION REQUESTS AND SPONSOR RESPONSES ............................... 3
2.1. CBER Request 1 ................................ ................................ ................................ ........3
2.2. CBER Re quest 2................................ ................................ ................................ ........3
2.3. CBER Request 3 ................................ ................................ ................................ ........3
2.4. CBER Request 4 ................................ ................................ ................................ ........4
2.5. CBER Request 5 ................................ ................................ ................................ ........4
2.6. CBER Request 6 ................................ ................................ ................................ ........8
2.7. CBER Request 7 ................................ ................................ ................................ ........8
2.8. CBER Request 8 ................................ ................................ ................................ ........8
2.9. CBER Request 9 ................................ ................................ ................................ ........9
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BNT162b2
BLA STN 125742/0
M 1.11.3 Response to FDA Information Request
PFIZER CONFIDENTIAL
31.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 .
The purpose of this document is to respond to CBER ’s22 July2021 Information Request to
Pfizer, received via email fromLaura Gottschalk, PhD (CBER). The requests are regarding
clinical shell tables for Study C4591001 that correspond to data filed in the BLA ,which is in
ongoing CBER review .
CBER requests are provided below in bold italics with Sponsor responses in plain text. Note
that Questions 7, 8, and 9 were duplicates of Questions 3, 4, and 5 . Sponsor requests
clarification as to whether additional questions from CBER were intended .
2.CBER INFORMATION REQUESTS AND SPONSOR RESPONSES
2.1.CBER Request 1
Please provide the number and percentage of clinical COVID cases that meet the case
definition but not confirmed by PCR for any reason (e.g., not done, sample lost, out of
window), by study arm.
Sponsor Response
Pfizer/BioN Tech will providethis informatio n by 28July 2021.
2.2.CBER Request 2
Please provide the cumulative incidence rates for the vaccine group as compared to the
placebo group at 2, 4, and 6 months post dose 1 to complement the cumulative incidence
curve submitted (Figure 2, pg 104, from c4591001 -interim-mth6-report-body.pdf).
Sponsor Response
Pfizer/BioNTech will provide this information by 28 July 2021.
2.3.CBER Request 3
It appears that you have included Subject 10941002 in the efficacy analysis for first
COVID-19 occurrence from 7 days after dose 2 over blinded placebo- controlled follow -up
period in subjects without evidence of infection prior to 7 days after dose 2 (e.g. Table 16
of C4591001 -interim-6-Month Report Body). However, this subject reported “covid -19
antibody test positive” in medical history, and the baseline COVID status was categorized
as positive, as indicated in the ADSL data set. Please confirm whether th is subject is
included in the VE analysis in subjects without evidence of infection prior to 7 days after
dose 2, and if yes, please provide a rationale for including this subject in the analysis
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BNT162b2
BLA STN 125742/0
M 1.11.3 Response to FDA Information Request
PFIZER CONFIDENTIAL
4Sponsor Response
Subject 10941002 is included in the VE ana lysis in subjects without evidence of infection
prior to 7 day s after Dose 2. As illustrated bythe flowchart in A ppendix 3 of the Statistical
Analysis Plan(SAP)and clarified in the footnote of VE tables, “subjects who had no
serological or virological evidence (prior to 7 day s after receipt of the last dose) of past
SARS-CoV-2 infection (ie, N -binding antibody [serum] negative at Visit 1 and SARS -CoV-2
not detected b y NAAT [nasal swab] at Visits 1 and 2), and had negative NAAT (nasal swab)
at any unscheduled visit prior to 7 day s after Dose 2,” were included in the anal ysisof
subjects without evidence of infection . This subject had negative results on all required
N-binding antibody and NAAT tests prior to 7 day s after Dose 2, thus being included in the
analysis.We based our “without evidence of infection” definition solely on objective
serological and virological parameters due to the potential uncertaint y of a medical history
entry without knowledge of circumstances, assay performed etc. However, as r equested in
the FDA EUA guidance document, baseline COVID -19 status categorization did take
account of the medical history .
2.4.CBER Request 4
It appears that Subject 10031167 was considered to have a confirmed COVID case, with
an onset date 11/02/2020, in yo ur efficacy analysis. We note that this subject reported three
episodes of symptoms (from 10/08/2020 to 10/16/2020, 11/2/2020 to 12/11/2020, and
12/17/2020 to 01/16/2021, respectively), and the PCR tests were negative for the first two
episodes and positiv e for the third episode. In Appendix 3 of the SAP, it is stated that “if
new symptoms are reported within 4 days after resolution of all previous symptoms, they
will be considered as part of a single illness.” Since the second and third episodes were
more than 4 days apart, it appears that they should be counted as separate episodes.
Hence, the subject would be considered to have a COVID case with an onset on
12/17/2020. Since this subject was unblinded on 12/16/2020, this case occurred after
unblinding and should not be included in the efficacy analysis during the blinded placebo -
controlled follow up period. Please comment .
Sponsor Response
While the regular COVID-19symptoms do have the start and stop dates specified by CBER,
this subject has the severe symptom of hospitalization for COVID-19 starting on
22November 2020 and ending on 23 December 2020 . As the hospitalization spans both the
COVID B and COVID C symptoms, they were merged into a single COVID -19case.
2.5.CBER Request 5
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 COVI D symptoms but had missing/unknown PCR
results prior 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
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BNT162b2
BLA STN 125742/0
M 1.11.3 Response to FDA Information Request
PFIZER CONFIDENTIAL
5infection. However, based on your an alyses, 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
from 7 days post dose 2. For example, Subject 10011087 was excluded since he/she
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 c omment 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 f ully conditional specification method.” Please clarify
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 s ymptoms but had missing/unknown PCR results .
Sponsor Response
a.Subjects who reported s ymptoms and had missing/unknown PCR results do not have
a chance to be counted in the numerator ( confirmed cases) . Including them in the
denominator only (surveillance time among subjects at risk) would implicitly assume
that all PCR results for these subjects were negative , and thus could underestimate the
incidence rate . Therefore,such subjects were excluded from both numerator and
denominator in the calculation of incidence rate s for both active vaccine and placebo
groups.As the percentages of subjects who reported sy mptoms but has
missing/unknownPCR results were small and slightl y higher in the placebo group,
excluding them from the anal yses had negli gible impact o n VE results.Sensitivity
analysis through imputing the missing/unknown PCR results and including such
subjects inthe VE calculation (resultspresented in response b below), further support
that main conclusion sforvaccine efficacy will notbe altered even under some
extreme MNAR assumptions.
b. Asensitivity analysis with missing data imputation described in the SAP was
performed usingthe final efficacy analysis of at least 164 cases d ata (original EUA
database)based upon a request from the European Medicines Agency (EMA).Atotal
of 348 subjects (141 and 207 participants in BNT162b2 group and placebo group,
respectivel y) had protocol defined s ymptoms but missing laboratory results 7 day s
after Dose 2 as of the data cutoff of 14 November2020. Sensitivity analysis of
missing laboratory data was performed for the primary endpoint.
Under the missing at random (MAR) assumption for the missing data mechanism,
missing efficacy endpoint (laboratory -confirmed COVID -19 results) was imputed
based on predicted probability from logistic regression model using the fully
conditional specification method. I n addition, a conservative approach was applied to
the model by assuming a higher than the observed case rate when imputing missing
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BNT162b2
BLA STN 125742/0
M 1.11.3 Response to FDA Information Request
PFIZER CONFIDENTIAL
6efficacy endpoints fr om participants in the BNT162b2 group onl y, to reflect
potentially unknowable missing not at random (MNAR) effects that are unfavorable
for efficacy results of the study .
As shown in Table 1, average VE after imputation was over 80% even with up to
15-fold increase of positivity rate applied to the BNT162b2 group. This further
demonstrated robust vaccine efficacy of BNT162b2.
In the updated descriptive anal yses included in the BLA, similarly high VE(91%) of
BNT162b2 was observed with up to 6 monthsblinded follow up. The sensitivity
analysis was not repeated. We will perform the sensitivity analysis using BLA data
and provide the result by 02 August 2021. It’s expected that missing data will have
minimal impact on the overall result.
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BNT162b2
BLA STN 125742/0
M 1.11.3 Response to FDA Information Request
PFIZER CONFIDENTIAL
7Table 1. 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 Efficac y(7 Days) Population
Assumed
Missing
Data
MechanismAverage
Positive Rate (%)
Across all Imputations
(BNT162b2:Placebo)aInfection Rates Based on
Existing and
Imputed Values
(BNT162b2:Placebo)bAverage
Posterior
Probability of
VE > 30%Median
Posterior
Probability of
VE > 30%Number of
Posterior
Probability
of VE > 30%
greater than
98.6%Percentage of
Posterior
Probability
of VE > 30%
greater than
98.6%Average
VE (%)
MAR 1.3:16.2 0.56:11.03 100.00 100.00 500 100.00 94.93
MNAR1 3.6:16.2 0.74:11.03 100.00 100.00 500 100.00 93.33
MNAR2 9.0:16.2 1.18:11.03 100.00 100.00 500 100.00 89.39
MNAR3 21.4:16.2 2.17:11.03 100.00 100.00 500 100.00 80.46
MNAR4 41.9:16.2 3.82:11.03 99.98 100.00 498 99.60 65.67
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 Cond itional 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 miss ing data after
each imputation. Under the MAR assumption, the imputation model assumes the probability of positive cases for each vaccine gr oup to be the same as
observed from subjects w ith no missing data in that group. Under each MNAR assumption, while k eeping 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 s cenario for efficacy results of
the study.
b. Infection rate in each v accine group was the number of cases divided by a total number of subjects in that vaccine group times 1000.
PFIZER CONFIDENTIAL SDTM Creation: 17NOV2020 (09:54) Source Data: adc19ef Table Generation: 09DEC2020 (10:27)
(Cutoff Date: 14NOV2020, Snapshot Dat e: 16NOV2020) Output File: ./nda2_unblinded/C4591001_EUA_FAEF_RR/adc19ef_ve_7pd2_w o_sen_eval_eua
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BLA STN 125742/0
M 1.11.3 Response to FDA Information Request
PFIZER CONFIDENTIAL
82.6.CBER Request 6
Please complete the following tables, based on the Study C4591001 Phase 2/3 populations,
limited to participants 16 years of age and older (please exclude participants 12 -15 years of
age) from the March data cutoff, unless otherwise specified. Please add rows, as needed to
list additional items.
Sponsor Response
Therequested508-complaint tables will require extensive customization and significant
amount of changes to our existing standard macros and programming code. Considering the
complexity of this task, we will need up to 3 weeks to complete these . Accordingl y,we will
provide the requested tables by 13 August 2021.
2.7.CBER Request 7
It appears that you have included Subject 10941002 in the efficacy analysis for first
COVID-19 occurrence from 7 days after dose 2 over blinded placebo- controlled follow -up
period in subj ects without evidence of infection prior to 7 days after dose 2 (e.g. Table 16
of C4591001 -interim-6-Month Report Body). However, this subject reported “covid -19
antibody test positive” in medical history, and the baseline COVID status was categorized
as positive, as indicated in the ADSL data set. Please confirm whether this subject is
included in the VE analysis in subjects without evidence of infection prior to 7 days after
dose 2, and if yes, please provide a rationale for including this subject in the analysis.
Sponsor Response
Please refer to the Sponsor Response to CBER Request 3 ( Section2.3).
2.8.CBER Request 8
It appears that Subject 10031167 was considered to have a confirmed COVID case, with
an onset date 11/02/2020, in your efficacy analysis. We note that this subject reported th ree
episodes of symptoms (from 10/08/2020 to 10/16/2020, 11/2/2020 to 12/11/2020, and
12/17/2020 to 01/16/2021, respectively), and the PCR tests were negative for the first two
episodes and positive for the third episode. In Appendix 3 of the SAP, it is st ated that “if
new symptoms are reported within 4 days after resolution of all previous symptoms, they
will be considered as part of a single illness.” Since the second and third episodes were
more than 4 days apart, it appears that they should be counted a s separate episodes.
Hence, the subject would be considered to have a COVID case with an onset on
12/17/2020. Since this subject was unblinded on 12/16/2020, this case occurred after
unblinding and should not be included in the efficacy analysis during the blinded placebo -
controlled follow up period. Please comment .
Sponsor Response
Please refer to the Sponsor Response to CBER Request 4 ( Section 2.4).
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BNT162b2
BLA STN 125742/0
M 1.11.3 Response to FDA Information Request
PFIZER CONFIDENTIAL
92.9.CBER Request 9
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 subje cts who had reported COVID symptoms but had missing/unknown PCR
results prior 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
from 7 days post dose 2. For example, Subject 10011087 was excluded since he/she
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 clarify
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
Please refer to the Sponsor Response to CBER Request 5 ( Section 2.5).
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