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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 02 August 2021 CBER Information Request Regarding
Validation Report VR -MVR -10077
05August 2021
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FDA-CBER-2021-5683-0950867
BNT162b2
BLA STN 125742/0
M 1.11.3 Response to FDA Information Request
PFIZER CONFIDENTIAL
Page 2TABLE OF CONTENTS
LIST OF ABBREVIATION S................................ ................................ ................................ ....3
1. INTRODUCTION ................................ ................................ ................................ ................. 4
2. CBER REQUESTS ................................ ................................ ................................ ................ 4
2.1. CBER Request 1................................ ................................ ................................ ........ 4
2.2. CBER Request 2 ................................ ................................ ................................ ........ 5
2.3. CBER Request 3 ................................ ................................ ................................ ........ 5
2.4. CBER Request 4 ................................ ................................ ................................ ........ 5
2.5. CBER Request 5 ................................ ................................ ................................ ........ 6
2.6. CBER Request 6 ................................ ................................ ................................ ........ 6
2.7. CBER Request 7 ................................ ................................ ................................ ........ 6
2.8. CBER Request 8 ................................ ................................ ................................ ........ 7
2.9. CBER Request 9 ................................ ................................ ................................ ........ 7
2.10. CBER Request 10 ................................ ................................ ................................ ....7
2.11. CBER Request 11 ................................ ................................ ................................ ....8
3. APPENDI CES ................................ ................................ ................................ ....................... 9
Appendix 1. Figure 4. L inearity for SARS -Cov-2 -Reportable
Sample Concentration ................................ ................................ ................................ .9
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BLA STN 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
CV coefficient of variation
dLIA direct -binding Luminex immunoassay
EUA Emergency Use Authorization
FDA United States Food and Drug Administration
IgG immunoglobulin G
IR Information Request
LLOQ lower limit of quantitation
NA not applicable
NIBSC National Institute of Biological Standards and Control
QCS quality control sample
RMSE root mean square error
SARS -CoV -2 severe acute respiratory syndrome coronavirus 2
ULOQ upper limit of quantitation
WHO World Health Organization
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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 (I R)
communicated from Captain Michael Smith ,PhD (CBER) to Elisa Harkins Tull (Pfizer I nc.)
viaemail on 02August 2021, with questions regarding the validation report
VR-MVR -10077. CBER has requested a response by 05 August 2021.
CBER’s comments/ requests in bold italics are followed b y the Sponsor’s responses below.
2.CBER REQUEST S
The review team has the below set of questions for Pfizer regarding the Validation Report
(VR-MVR-10077) entitled “Validation Report for a
that was
submitted in STN 125742.0.19 on July 28, 2021.
2.1. CBER Request 1
In your C4591001 clinical protocol amendment 17 (submitted to IND 19736 in amendment
414 on July 20, 2021), you stated that assay or S1 -binding IgG
assay will be used for the exploratory immunogenicity endpoint. Please clarify which
immunoassay has been used for the assessment of binding antibodies for your Phase 2 and
3 studies. If both assays are used, please provide the validation st udy report for the S1 IgG
dLIA assay. In addition, please provide the SOP of the assay
(VR-TM-10309), including a description of critical materials (e.g., reference standard,
quality control sample (QCS), antigen, , etc.), assay
validity criteria, sample validity criteria, and interpretation of results. Please also provide
the test method VR -TM-10309, and the validation protocol VR- MVP -10077.
Response
The S1 IgG dLIA (and not the ) was qualified and used for
immunogenicit y assessments in Phase 1 (C4591001 sentinel cohort) and Phase 2 (C4591001
Phase 2 immunogenicit y cohort) studies. Onl y data from these immunogenicity studies using
the qualified S1 IgG dLIA assay have been submitt ed to the EUA and the BLA. The S1 IgG
dLIAwas discussed and agreed previousl y with CBER under BB -IND 19736. Final
qualification re ports were submitted to the I ND as part of the Response to 29 July 2020
Information Request –Clinical Assay Qualification on25 August 2020 (Serial Number
0068) and are also included in the BLA. The validated
will be used for the study and several other studies that, based on agreement
with CBER ,will not be part of the origin al BLA filing.
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M 1.11.3 Response to FDA Information Request
PFIZER CONFIDENTIAL
Page 5Given that the validation of the is not pertinent to the BLA at this time, Pfizer
respectfull y requests to provide all information requested for the assay at a later time in a
separate submission to BB-IND 19736 . Does CBER agree ?
2.2.CBER Request 2
We note that assay cross -reactivity was not assessed in your validation studies. Please
provide data for specificity analysis, including inhibition experiments comparing the
effects of heterologous antigens (e.g., antigen from other coronaviruses) and
homologous antigens (e.g., antigens at different concentrations) when spiked into the
panel of samples. Alternatively, you can evaluate the assay cross -reactivity using a set of
antibodies or serum samples with known reactivity to disti nct strains of human seasonal
coronaviruses.
Response
Cross -reactivity of the was assessed outside of the formal validation and
demonstrated excellent specificit y to the of SARS -CoV -2. The results of these
assessments will be subm itted to BB-IND 19736 at a later date .
2.3.CBER Request 3
We note that assay robustness was not assessed in your validation studies. Please consider
evaluating the assay robustness for any variables that may potentially affect assay results,
for example, stabi lity of the antigen -coated beads, assay incubation time and temperature,
etc.
Response
Assay robustness of the was assessed outside of the formal validation. The
results of these assessments will be submitted to BB-IND 19736 at a later date .
2.4.CBER Request 4
Please provide information on the source, preparation instructions, and titer assignment
for the reference standard and quality control samples that contains
in the validation study. A negative QCS below or at the lower limit of
quantitation (LLOQ) level should be included in routine testing for the assay.
Please explain how you determine the cut -off values for specific levels in the
seronegative samples.
Response
Information on the reference standard and QCS will be submitted to BB- IND
19736 at a later date.
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M 1.11.3 Response to FDA Information Request
PFIZER CONFIDENTIAL
Page 62.5.CBER Request 5
Please note that your assay needs to be validated using incurred samples from the vaccine
trials for precision and accuracy via linearity including verification of the
LLOQ, ULOQ, and the assay range. The assay should be fully validated prior t o testing
the Phase 3 clinical samples
Response
The was fully validated using both COVID -19
The sample ty pe is coded as
as shown in Table 11.2 for linearity and Table 11.3 for precision in
theVR-MVR -10077 validation report.
2.6.CBER Request 6
Performance of your assay would be strengthened by inclu sion of the WHO SARS -CoV-2
International Antibody Standard. You might inquire from the National Institute of
Biological Standards and Control (NIBSC) about the availability of this reagent. We
recommend assessing the performance of your assay using the I nternational Antibody
Standard and convert your results to International Units.
Response
Unfortunatel y, Pfizer was not invited to participate in the development of the WHO
SARS -CoV -2 International Antibody Standard. We have obtained a limited supply of thi s
reagent and have tested it in the . Results of this analy sis will be submitted to
BB-IND 19736 at a later date .
2.7.CBER Request 7
You set the LLOQ to be , which was obtained by
Such LLOQ could serve as a theoretical
LLOQ, but data are needed to support adequate assay performance at such LLOQ. We
note that the precision near the lower assay limit on well concentration level was evaluated
mostly with data at the
(green stars and light green diamonds in Figure 2 on Page 17 of the report). We
also note that the lowest incurred sample included in the precision evaluation has
concentration of (Table 12 on Pages 36- 37 of the report), which is far above the
theoretical LLOQ (i.e., ). Please explain how the current data support
adequate precision at the proposed LLOQ of or provide additional data.
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M 1.11.3 Response to FDA Information Request
PFIZER CONFIDENTIAL
Page 7Response
A further explanation of how the LLOQ was set for the will b e submitted to the
BB-IND 19736 at a later date .
2.8.CBER Request 8
We note that, in Table 10 on Page 34 of the report, the
do not include the for some samples. Taking Sample
as an example, the
which does not include the Please verify the numbers in this table
and make corrections, if needed.
Response
We will verify these analyses and an update will b e submitted to BB-IND 19736 at a later
date.
2.9.CBER Request 9
You stated in Section 5.2.7.2 of the report that the mean, standard deviation, and
However, as shown in Table 8 on Page 21 of the report,
Response
Further explanation on this statistical analy sis will be submitted to BB- IND 19736 at a later
date.
2.10. CBER Request 10
Please submit the data sets used for the linearity and precision analyses in an
analyzable format (e.g., spreadsheet).
Response
The validation datasets in spreadsheet format for linearity and precision will be
submitted to BB-IND 19736 at a later date .
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M 1.11.3 Response to FDA Information Request
PFIZER CONFIDENTIAL
Page 82.11. CBER Request 11
The x- axis in Figure 4 on page 35 of the report is blurry. Please resubmit the figure in
higher quality so that it is readable.
Response
A higher resolution version of Figure 4 will be replaced in the validation report, submitted to
BB-IND 19736 at a later dat e,and is also included in Appendix 1 below .
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M 1.11.3 Response to FDA Information Request
PFIZER CONFIDENTIAL
Page 93.APPENDICES
Appendix 1 .
Figure 4. Linearity for SARS -Cov-2 -Reportable Sample Concentration
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