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125742/45 Data validation Report Summary and Subsequent follow-up with Pfizer
Our Reference: STN 125742/45 (studied under IND 19736/EUA 27034)
Sponsor: Pfizer-BioNTech SE
Product: COVID-19 (BNT162b2)
Proposed Indication: Prevention of COVID-19 in individuals 12 through 15 years of
age
On December 16, 2021, the sBLA was submitted and included datasets for C4591001.
x C4591001 - Phase 1/2/3 Study to Evaluate the Safety, Tolerability,
Immunogenicity, and Efficacy of RNA Vaccine Candidates Against COVID-19 in
Healthy Individuals. The proposed GRVDJHLVȝJYLDLQWUDPXVFXODU ,0
injection following a dosing regimen of two 0.3-mL doses given 3 weeks apart. Data cutoff date is Sep 2, 2021.
On January 6, 2022, the eDATA team discussed the validation results of C4591001 with
the review committee for STN 125742/45. Based on the validation results (beginning
page 3 below) and a deeper dive into the study datasets, the following concerns were identified:
1. There are 2 subjects (10961068 and 11631062) with AE records that have
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Please explain.
2. :HKDYHIRXQGWKDWVXEMHFW ZDVLQFOXGHGLQ6'70'0EXW QRW$'6/
Please explain.
3. As previously communicated and discussed under BLA 125742 and other
BLAs/INDs reactogenicity events that begin within the prespecified assessment period should have been reported in FACE and summarized with the subject
diary data in CE. Since this was not implemented, we request that:
a. reactogenicity events that begin within the prespecified assessment period
that are currently reported in the AE dataset be included in FACE, and
then be flagged in AE so that we know that it is being included in the
FACE dataset.
b. Include all individual supporting assessments (daily e-diary and any
unplanned assessments) and the assessor for each finding (identified
using FAEVAL=STUDY SUBJECT or INVESTIGATOR) in the FACE domain.
c. 0DLQWDLQRQHURZSHUVXEMHFWYDFFLQDWLRQV\PSWRPLQ the CE domain, with
CE summarizing the duration of the event and maximum severity. 0D[LPXPVHYHULW\ &(6(9 VKRXOGEHEDVHGRQWKHKLJKHVW -level severity Brenda R.
Baldwin -SDigitally signed by Brenda R. Baldwin -S Date: 2022.04.22 12:37:06 -04'00'
FDA-CBER-2022-5812-0500394
reported by the subject (via e-diary) or investigator (in the unplanned
assessment CRF).
d. Use SUPPCE CESEV1 and CEDIFFRS to show assessment of severity
by study subject and reason investigator’s assessment of severity differed from study subject as needed for events reported in CE.
e. Update the analysis dataset(s) with records covering the entire event
duration (which could go beyond the protocol-defined assessment period)
with start/end dates and durations (based on first and last days the
symptom was present as recorded in the e-diary and/or Symptom Resolved Dates CRF, ignoring any gaps) derived from both the e-diary and CRF data.
These comments were conveyed to Pfizer on January 19, 2022. On February 2,
2022, Pfizer provided their responses in amendment 2.
In response to comment 1, Pfizer provided clarifications and also indicated that
these subjects are not included in the analysis of the age group under review in this supplement as neither are adolescents.
In response to comment 2, Pfizer stated that Participant 11311279 was 15 years
of age at the time of enrollment but turned 16 years of age at the time of vaccination, therefore, this participant was not included in the ADSL. In response to comment 3, Pfizer indicated that the tabulation and analysis
package submitted to FDA in the original 125742/0 submission on 0D\ 06, 2021
included the data to support the review for participants 12-15 years of age (in
legacy tabulation datasets). With this response, Pfizer/BioNTech are providing additional documents including a roadmap, supplemental ADRG, reactogenicity
tables with tracked changes, summary of differences between CSR and updated
reactogenicity data, and reactogenicity supplemental TLFs. These are specific to the 12 to 15 year old adolescents.
All explanations are acceptable.
FDA-CBER-2022-5812-0500395
Data Fitness Findings Report
BLA125742
BioNTech SE and Pfizer, December 2021
Findings Notes
C4591001 – 1mth - sBLA (12-15 Years of Age)
Title: A Phase 1/2/3 Study to Evaluate the Safety, Tolerability, Immunogenicity, and Efficacy of RNA Vaccine Candidates Against COVID-
19 in Healthy Individuals.
Document / Standard Version Notes
annotated CRF Seems fine
SDTM Implementation
Guide SDTM-IG v3.2
SDTM Controlled Terminology 2020-03-27
SDTM define.xml V2.0 Seems fine
Medications Dictionary WHODD GLOBALV3Mar20
Medical Events Dictionary
(MedDRA) V23.1
SDTM Reviewer’s Guide PhUSE template Seems fine
From ADRG: All data up through 13Mar2021 cutoff are included in the SDTM datasets and used for ADaM datasets and analyses.
Furthermore, any data related to the booste r portion of the Phase 1 subjects was also programmatically excluded from SDTM data.
FDA-CBER-2022-5812-0500396
C4591001 – 6mth - sBLA Analysis for Participants, 12-15 Years of Age
Title: A Phase 1/2/3 Study to Evaluate the Safety, Tolerability, Immunogenicity, and Efficacy of RNA Vaccine Candidates Against COVID-
19 in Healthy Individuals.
Document / Standard Version Notes
annotated CRF Seems fine
SDTM Implementation
Guide SDTM-IG v3.2
SDTM Controlled
Terminology 2020-03-27
SDTM define.xml V2.0 Seems fine
Medications Dictionary WHODD GLOBALB3Mar21
Medical Events
Dictionary
(MedDRA) V24.0
SDTM Reviewer’s Guide PhUSE template Seems fine
From ADRG: All data up through 02Sep2021 cutoff are included in the SDTM datasets and used for ADaM datasets and analyses.
FDA-CBER-2022-5812-0500397
Data Issues
The cSDRG/ADRG do not really clearly explain the difference in number of subjects/records between the 2 versions of data
x Study C4591001 1mth – 48,091 subjects total
o Subjects included have ages from 12 to 91
x Study C4591001 6mth – 2,265 subjects total
o Subjects included have ages from 12 to 15
o Note that there are 42 additional subjects from the 1mth vers ion, with ages from 12 to 15, that weren’t included in the
6mth version of the data…but these are all SCREEN FAILURE or NOT ASSIGNED subjects
There are subjects with AE records that have AEACN = DRUG WITHDRAWN, but they only have COMPLETED records in DS
x Study C4591001 1mth – 2 subjects
o See report “ BLA125742 - c4591001 - 1mth - subjects with AE DRUG WITHDRAWN but only COMPLETED records in
DS.xlsx ”
FDA-CBER-2022-5812-0500398
Application: BLA125742 Generated: 2021-12-28T17:14:00
Study: c4591001-6mth Version: 2.5.3
EDR Sequence: 0211 Data Standards Training
EDR Link: \\cber-fs3\m\eCTD Submissions\BLA125742\0211\m5\datasets\c4591001\tabulations\sdtm-6mth
EDR Link: \\cber-fs3\m\eCTD Submissions\BLA125742\0211\m5\datasets\c4591001\analysis\adam\datasets-6mth
Summary Potential Data Quality Findings
Documents Demographics
SDTM Define.xml 53 of 2 265 (2.3%) RACE values not found in CDISC codelist
Study Data Reviewer's Guide 4 of 2,265 (0 2%) subjects have a different actual arm than planned
ADaM Define xml Disposition
Analysis Data Reviewer's Guide 16 of 15 919 (0.1%) disposition statuses or protocol milestones are potential duplicates
Exposure
Standards / Dictionaries 59 of 6 511 (0.9%) treatments have ended after the last disposition date
SDTM-IG 3 2 Adverse Events and Potential Adverse Events
MedDRA 24.0 34 of 1,558 (2.2%) adverse events have started after the last disposition date
1 558 of 1 558 (100.0%) adverse events are missing treatment emergent flag in SUPPAE
Subjects / Actual Arms 480 of 1,558 (30.8%) adverse events have neither severity or toxicity grade populated
2265 - Subjects Clinical Events
1132 (50 0%) - B2_P23_30 169 of 54 538 (0.3%) events are missing start time-point
1129 (49 8%) - PLACEBO Laboratory
4 (0.2%) - Likely Not Treated Laboratory results use inconsistent values for Standard Units (LBSTRESU)
1 of 645 (0 2%) observations are missing Reference Range Upper Limit in Standard Units (LBSTNRHI)
Datasets 2 261 of 2 265 (99.8%) subjects are either missing a lab test or a baseline value
42 - Total SDTM Datasets Vital Signs
0 - Custom Datasets No significant findings
15 - Suppqual Datasets General Findings
9 - ADaM Datasets (ADAE, ADC19EF, ADCM, ADDS, Study events are missing end time-points
ADDV, ADMH, ADSL, ADSYMPT, ADXB) Study subjects are missing all baseline flags for all tests present in the dataset
Traceability
Reports to Help Basic Review Activities 1 of 2,265 (< 0.1%) subjects in SDTM DM are not included in ADSL
Deaths 481 of 1 558 (30.9%) Adverse Events in SDTM AE are not present in ADAE
No mention of death in any dataset
Adverse Events
Adverse Events Coding Quality
Disposition
Disposition Coding Quality
Supplemental Info
Supplemental ContentsA PHASE 1/2/3, PLACEBO-CONTROLLED, RANDOMIZED, OBSERVER-BLIND, DOSE-FINDING STUDY TO EVALUATE THE SAFETY, TOLERABILITY, IMMUNOGENICITY, AND EFFICACY OF SARS-
COV-2 RNA VACCINE CANDIDATES AGAINST COVID-19 IN HEALTHY ADULTS
FDA-CBER-2022-5812-0500399