Document text
Statistical Review
STN: 125742/0
Page i Application Type Original BLA
STN 12574 2/0
CBER Received Date May 18, 2021
PDUFA Goal Date January 16, 2022
Division / Office OVRR
Committee Chair Ramachandra Naik
Product Reviewer Xiao Wang
Project Manager Mike Smith and Laura Gottschalk
Priority Review Yes
Reviewer Name Xinyu Tang
Review Completion Date / Stamped
Date
Concurrence Lei Huang, Concurring Reviewer , VEB, DB, OBE
Tsai-Lien Lin, Branch Chief , VEB, DB, OBE
John A. Scott, Director, DB, OBE
Applicant BioNTech Manufacturing GmbH in partnership
with Pfizer, Inc.
Established Name COVID -19 Vaccine , mRNA
Trade Name COMIRNATY®
Pharmacologic Class Vaccine
Formulation, including Adjuvants, etc. After preparation, each 0.3 mL dose contains 30 µg
modified mRNA encoding SARS -CoV -2 spike
glycoprotein
Dosage Form and Route of
Administration Injectable Suspension, Intramuscular
Dosing Regimen Two 0.3 mL doses, 3 weeks apart
Indication and Intended Population Active immunization to prevent coronavirus disease
2019 (COVID -19) caused by severe acute
respiratory syndrome coronavirus 2 (SARS -CoV- 2)
in individuals 16 years of age and older
Statistical Review
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Page ii Table of Contents
Glossary ............................................................................................................................. 3
1. Executive Summary ...................................................................................................... 3
2. Regulatory Background ............................................................................................... 4
3. Sources of Data and Other Information Considered in the Review ........................ 5
4. Review of the Method Validation of the SARS -CoV -2 mNeonGreen Virus
Microneutralization Assay ............................................................................................ 5
4.1 Introduction ..................................................................................................................................... 5
4.2 Experimental Design ....................................................................................................................... 6
4.3 Statis tical Analysis ........................................................................................................................... 7
4.4 Linearity ......................................................................................................................... 7
4.4 Precision ........................................................................................................................................... 9
4.5 Limits of Quantitation ................................................................................................................... 10
4.6 Assay Intermediate Precision ....................................................................................................... 10
4.7 Limit of Detection .......................................................................................................................... 11
4.8 Extravariability of Replicates ....................................................................................................... 11
5. Review of the Report for Co-validation of Test Method TM100010380 -
Determination of the of PF-07302048 (BNT162b2 Construct,
Drug Product) by ............................................................................ 11
5.1 Introduction ................................................................................................................................... 11
5.2 Validation Outline ......................................................................................................................... 12
5.3 Precision – Repeatability .............................................................................................................. 13
5.4 Precision – Reproducibility .......................................................................................................... 14
5.5 Specificity ....................................................................................................................................... 15
5.6 Detection Limi t .............................................................................................................................. 15
5.7 Robustness ...................................................................................................................................... 17
6. Conclusions .................................................................................................................. 17
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Page 3 GLOSSARY
BLA biologics license application
CI confidence interval
COVID-19 Coronavirus Di sease 2019
DL detection limit
dLIA direct Luminex a ssay
DP drug product
DPC drug product control
DS drug substance
GMT geometric mean titer
IR information request
LLOQ lower limit of quantitation
IM intramuscular
IND Investigational New Drug application LNP lipid nanoparticle
LOD limit of detection
mRNA messenger RNA
RSD relative standard deviation
SARS-CoV-2 severe acute respiratory syndrome coronavirus -2
SARS -CoV- 2 mNG NT SARS -CoV-2 mNeonGreen virus microneutralization assay
S/N signal- to-noise
TDV Titer Determining Value
ULOQ upper limit of quantitation
VCA variance components analysis
1. Executive Summary
BioNTech and Pfizer submitted an original Biologics License Application (BLA) on May
18, 2021 for BNT162b2. BNT162b2 is a prophylactic vaccine that prevents Coronavirus
Disease 2019 (COVID -19) caused by severe acute respiratory syndrome coronavirus- 2
(SARS -CoV -2). The proposed indication is active immunization to prevent COVID -19
caused by SARS- CoV- 2 in individuals ≥16 years of age . The proposed dosage is 30 µg
via intramuscular (IM) injection following a dosing regimen of two 0.3-mL doses given three weeks apart .
This revi ew memo focuses on the statistical review of the non -clinical aspects of this
submission, including the validation of the clinical immunogenicity assay as well as the in-vitro potency assay. Specifically, this review memo covers:
• the validation of the SARS -CoV-2 mNeonGreen virus microneutralization assay
(SARS -CoV -2 mNG NT) for the detection of serum antibodies capable of
neutralizing SARS -CoV-2 (VR- MVR -10083), and
• the validation of Test M ethod TM100010380 v5.0 for d etermination of the
of PF-07302048 (BNT162b2 construct, Drug Product) by
(VAL 100147509)
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Page 4 based on the validation reports submitted in Module 5.3.1.4 of BLA125742/0.0 and Module 3.2.R of BLA125741/0.19, which have not been reviewed previously. With respect to the validation of the SARS -CoV- 2 mNG NT assay , results from the
validation study suggest acceptable accuracy and precision. The limit of detection (LOD),
lower limit of quantitation (LLOQ), and upper limit of quantitation (ULOQ) were determined to be , respectively . The LOD study demonstrated an
acceptable false positive rate but did not evaluate the false negative rate at the LOD .
Because this assay was not used in the determination of serostatus in clinical studies included in this BLA submission, the unknown false negative rate does not impact the
approval of this BLA. However, the false negative rate may be a concern in the future, depending on future use of this assay.
With respect to the validation of Test Method TM100010380 v5.0 (referred to as the
assay hereafter) , results from the validation study suggest acceptable
specificity and robust ness to
. The detection limit (DL) was determined to be
The repeatability and
reproducibility of the assay were estimated to be relative standard deviation
(RSD), respectively. Since the assay was validated as a limit test, the
repeatability and reproducibility results were evaluated for information only.
In conclusion, I consider both the SARS -CoV- 2 mNG NT and assay s
adequate for their intended uses in support of this BLA .
2. Regulatory Background
The Investigational New Drug Application (IND 19736) for BNT162b2 was submitted on
April 29, 2020. Fast Track Designation was granted on July 7, 2020 for individuals 18 years of age and older. On December 11, 2020, Emergency Use Authorization (EUA 27034) of BNT162b2 for active immunization to prevent COVID-19 in individuals 16 years o f age and older was granted (EUA product identified as Pfizer- BioNTech COVID-
19 Vaccine). BioNTech and Pfizer submitted this BLA on May 18, 2021 for BNT162b2.
The following documents regarding clinical assays were submitted in Module 5.3.1.4 of
BLA125741/0.0:
• Report on Method Validation of a Cepheid Xpert® Xpress PCR Assay to Detect SARS -CoV- 2 (VR- MVR -10080, Version 3.0),
• Method Validation Report for the Elecsys Anti- SARS -CoV- 2 Assay (VR -MVR-
10081, Version 2.0),
• Qualification Report for a Direct Luminex Assay (dLIA) for Quantitation
of IgG Antibodies to SARS- CoV-2 S1 Protein in Human Sera (VR- MQR-10211,
Version 2.0),
• Qualification Report for a Direct Luminex Assay (dLIA) for Quantitation
of IgG Antibodies to SARS- CoV- 2 RBD Protein i n Human Sera (VR- MQR -10212,
Version 2.0),
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Page 5 • Qualification of the SARS -CoV-2 mNeonGreen Virus Microneutralization Assay
(VR- MQR-10214, Version 2.0), and
• Method Validation of the SARS- CoV -2 mNeonGreen Virus Microneutralization
Assay (VR -MVR-10083, Version 1.0).
All these qualification and validation reports have been reviewed during the IND stage,
except for the validation report for the SARS -CoV- 2 mNG NT assay , which is covered in
this review memo .
The following document regarding the potency assay was submitted in Module 3.2.R of
BLA125741/0.19:
• Report for Co -Validation of Test Method TM100010380 – Determination of the
of PF-07302048 (BNT162b2 Construct, Drug Product) by
(VAL100147509, Version 1.0).
This validation report has not been previously reviewed during the IND stage and is
covered in this review memo as well .
3. SOURCES OF DATA AND OTHER INFORMATION CONSIDERED IN THE REVIEW
The following documents submitted to the BLA are reviewed:
• Method Validation of the SARS -CoV -2 mNeonGreen virus microneutralization assay
used for the detection of serum antibodies capable of neutralizing SARS- CoV- 2 (VR-
MVR-10083, Version 1.0) (BLA125742/0.0, dated February 9, 2021, received May 6, 2021),
• Report for Co -Validation of Test Method TM100010380 – Determination of the
of PF-07302048 (BNT162b2 Construct, Drug Product) by
(VAL100147509, Version 1.0) (BLA125742/0.19, Module 3.2.R, dated
July 16, 2021, received July 28, 2021).
• Response to 04 Aug 2021 FDA Information Request (IR) (BLA125742/0.34, Module 1.11.1, dated August 6, 2021, received August 6, 2021), and
• Validation of Analytical Procedure – (BLA125742/0.34,
Module 3.2.P.5.3, dated August 6, 2021, received August 6, 2021).
The following document submitted to the IND is also referred to when reviewing the validation of the SARS- CoV- 2 mNG NT assay :
• Validation Protocol for t he SARS -CoV- 2 mNeonGreen Virus Microneutralization
Assay (VR -MVP-10074, Version 2.0) (IND19736/157, Module 5.3.1.4, dated
December 2, 2020, received December 4, 2020).
4. REVIEW OF THE METHOD VALIDATION OF THE SARS -COV-2 MNEONGREEN
VIRUS MICRONEUTRALIZATION ASSAY
4.1 Introduction
The SARS -CoV- 2 mNG NT assay is a biofunctional assay that measures neutralizing
antibodies against SARS- CoV-2. This assay is described in T est Method VR- TM-10298.
Briefly,
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This validation study evaluated assay linearity, precision, limit of detection,
and intermediate precision . The linearity and precision results were used to
define the limits of quantitation and extravariability criterion .
4.2 Experimental Design
Validation of the SARS -CoV- 2 mNG NT assay was performed as described in the
validation protocol ( VR-MVP -10074).
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5.1 Introduction
Test Method TM100010380 “ Determination PF-07302048
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5.2 Validation Outline
This validation report contains the results of validation study conducted according to the following method validation protocols:
• VAL100138078, V1.0 Protocol for co -validation of test method TM100010380,
which was the o riginal method validation protocol to evaluate repeatability,
reproducibility, specificity, and detection limit,
• INX100459445, V1.0 Amendment for protocol for co -validation of test method
TM100010380, which was an amendment to original method validation protocol
VAL100138078 to evaluate the robustness of
during reproducibility studies.
In routine tests , the assay is analyzed
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6. CONCLUSIONS
This review memo focuses on the validation of the SARS -CoV- 2 mNG NT assay for the
detection of serum antibodies capable of neutralizing SARS -CoV-2 and the validation of
the potency assay, TM100010380 v5.0, for determination of the
of PF-07302048 by .
With respect to the validation of the SARS -CoV- 2 mNG NT assay , results from the
validation study suggest acceptable accuracy and precision. The LOD, LLOQ, and
ULOQ were determined to be , respectively. The LOD study
demonstrated
With respect to the validation of the assa y, results from the validation
study suggest acceptable specificity and is robust to
. The detection limit (DL) was determined to be
. The
repeatability and reproducibility of the assay were estimated to be
, respectively. Since the assay was validated as
a limit test, the repeatability and reproducibility results were evaluated for information
only. In conclusion , I consider both the SARS -CoV- 2 mNG NT and assay s
adequate for their intended uses in support of this BLA.
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