docs/Statistical Review -- COMIRNATY.txt

Statistical Review
STN: 125742/0
Application Type
Original BLA
STN
125742/0
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
Lei Huang, Concurring Reviewer, VEB, DB, OBE
Concurrence
Tsai-Lien Lin, Branch Chief, VEB, DB, OBE
John A. Scott, Director, DB, OBE
BioNTech Manufacturing GmbH in partnership
Applicant with Pfizer, Inc.
Established Name
COVID-19 Vaccine, mRNA
Trade Name
COMIRNATY@
Pharmacologic Class
Vaccine
After preparation, each 0.3 mL dose contains 30 ug
Formulation, including Adjuvants, etc.
modified mRNA encoding SARS-CoV-2 spike glycoprotein
Dosage Form and Route of
Administration
Dosing Regimen
Injectable Suspension, Intramuscular Two 0.3 mL doses, 3 weeks apart
Active immunization to prevent coronavirus disease
2019 (COVID-19) caused by severe acute
Indication and Intended Population respiratory syndrome coronavirus 2 (SARS-CoV-2)
in individuals 16 years of age and older
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Table of Contents
GlossarY ..........
3
1. Executive Summary...
2. Regulatory Background.
3. Sources of Data and Other Information Considered in the Review .....
4. Review of the Method Validation of the SARS-CoV-2 mNeonGreen Virus
Microneutralization Assay ...........
4.1 Introduction...............
4.2 Experimental Design .......
4.3 Statistical Analysis..
4.4 (b) (4) Linearity...
4.4 Precision......
4.5 Limits of Quantitation.....
4.6 Assav Intermediate Precision.....
4.7 Limit of Detection..
4.8 Extravariability of Replicates.
11
..... 11
5. Review of the Report for Co-validation of Test Method TM100010380 -
Determination of the (b) (4)
of PF-07302048 (BNT162b2 Construct,
Drug Product) by (b) (4)
11
5.1 Introduction............
5.2 Validation Outline...........
5.3 Precision - Repeatability
5.4 Precision - Reproducibility
5.5 Specificity......
5.6 Detection Limit
.................... 11
.......... 12
.................. 13
14
15
15
5.7 Robustness........
........................... 17
6. Conclusions................
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GLOSSARY
BLA
CI
COVID-19
DL dLIA
DP
DPC
DS
GMT
IR
LLOO
IM
IND
ENP
LOD (b) (4)
mRNA
(b) (4)
biologics license application confidence interval
Coronavirus Disease 2019 detection limit direct Luminex assay drug product drug product control drug substance geometric mean titer information request lower limit of quantitation intramuscular
Investigational New Drug application lipid nanoparticle limit of detection
messenger RNA
RSD
SARS-CoV-2
SARS-CoV-2 mNG NT
SIN
TDV
ULOQ
VCA
relative standard deviation
severe acute respiratory syndrome coronavirus-2
SARS-CoV-2 mNeonGreen virus microneutralization assay signal-to-noise
Titer Determining Value upper limit of quantitation variance components analysis
1. Executive Summary
BioNTech and Pfizer submitted an original Biologics License Application (BLA) on May 18, 2021 for BNT1622. 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 g via intramuscular (IM) injection following a dosing regimen of two 0.3-mL doses given three weeks apart.
This review 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 Method TM100010380 v5.0 for determination of the (b) (4)
of PF-07302048 (BNT16262 construct, Drug Product) by (b) (4)
(VAL100147509)
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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 (b) (4)
, 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 (b) (4)
assay hereafter), results from the validation study suggest acceptable
specificity and robustness to b) (4)
. The detection limit (DL) was determined to be b) (4)
The repeatability and
reproducibility of the assay were estimated to be (b) (4)
relative standard deviation
(RSD), respectively. Since the (b) (4)
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 (b) (4) adequate for their intended uses in support of this BLA.
assays
2. Regulatory Background
The Investigational New Drug Application (IND19736) for BNT16262 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 BNT16262 for active immunization to prevent COVID-19 in individuals 16 years of 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 PC 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 (b) (4)
Direct Luminex Assay (dLIA) for Quantitation
of IgG Antibodies to SARS-CoV-2 S1 Protein in Human Sera (VR-MQR-10211,
Version 2.0),
• Oualification Report for a b) (4)
Direct Luminex Assay (dLIA) for Ouantitation
of IgG Antibodies to SARS-CoV-2 RBD Protein in Human Sera (VR-MQR-10212,
Version 2.0),
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• Oualification 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 (b) (4)
(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 (4)
of PF-07302048 (BNT162b2 Construct, Drug Product) by (b) (4)
(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 - (b) (4)
(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 the 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 Test Method VR-TM-10298
Briefly, (b) (4)
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(b) (4)
This validation study evaluated assay (b) (4) linearity, precision, limit of detection, and intermediate precision. The ) (4) 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). (b) (4)
(b) (4)
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(b) (4)
5.1 Introduction
Test Method TM100010380 Determination (b) (4)
(b) (4)
Statistical Review
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PF-07302048
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(b) (4)
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 original 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 (b) (4)
during reproducibility studies.
In routine tests, the assay is analyzed (b) (4)
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(b) (4)
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 (b) (4) potency assay, TM100010380 v5.0, for determination of the (b) (4)
of PF-07302048 by (b) (4)
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 ULOO were determined to be b) (4)
, respectively. The LOD study
demonstrated (b) (4)
With respect to the validation of the (b) (4)
assay, results from the validation
study suggest acceptable specificity and is robust to (b) (4)
. The detection limit (DL) was determined to be (b) (4)
The
repeatability and reproducibility of the assay were estimated to be (b) (4)
, respectively. Since the (b) (4)
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 (b) (4) adequate for their intended uses in support of this BLA.
assays
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