Document text
Analysis Data Reviewer Guide
for BLA Sequencing Data
Analysis
BioNTech SE and PFIZER INC. Study
C4591001
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ANALYSIS DATA REVIEWER GUIDE
REVISION HISTORY
Version Summary of Major Change(s) and Impact Version Date
1.0 First approved version of Analysis Data Reviewer Guide for
Sequencing data Analysis 03-Jun-2021
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Analysis Data Reviewer Guide
Contents
1. Introduction ................................ ................................ ................................ ................................ .. 4
1.1 Purpose ................................ ................................ ................................ ...................... 4
1.2 Acronyms ................................ ................................ ................................ .................. 5
1.3 Study Data Standards and Dictionary Inventory ................................ ....................... 6
1.4 Source Data Used for Analysis Dataset Creation ................................ ...................... 6
2. Protocol Description ................................ ................................ ................................ ..................... 6
2.1 Protocol Number and Title ................................ ................................ ........................ 6
2.2 Protocol Design in Relation to ADaM Concepts ................................ ....................... 6
3. Analysis Considerations Related to Multiple Analysis Datasets ................................ .................. 6
3.1 Study Populations and Core Variables ................................ ................................ ...... 6
3.2 Treatment Variable ................................ ................................ ................................ .... 6
3.3 Subject Issues that Require Special Analysis Rules ................................ .................. 7
3.4 Use of Visit Windowing, Unscheduled Visits, and Record Selection ....................... 7
3.5 Imputation/Derivation Methods ................................ ................................ ................ 8
4. Analysis Data Creation and Processing Issues ................................ ................................ ............. 8
4.1 Split Datasets ................................ ................................ ................................ ............. 8
4.2 Data Dependencies ................................ ................................ ................................ .... 8
4.3 Intermediate Datasets ................................ ................................ ................................ 8
5. Analysis Dataset Descriptions ................................ ................................ ................................ ...... 8
5.1 Overview ................................ ................................ ................................ ................... 8
5.2 Analysis Datasets ................................ ................................ ................................ ...... 8
5.2.1 ADSL – Subject -Level Analysis Dataset ................................ ................................ .. 9
5.2.2 ADXB – Sequencing Analysis Dataset ................................ ................................ ..... 9
6. Data Conformance Summary ................................ ................................ ................................ ..... 11
6.1 Conformance Inputs ................................ ................................ ................................ 11
6.2 Issues Summary (Pinnacle 21 Enterprise Validation Report) ................................ . 11
7. Submission of Programs ................................ ................................ ................................ ............. 11
7.1 ADaM Programs ................................ ................................ ................................ ..... 11
7.2 Analysis Output Programs ................................ ................................ ....................... 12
8. Appendix ................................ ................................ ................................ ................................ .... 12
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1. Introduction
1.1 Purpose
This document provides context for the analysis datasets and terminology that benefit from
additional explanation beyond the Data Definition document (define.xml) for an individual
study. In addition, this document provides a summary of ADaM conformance findings. This
ADRG is a supplement to the primary ADRG already submitted for the BLA and covers the
efficacy sequencing data analyses in blinded placebo -controlled follow -up period for the
COVID -19 cases data (cutoff date: 13Mar 2021 ).
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5 1.2 Acronyms
Acronym Translation
ADaM Analysis Dataset Model
ADRG Analysis Data Reviewer’s Guide
BLA Biologic s License Application
COVID -19 Coronavirus Disease 2019
IG Implementation Guide
NA Not Applicable
SAP Statistical Analysis Plan
SDTM Study Data Tabulation Model
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1.3 Study Data Standards and Dictionary Inventory
Standard or Dictionary Versions Used
SDTM •SDTM v1.4
•SDTM -IG v3.2
SDTM Controlled Terminology CDISC SDTM Controlled Terminology, 2020 -03-27
ADaM •ADaM v2.1
•ADaM -IG v1.1
ADaM Controlled Terminology CDISC ADaM Controlled Terminology, 2020 -03-27
Data Definitions Define -XML v2.0
Pinnacle 21 Pinnacle 21 Enterprise 4.2.0
1.4 Source Data Used for Analysis Dataset Creation
The ADaM dataset s were derived from the SDTM datasets.
2. Protocol Description
2.1 Protocol Number and Title
Refer to the primary ADRG .
2.2 Protocol Design in Relation to ADaM Concepts
Refer to the primary ADRG .
3. Analysis Considerations Related to Multiple Analysis Datasets
3.1 Study Populations and Core Variables
Refer to the primary ADRG .
3.2 Treatment Variable
ARM versus TRTxxP
Are the values of ARM equivalent in meaning to values of TRT xxP?
No, TRT01P is null when ARM equals to “NOT ASSIGNED” or “SCREEN FAILURE” .
ARM represents the planned arm for the blinded placebo -controlled period based on
randomization file . TRT01P ha s the planned treatment for the blinded placebo -controlled
period . TRT02P is only available in ADSL , and was not included and used in the
sequencing data analysis . See details in below table.
PHASE ARM TRT01P TRT02P
Phase 1 BNT162b1 Phase 1 (10
mcg) BNT162b1 Phase 1 (10
mcg) -
BNT162b1 Phase 1 (20
mcg) BNT162b1 Phase 1 ( 20
mcg) -
BNT162b1 Phase 1 (30
mcg) BNT162b1 Phase 1 ( 30
mcg) -
BNT162b1 Phase 1 (100/10
mcg) BNT162b1 Phase 1 (100/10
mcg) -
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7 PHASE ARM TRT01P TRT02P
BNT162b2 Phase 1 (10
mcg) BNT162b 2 Phase 1 (10
mcg) -
BNT162b2 Phase 1 (20
mcg) BNT162b 2 Phase 1 (20
mcg) -
BNT162b2 Phase 1 (30
mcg) BNT162b 2 Phase 1 (30
mcg) -
Placebo Placebo -
Placebo Placebo BNT162b2 Phase 1
(30 mcg)
NOT ASSIGNED - -
SCREEN FAILURE - -
Phase 2/3
BNT162b2 Phase 2/3
(30 mcg) BNT162b2 Phase 2/3
(30 mcg) -
Placebo Placebo -
Placebo Placebo BNT162b2 Phase 2/3
(30 mcg)
NOT ASSIGNED - -
SCREEN FAILURE - -
Note: Unit of dose ‘mcg’ was displayed as ‘μg’ in all of outputs.
ACTARM versus TRTxxA
If TRT xxA is used, then are the values of ACTARM equivalent in meaning to values of
TRT01A?
No. TRT01A is not used in sequencing analysis data . TRT02A is only available in
ADSL, and was not included and used in the sequencing data analysis .
Use of ADaM Treatment Variables in Analysis
Are both planned and actual treatment variables used in analyses?
No. Only the planned treatment was used in the sequencing data analysis.
Use of ADaM Treatment Grouping Variables in Analysis
Are both planned and actual treatment grouping variables used in analysis?
No. Neither planned nor actual treatment grouping variables are used in analysis
3.3 Subject Issues that Require Special Analysis Rules
No change to this section, please refer to the details from the primary ADRG .
3.4 Use of Visit Windowing, Unscheduled Visits, and Record Selection
Was windowing used in one or more analysis datasets?
No.
Were unscheduled visits used in any analyses?
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8 No.
3.5 Imputation/Derivation Methods
If date imputation was performed, were there rules that were used in multiple analysis datasets?
No.
Was DTYPE used in one or more analysis datasets?
No.
4. Analysis Data Creation and Processing Issues
4.1 Split Datasets
There are no split datasets.
4.2 Data Dependencies
ADXB dataset pull core variable values from ADSL , and also uses ADC19EF dataset as an
input to create efficacy parameter variables.
4.3 Intermediate Datasets
No intermediate analysis datasets were created in this trial.
5. Analysis Dataset Descriptions
5.1 Overview
Are data for screen failures, including data for run-in screening (for example, SDTM values of
ARMCD=’SCRNFAIL’, or ‘NOTASSGN’) included in ADaM datasets?
Yes. Subjects with ‘NOTASSGN’ ‘SCRNFAIL ’ are only included in ADSL .
Are data taken from an ongoing study?
Yes. The sequencing data contains SARS -CoV-2 lineage data for the COVID -19 cases as of
13Mar 2021 cutoff . For the other data, please refer to the primary package.
Do the analysis datasets support all protocol - and statistical analysis plan-specified objectives?
No. The analysis dataset in this supplemental package only supports analysis of SARS -
CoV -2 lineage for COVID -19 cases .
Additional Content of Interest
No additional content of Interest.
5.2 Analysis Datasets
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Dataset Label
Class
Efficacy
Safety
Baseline or
other subject
PK/PD
Primary
Structure
ADSL
Subject -Level
Analysis Dataset SUBJECT
LEVEL
ANALYSIS
DATASET X One record per subject
ADXB
Sequencing
Analysis Dataset
BASIC DATA
STRUCTURE X One record per subject
per analysis parameter
per analysis timepoint
5.2.1 ADSL – Subject -Level Analysis Dataset
The ADSL is identical to the dataset included in the BLA esub package , for Pinnacle 21 validation
checks .
5.2.2 ADXB – Sequencing Analysis Dataset
The purpose of this dataset is to get SARS -CoV -2 lineage phylogenetic analysis information for
the COVID -19 cases. Key variab les in this dataset are
Variable Name Variable Description
FC19D27 First COVID Onset 7D Post D2 (PD)
FSEVPD27 First Sev COVID Onset 7D Post D2 (PD)
FSEVCD27 First Sev COVID Onset 7D Post D2 (CDC)
FSEVPD1 First Sev COVID Onset Post D1 (PD)
FSEVCD1 First Sev COVID Onset Post D1 (CDC)
CDC= Centers for Disease Control and Prevention defined ; D1=Dose 1; D2=Dose 2; PD=Protocol -define d;
Sev=Severe .
Table below describes subset condition for total number of subjects with various definition of
confirmed COVID -19 cases (N) from ADC19EF and ADSL .
Analysis Population Total Number
of Subjects ( N) Subset Condition for
Total N Sub-condition BNT162b2 Placebo
Evaluable
Efficacy Subjects with first
COVID -19 occurrence
From 7 Days After
Dose 2 81 873 ADSL.EVALEFFL="Y" and
ADSL.PHASEN ne 1 and
ADSL.MULENRFL ne "Y" and
ADSL. HIVFL = 'N' and
UPCASE(ADC19EF.PARAMCD)
= "C19ONST" and
FIND(ADC19EF.AVALC, 'POS' ,
'i') and ADC19EF.ILD27FL = "Y"
and ADC19EF.FILOCRFL = "Y"
and ADC19EF.PDRMUPFL = "N"
and ((NOT
MISSING(ADC19EF.DVSTDT)
and ADC19EF.ADT <=
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10 Analysis Population Total Number
of Subjects ( N) Subset Condition for
Total N Sub-condition BNT162b2 Placebo
ADC19EF.DVSTDT) or
MISSING(ADC19EF.DVSTDT))
Subjects with first
severe COVID -19
occurrence Based on
FDA -Definition From
7 Days After Dose 2 1 21 ADSL.EVALEFFL="Y" and
ADSL.PHASEN NE 1 and
ADSL.MULENRFL NE "Y" and
ADSL. HIVFL = 'N' and
UPCASE( ADC19EF. PARAMCD)
= "SEVCONST" and
FIND( ADC19EF .AVALC, 'POS' ,
'i') and ADC19EF. ILD27FL = "Y"
and ADC19EF. FILOCRFL = "Y"
and ADC19EF. PDRMUPFL = "N"
and ((NOT
MISSING( ADC19EF .DVSTDT)
and ADC19EF .ADT <=
ADC19EF .DVSTDT) or
MISSING( ADC19EF .DVSTDT))
Subjects with first
severe COVID -19
occurrence Based on
CDC -Definition From
7 Days After Dose 2 0 32 ADSL.EVALEFFL="Y" and
ADSL.PHASEN NE 1 and
ADSL.MULENRFL NE "Y" and
ADSL. HIVFL = 'N' and
UPCASE( ADC19EF. PARAMCD)
= "CDCSONST" and
FIND( ADC19EF .AVALC, 'POS' ,
'i') and ADC19EF. ILD27FL = "Y"
and ADC19EF. FILOCRFL = "Y"
and ADC19EF. CDRMUPFL= "N"
and ((NOT
MISSING( ADC19EF .DVSTDT)
and ADC19EF .ADT <=
ADC19EF .DVSTDT) or
MISSING( ADC19EF .DVSTDT))
Dose 1
All-
Available
Efficacy Subjects with first
severe COVID -19
occurrence Based on
FDA -Definition After
Dose 1 1 30 ADSL. AAI1EFFL ="Y" and
ADSL.PHASEN ne 1 and
ADSL.MULENRFL ne "Y" and
ADSL. HIVFL = 'N' and
UPCASE (ADC19EF. PARAMCD )
= "SEVCONST" and
FIND( ADC19EF .AVALC, 'POS' ,
'i') and ADC19EF .ADT >=
ADC19EF .VAX101DT and
ADC19EF .FILOCRFL= "Y" and
ADC19EF .PDRMUPFL = "N"
Subjects with first
severe COVID -19
occurrence Based on 1 45 ADSL. AAI1EFFL ="Y" and
ADSL.PHASEN ne 1 and
ADSL.MULENRFL ne "Y" and
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11 Analysis Population Total Number
of Subjects ( N) Subset Condition for
Total N Sub-condition BNT162b2 Placebo
CDC -Definition After
Dose 1 ADSL. HIVFL = 'N' and
UPCASE (ADC19EF. PARAMCD )
= "CDCSONST " and
FIND( ADC19EF .AVALC, 'POS' ,
'i') and ADC19EF .ADT >=
ADC19EF .VAX101DT and
ADC19EF .FILOCRFL= "Y" and
ADC19EF .CDRMUPFL = "N"
6. Data Conformance Summary
6.1 Conformance Inputs
Specify the software name and version for the analysis datasets
Pinnacle 21 Enterprise 4. 2.0., Validation Engine version FDA 2010.1
Specify the version of the validation rules (i.e. CDISC, FDA) for the analysis datasets
CDISC ADaM -CT 2020 -03-27
Specify the software name and version for the define.xml
Pinnacle 21 Enterprise 4.2.0.
Specify the version of the validation rules (i.e. CDISC, FDA) for the define.xml
CDISC ADaM CT 2020 -03-27
6.2 Issues Summary (Pinnacle 21 Enterprise Validation Report )
Note: The issue s associated with ADSL are not included as they are covered in the BLA esub
package.
Check
ID Diagnostic
Message FDA
Severity Dataset Count
(Issue
Rate) Explanation
CT2002 RACE value not
found in 'Race'
extensible codelist Warning ADXB 36
(3.14%)
New terms were added to extensible
codelist RACE for the study protocol
needs:
Multiple
7. Submission of Programs
All programs for analysis datasets are submitted as shown below. All programs were created
on a SAS platform using 9.4. ADSL.sas (adsl -sas.txt) must be run first before any other
ADaM datasets; ADXB program is dependent on ADSL and ADC19EF . Please be aware
ADC19EF and ADSYMPT ( ADSYMPT was used to populate efficacy listing ) have been
included in the primary package so will not be submitted again .
7.1 ADaM Programs
Program
Name
Output Input
Macro Used
adxb -sas.txt adxb .xpt xb adsl adc19ef NA
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12 7.2 Analysis Output Programs
NA
8. Appendix
NA
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