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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
Silver Spring, MD 20993
CENTER FOR BIOLOGICS EVALUATION AND RESEARCH
OFFICE OF VACCINES RESEARCH AND REVIEW
DIVISION OF VACCINES AND RELATED PRODUCTS APPLICATIONS
DATE: July 22, 2021 PAGES: 17
TO: BioNTech RNA Pharmaceuticals GmbH/Pfizer. Inc.
Attention: Elisa Harkins
500 Arcola Road Collegeville, PA 19426
Phone: 215- 280-5503
Fax number: 845- 474-3500
E-mail: [email protected]
FROM: Laura Gottschalk , Ph.D.
Division of Vaccines and Related Products Applications
Office of Vaccines Research and Review
Center for Biologics Evaluation and Research 10903 New Hampshire Avenue
Silver Spring, MD 20993- 0002
Phone number: 301-796-2640
Fax number: 301-595-1244
CBER Reference: BLA STN 125742/0
SUBJECT: Information request regarding clinical shell tables for study C4591001
Dear Ms. Harkins :
Reference is made to your original BLA STN 125742/0 for COVID -19 mRNA Vaccine
(COMIRNATY), for active immunization to prevent COVID -19 caused by SARS -CoV-2 in
individuals ≥16 years of age. Our review of your application is ongoing and we have the
following information requests at this time. Information Requests, regarding Study C4591001:
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.
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) .
FDA-CBER-2021-5683-1024697
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3. It appears that you have included Subject 10941002 in the efficacy a nalysis 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 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.
4. 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 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 positive 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.
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 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.
6. P
lease 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.
FDA-CBER-2021-5683-1024698
Page 3 – Ms. Elisa Harkins BLA STN 125742/0
Table A: Please complete with data from the All- available efficacy analysis population,
Participants 16 years of age and Older
Subject Disposition
Table B: Study Disposition of All Randomized Participants 16 years of age and Older,
through March data cut off
BNT162b2
(N= )
n (%) Placebo
(N= )
n (%) Total
(N= )
n (%)
Randomized
Vaccinated : Original blinded follow up period
Completed 1 dose
Completed 2 doses
Discontinued from original blinded follow up period
Reason for discontinuation
Lost to follow up
Withdrawal by subject
Adverse Event
Other (list…)
Withdrawn from Study
RT-PCR NP Swab Results and Serostatus
at Different Time Points BNT162b2
N=
Cases
n
Attack Rate or
other measure
(%) Placebo
N=
Cases
n
Attack Rate or other
measure
(%) Vaccine Efficacy
(if applicable)
Pre-Dose 1 SARS -CoV-2 RT-PCR (NP
swab)
Positive
Negative
Pre-Dose 2 SARS -CoV-2 RT-PCR (NP
swab)
Positive
Negative
Subjects with negative PCR pre -dose 1
and positive PCR pre -dose 2
Subjects with documented COVID -19
symptoms between dose 1 and 2
Subjects with no documented COVID -
19 symptoms between dose 1 and 2
Pre-Dose 1 N -binding antibody
Positive
Negative
FDA-CBER-2021-5683-1024699
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After Dose 1 and before Dose 2
After Dose 2 and before 1 -month post Dose 2
After 1 -month post Dose 2
Reason for Withdrawal
Adverse Event
Death
Withdrawal by Subject
Lost to Follow -up
Protocol Deviation
Other (list)
Open Label Follow -up Period
Originally randomized to BNT162b2
Completed 6 -month post Dose 2 visit
Withdrawn from the study
Reason for withdrawal (list..)
Originally randomized to placebo
Completed 6 -month post Dose 2 visit
Received Dose 3 (Dose 1 of BNT162b2)
Received Dose 4 (Dose 2 of BNT162b2)
Completed 1 -month post -Dose 4 visit
Discontinued from open -label follow up period
Reason for discontinuation (list…)
Withdrawn from the study
Reason for withdrawal (list…)
Table C. Disposition of Participants 16 Years of age and Older, Safety Populations
Treatment Group BNT162b2
(N= )
n (%) Placebo
(N= )
n (%) Total
(N= )
n (%)
Randomized (N)a
Not vaccinated
Vaccinated
Completed 1 dose
Completed 2 doses
Safety population
Reactogenicity subset
HIV-positive
Participants excluded from safety
population
Reason for exclusionb
Did not receive study vaccination
Other (list)
Completed at least 6 months follow -up
after Dose 2
Completed 1 -month after Dose 2 visit
(vaccination period)
FDA-CBER-2021-5683-1024700
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Treatment Group BNT162b2
(N= )
n (%) Placebo
(N= )
n (%) Total
(N= )
n (%)
Discontinued from vaccination period but
continued in the study up to 1 -month
after Dose 2 visit
Discontinued after Dose 1 and before
Dose 2
Discontinued after Dose 2 and before
1-month post -Dose 2 visit
Reason for discontinuation from
vaccination period
No longer meets eligibility criteria
Withdrawal by subject
Pregnancy
Adverse event
Physician decision
Protocol deviation
Lost to follow -up
Other
Withdrawn from study before 1 -month
post-Dose 2 visit
Withdrawn after Dose 1 and before
Dose 2
Withdrawn after Dose 2 and before 1 -
month post -Dose 2 visit
Reason for withdrawal
Adverse event
Death
Withdrawal by subject
Lost to follow -up
Protocol deviation
Withdrawal by parent/guardian
Physician decision
Other (list)
Table D. Disposition of Participants 16 years of age and older, Efficacy Populations
BNT162b2
na (%) Placebo
na (%) Total
na (%)
Randomizedb
Dose 1 all -available efficacy population
Participants without evidence of infection before
Dose 1
Participants excluded from Dose 1 all -available
efficacy population
Reason for exclusionc
Did not receive at least 1 vaccination
Did not provide informed consent
FDA-CBER-2021-5683-1024701
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BNT162b2
na (%) Placebo
na (%) Total
na (%)
Dose 2 all -available efficacy population
Participants without evidence of infection prior to 7
days after Dose 2
Participants excluded from Dose 2 all -available
efficacy population
Reason for exclusionc
Did not receive 2 vaccinations
Unblinded prior to 7 days after Dose 2
Evaluable efficacy (7 days) population
Participants without evidence of infection prior to 7
days
after Dose 2
Participants excluded from evaluable efficacy (7
days) population
Reason for exclusionc
Randomized but did not meet all eligibility criteria
Did not provide informed consent
Did not receive all vaccinations as randomized or
did not receive Dose 2 within the predefined
window (19 -42 days after Dose 1)
Had other important protocol deviations on or prior
to 7 days after Dose 2
Had other important protocol deviations on or prior
to 14 days after Dose 2
Other (list…)
Table E. Demographics and Other Baseline Characteristics, Participants 16 Years of age
and Older, Safety Populations
Characteristic BNT162b2
N=
na (%) Placebo
N=
na (%) Total
N=
na (%)
Sex: Female
Sex: Male
Age: Mean years (SD)
Age: Median (years)
Age at Vaccination: Min, max (years)
Age Group: 16 to <18 years
Age Group: 1 8 to <55 years
Age Group: >55 years
Age Group: ≥65 years
Race: American Indian or Alaska Native
Race: Asian
Race: Black or African American
Race: Native Hawaiian or other Pacific Islander
Race: Multiracial
Race: White
FDA-CBER-2021-5683-1024702
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Characteristic BNT162b2
N=
na (%) Placebo
N=
na (%) Total
N=
na (%)
Race: Not reported
Race: Other
Ethnicity: Hispanic or Latino
Ethnicity: Not Hispanic or Latino
Ethnicity: Not reported
Obese: Yes
Obese: No
Comorbidities: Yes
Comorbidities: No
Baseline evidence of prior SARS -CoV-2 infection:
Negative
Baseline evidence of prior SARS -CoV-2 infection:
Positive
Baseline evidence of prior SARS -CoV-2 infection:
Missing
Country: Argentina
Country: Brazil
Country: Germany
Country: South Africa
Country: Turkey
Country: United States of America
Other (list)
Table F. Demographics and Other Baseline Characteristics, Participants 16 Years of age
and Older, Evaluable Efficacy Population
Characteristic BNT162b2
N=
na (%) Placebo
N=
na (%) Total
N=
na (%)
Sex: Female
Sex: Male
Age: Mean years (SD)
Age: Median (years)
Age at Vaccination: Min, max (years)
Age Group: 16 to <18 years
Age Group: 1 8 to <55 years
Age Group: >55 years
Age Group: ≥65 years
Race: American Indian or Alaska Native
Race: Asian
Race: Black or African American
Race: Native Hawaiian or other Pacific Islander
Race: Multiracial
Race: White
Race: Not reported
FDA-CBER-2021-5683-1024703
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Characteristic BNT162b2
N=
na (%) Placebo
N=
na (%) Total
N=
na (%)
Race: Other
Ethnicity: Hispanic or Latino
Ethnicity: Not Hispanic or Latino
Ethnicity: Not reported
Obese: Yes
Obese: No
Comorbidities: Yes
Comorbidities: No
Baseline evidence of prior SARS -CoV-2 infection:
Negative
Baseline evidence of prior SARS -CoV-2 infection:
Positive
Baseline evidence of prior SARS -CoV-2 infection:
Missing
Country: Argentina
Country: Brazil
Country: Germany
Country: South Africa
Country: Turkey
Country: United States of America
Other (list)
Efficacy Results:
*Provide all vaccine efficacy analyses using the evaluable efficacy population, limited to
participants 16 years of age and older (excluding participants 12 through 15 years of
age).
Table G. Final Analysis of Efficacy of BNT162b2 Against Confirmed COVID -19 From 7
Days After Dose 2 in Participants Without Evidence of Prior SARS -CoV-2 Infection -
Evaluable Efficacy Population, 16 Years and Older (data cutoff November 2020)
Pre-specified Age Group BNT162b2
Na =
Cases
n1b
Surveillance
Timec (n2d) Placebo
Na =
Cases
n1b
Surveillance
Timec (n2d) Vaccine
Efficacy %
(95% CI) Met
Predefined
Success
Criterion*
All participants
16 to 55 years NA
> 55 years and older NA
FDA-CBER-2021-5683-1024704
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Table H. Updated Efficacy of BNT162b2 Against Confirmed COVID -19 From 7 Days After
Dose 2 in Participants Without Evidence of Prior SARS -CoV-2 Infection - Evaluable
Efficacy Population, 16 Years and Older (data cutoff March 13, 2021)
Pre-specified Age Group BNT162b2
Na =
Cases
n1b
Surveillance Timec
(n2d) Placebo
Na =
Cases
n1b
Surveillance Timec
(n2d) Vaccine
Efficacy %
(95% CI)
All participants
16 to 55 years
> 55 years and older
Table I. Updated Efficacy of BNT162b2 Against Confirmed COVID -19 From 7 Days After
Dose 2 in Participants With and Without Evidence of Prior SARS -CoV-2 Infection -
Evaluable Efficacy Population, 16 Years and Older (data cutoff March 13, 2021)
Pre-specifie d Age Group BNT162b2
Na =
Cases
n1b
Surveillance Timec
(n2d) Placebo
Na =
Cases
n1b
Surveillance Timec
(n2d) Vaccine
Efficacy %
(95% CI)
All participants
16 to 55 years
> 55 years and older
Table J. Subgroup Analyses of Updated Second Primary Endpoint: First COVID -19
Occurrence From 7 Days After Dose 2, by Subgroup, Participants With and Without
Evidence of Infection Prior to 7 Days After Dose 2, Evaluable Efficacy Population (data
cutoff Mar ch 13, 2021)
Efficacy Endpoint
Subgroup BNT162b2
Na=
Cases n1b
Surveillance
Timec (n2d) Placebo
Na=
Cases n1b
Surveillance
Timec (n2d) Vaccine
Efficacy %
(95% CI)e
Overall
Age group : 16 to <18 years
Age group : 18 to <65 years
Age group : ≥65 years
Age group : 65 to 74 years
Age group : ≥75 years
At risk : Yes
At risk : No
Age group and Risk: 16-64 and not at risk
Age group and Risk: 16-64 and at risk
Age group and Risk: ≥65 and not at risk
Age group and Risk: ≥65 and at risk
Obese : Yes
FDA-CBER-2021-5683-1024705
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Efficacy Endpoint
Subgroup BNT162b2
Na=
Cases n1b
Surveillance
Timec (n2d) Placebo
Na=
Cases n1b
Surveillance
Timec (n2d) Vaccine
Efficacy %
(95% CI)e
Obese : No
Age group and obese :16-64 and not obese
Age group and obese : 16-64 and obese
Age group and obese : ≥65 and not obese
Age group and obese : ≥65 and obese
Sex: Female
Sex: Male
Ethnicity : Hispanic or Latino
Ethnicity : Not Hispanic or Latino
Race : American Indian or Alaska native
Race : Asian
Race : Black or African American
Race : Native Hawaiian or other Pacific
Islander
Race : White
Race : Multiracial
Race : Not reported
Baseline SARS -CoV-2 Status :Positive
Baseline SARS -CoV-2 Status :Negative
Baseline SARS -CoV-2 Status :Unknown
Country: Argentina
Country: Brazil
Country: Germany
Country: South Africa
Country: Turkey
Country: United States
Table K. Demographic Characteristics, Participants 16 years of age and Older, With
Protocol -Defined Case (Without Evidence of Infection Prior to 7 Days After Dose 2) (data
cutoff March 13, 2021)
Characteristic BNT162b2
Na=
nb (%) Placebo
Na=
nb (%) Total
Na=
nb (%)
Age at Vaccination: Mean years (SD)
Age a t Vaccination: Median (years)
Age at Vaccinatio n: Min, max (years)
Age Group: 16 to < 18 years
Age Group: 18 to < 65 years
Age group : ≥65 years
Age Group: ≥ 65 to < 75 years
Age Group: ≥ 75 years
Race: American Indian or Alaska Native
Race: Asian
FDA-CBER-2021-5683-1024706
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Characteristic BNT162b2
Na=
nb (%) Placebo
Na=
nb (%) Total
Na=
nb (%)
Race: Black or African American
Race: Nat ive Hawaiian or Other Pacific
Islander
Race: White
Race: Mult iracial
Race: Not reported
Sex: Female
Sex: Male
Ethnicity: Hispanic or Latino
Ethnicity: Not Hispanic or Latino
Ethnicit y: Not reported
Comorbidities : Yes
Comorbidities: No
Comorbidity: Obesity
Country: Argentina
Country: Brazil
Country: Germany
Country: South Africa
Country: Turkey
Country: United States
Table L. Updated Vaccine Efficacy: First COVID -19 Occurrence From 7 Days After Dose 2,
by Comorbidity Status, Among Participants Without Evidence of Infection Prior to 7 Days
After Dose 2, Evaluable Efficacy Population. Participants 16 Years of age and Old er (data
cutoff March 13, 2021)
Efficacy Endpoint
Subgroup BNT162b2
Na=
Cases n1b
Surveillance Timec
(n2d) Placebo
Na=
Cases n1b
Surveillance Timec
(n2d) Vaccine Efficacy %
(95% CIe)
Overall
Comorbidity
No comorbidity
Any comorbidityf
Any malignancy
Cardiovascular
Chronic pulmonary disease
Diabetes
Obese (BMI≥30.0 kg/m2)
Hypertension
Diabetes (including
gestational diabetes)
FDA-CBER-2021-5683-1024707
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Table M. First Severe COVID -19 Occurrence from 7 Days after Dose 2 - Evaluable Efficacy
Population (data cutoff March 13, 2021)
Secondary Efficacy
Endpoint BNT162b2
Na=
Cases n1b
Surveillance Timec
(n2d) Placebo
Na=
Cases n1b
Surveillance Timec
(n2d) Vaccine Efficacy
%
(95% CI)
First severe COVID -19
occurrence from 7 days after
Dose 2 in participants
withou t evidence of prior
SARS -CoV-2 infection
Table N. First Severe COVID -19 Occurrence After Dose 1 – Dose 1 All -Available Efficacy
Population (data cutoff March 13, 2021)
Secondary Efficacy Endpoint BNT162b2
Na=
Cases n1b
Surveillance
Timec (n2d) Placebo
Na=
Cases n1b
Surveillance
Timec (n2d) Vaccine Efficacy %
(95% CI)
First severe case occurrence
after Dose 1
After Dose 1 to before Dose 2
Dose 2 to 7 days after Dose 2
≥7 Days after Dose 2
Table O. Primary Efficacy Endpoint – All-Available Efficacy Population (data cutoff March
13, 2021)
Efficacy Endpoint BNT162b2
Na=
Cases n1b
Surveillance
Timec (n2d) Placebo
Na=
Cases n1b
Surveillance
Timec (n2d) Vaccine Efficacy %
(95% CI)
First COVID -19 occurrence after
Dose 1 – Dose 1
After Dose 1 to before Dose 2
Dose 2 to 7 days after Dose 2
≥7 Days after Dose 2
FDA-CBER-2021-5683-1024708
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Safety Results:
Table P. Safety Overview, Participants 16 Years of Age and older, Phase 2/3 Safety Population
Event BNT162b2
n/N (%) Placebo
n/N (%)
Immediate unsolicited AE within 30 minutes after
vaccinationa
Dose 1
Dose 2
Solicited injection site reaction within 7 daysa
Dose 1
Dose 2
Solicited systemic AE within 7 daysa
Dose 1
Dose 2
From Dose 1 through 1 month after Dose 2b
Unsolicited non -serious AE
SAE
From Dose 1 to cutoff date or participant unblinding
(whichever is earlier)b
SAE
Withdrawal due to AEs
Deaths
Table Q. Characteristics of Solicited Local and Systemic Adverse Reactions, Participants
16 Years of age and older, Safety Population
Event BNT162b2
Dose 1
na/Nb (%) Placebo
Dose 1
na/Nb (%) BNT162b2
Dose 2
na/Nb (%) Placebo
Dose 2
na/Nb (%)
Any solicited local
reaction
Day of onset: median
(min, max) Day (min, max) Day (min, max) Day (min, max) Day (min, max)
Duration: median (min,
max) Days (min, max) Days (min,
max) Days (min, max) Days (min,
max)
Persisted beyond 7
days
e.g., Pain
Day of onset: median
(min, max) Day (min, max) Day (min, max) Day (min, max) Day (min, max)
Duration: median (min,
max) Days (min, max) Days (min,
max) Days (min, max) Days (min,
max)
Persisted beyond 7
days
Any solicited systemic
reaction
Day of onset: median
(min, max) Day (min, max) Day (min, max) Day (min, max) Day (min, max)
FDA-CBER-2021-5683-1024709
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Event BNT162b2
Dose 1
na/Nb (%) Placebo
Dose 1
na/Nb (%) BNT162b2
Dose 2
na/Nb (%) Placebo
Dose 2
na/Nb (%)
Duration: median (min,
max) Days (min, max) Days (min,
max) Days (min, max) Days (min,
max)
Persisted beyond 7
days
e.g., Myalgia
Day of onset: median
(min, max) Day (min, max) Day (min, max) Day (min, max) Day (min, max)
Duration: median (min,
max) Days (min, max) Days (min,
max) Days (min, max) Days (min,
max)
Persisted beyond 7 days
Table R. Frequency of Unsolicited AEs with Occurrence in ≥1% of Participants in Any
Treatment Group From Dose 1 to One Month After Dose 2 , Participants 16 Years of age
and Older, Safety Population
Primary System
Organ Class
(CODE) Preferred Term (CODE) BNT162b2
(N=)
Any % (Severe %) Placebo
(N=)
Any % (Severe %)
Each SOC Adverse events in any PT
Any PT (% severe)
Any PT (% severe)
Each SOC Adverse events in any PT
Any PT (% severe)
Any PT (% severe)
**Please repeat Table R for the following time periods:
1. From Dose 1 to Match data cutoff/participant unblinding (whichever is earlier) and
2. From participant unblinding to March data cutoff
SMQ analyses
***narrow SMQs: vasculitis, hypersensitivity, arth ritis, angioedema, peripheral neuropathy,
demyelinating disease of central nervous system, convulsions
We may send additional SMQ requests as we review the data.
Table S. Name of Standard MedDRA Query, Participants 16 Years of age and Older,
Safety Population
Dictionary Derived Term
Number of Subjects (%) BNT162b2
(n=) Placebo
(n=)
Subjects with any unsolicited
adverse events within SMQ xx (xx%) x (x%)
DDT x (x%) -
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Table T. SAEs considered related by Investigator - Participants 16 Years of age and Older,
Safety Population
Product
(Vaccine
or
Placebo) SAE Onset (Days After
Vaccination) Demographics :
Age/Sex/ Risk Factors Resolution Related per Investigator/
Pfizer
e.g., brachial
nerve neuritis 0 (day of
vaccination) 30 M; no relevant
medical history Resolving Yes/Yes
Table U. Deaths, Participants 16 Years of age and Older, Safety Population, through
March data cutoff
-Product
(BNT162b2 or
Placebo)
-Number of doses
received Subject
Number
Onset (Days After
Vaccination) Cause of
Death Positive
COVID -
19 test (Y/N)
Age/ Sex
Race/Ethnicity Demographics :
Risk Factors from Charlson Index
e.g.,
placebo/BNT162b2
2/1 4 e.g.,
myocardial inf arctio
n N 65 F B/NH
Table V. Clinical Trials Submitted in Support of Safety and Effectiveness of the Pfizer -
BioNTech COVID -19 Vaccine
Study
Number/
Country Description BNT162b2 (30 µg)
Participan ts
(N) Placebo
participants
(N) Study
Status
C4591001
Argentina,
Brazil,
Germany,
South Africa,
Turkey, U nited
States Phase 1:
Phase 2/3: Phase 1:
Phase 2/3: Ongoing
BNT162 -01
Germany Ongoing
N= total number of randomized participants 16 years of age and older, as of
March 13, 2020.
FDA-CBER-2021-5683-1024711
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Please also respond to the following information requests regarding Study C4591001:
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 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 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.
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
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 positive 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.
9. In the efficacy analyses, subjects at risk were determined (in part) by t he
“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 results p rior 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.
FDA-CBER-2021-5683-1024712
Page 17 – Ms. Elisa Harkins BLA STN 125742/0
Please provide your responses in an amendment to STN 125742/0 by COB Monday, July 26,
2021. We recommend that you restate each item and follow it with your explanation or
clarification. Use of this format helps organize the relevant information and provides a self -
contained document that facilitates future reference.
FDA-CBER-2021-5683-1024713