Study Data Reviewer’s Guide
A One-Month Oral Toxicology Study in the Rat
with C1234 followed by a One-Month
Recovery Period
(Study 54321)
A Pharma Company
500 Farm Road
West Orange, New Jersey 07052
United States
1
CONTENTS
1.
2.
Study Protocol Title, Number, and Version .............................................................................3
Study Design ........................................................................................................................................3
2.1
2.2
3.
4.
5.
Standards, Formats, and Terminologies and their Versions ............................................5
3.1
3.2
3.3
Standards Used ........................................................................................................................................5
Rationale for Selection ..........................................................................................................................5
Nonstandard Terminology ..................................................................................................................5
Description of Study Datasets ......................................................................................................5
4.1
4.2
Dataset Summary ....................................................................................................................................5
Use of Supplemental Qualifiers .........................................................................................................6
Data Standards Validation Rules, Versions, and Issues Conformance Issues ............6
5.1
5.2
5.3
5.4
5.5
6.
Summary.....................................................................................................................................................3
Trial Domain Overview ........................................................................................................................4
Validation Outcome Summary ...........................................................................................................6
Validation Method Used .......................................................................................................................6
Errors ...........................................................................................................................................................6
Warnings ....................................................................................................................................................6
Notices .........................................................................................................................................................8
Description of Sponsor Decisions Related to Data Standard Implementations ........8
6.1
6.2
6.3
6.4
Sponsor-Defined Standardization Descriptions .........................................................................8
Differences between SEND Datasets and Study Report ..........................................................8
Nonstandard Electronic Data Submitted ......................................................................................9
Legacy Data Conversion Plan .............................................................................................................9
2
1.
SDRG Introduction
1.1
Study Protocol Title, Number, and Version
Study Title
A One-Month Repeat-Dose Oral Toxicology Study in the Rat with C1234
followed by a One-Month Recovery Period
Study Number
54321
Study Version
There were no protocol or report amendments that affected data collection or
interpretation of this study
2.
Study Design
2.1
Study Design Summary
C12345 in in a 0.5% methylcellulose vehicle was administered orally by gavage once daily for 28
consecutive days to 3 groups of male and female rats. Dose levels were 10, 30, and 100 mg/kg/day for
Groups 2, 3, and 4, respectively. A concurrent control group (Group 1) received the vehicle on a
comparable regimen. The dose volume was 10 mL/kg for all groups.
Each group consisted of 20 males and 20 female rats. Following 28 consecutive days of dosing, all but 5
rats per sex from the control group (Group 1) and highest dose group (Group 4) euthanized. The
remaining animals continued onto a 28 day non-dose recovery period, and were then euthanized.
Complete necropsies were performed on all animals, and selected organs were weighed at the
scheduled necropsies. Selected tissues were examined microscopically from all animals
The animals were observed twice daily for mortality and moribundity. Clinical examinations were
performed weekly, and detailed physical examinations were performed daily. Individual body weights
and food consumption were recorded daily. Blood and urine was collected for hematology, coagulation,
serum chemistry, and urinalysis prior to the initiation of dose administration and on study day 28.
Blood samples for toxicokinetic evaluation were collected from 5 animals per group and sex prior to
and at 1, 2, 4, 8, and 24 hours after dose administration on study days 1 and 28.
Number of Animals
Group Treatment
Dose
Level
Dose
Dose
Concentration Volume
Main
Terminal
mg/kg/day
mg/mL
mL/kg
Male
TK
Recovery
Female Male Female
Main
Male
Female
1
Vehicle
0
0
10
10
10
5
5
5
5
2
C12345
10
1
10
15
15
--
--
5
5
3
C12345
30
2
10
15
15
--
--
5
5
4
C12345
100
10
10
15
15
5
5
5
5
3
2.2
Trial Design Domain Overview
The following diagram illustrates the trial design. Each color represents different Trial Element, with the
ELEMENT variable entry in each cell; refer to the TE domain for the associated ETCD
Study
Group
SPGRPCD
Trial Arms
Element in each Epoch
ARMCD
ARM
Predosing
Treatment
01
0 mg/kg Vehicle
Predosing
Vehicle
Trial Set
Recovery
1
01R
0 mg/kg Recovery
Predosing
Vehicle Recovery
2
02
10 mg/kg C1234
Predosing
10 mg/kg
3
03
30 mg/kg C1234
Predosing
30 mg/kg
04
100 mg/kg C1234
Predosing
100 mg/kg
Recovery
4
04R
100 mg/kg C1234 Recovery
Predosing
100 mg/kg Recovery
Recovery
SETCD
SET
01
0 mg/kg Vehicle Main
01TK
0 mg/kg Vehicle TK
01R
0 mg/kg Vehicle Recovery
02
10 mg/kg C1234 Main
02TK
10 mg/kg C1234 TK
03
30 mg/kg C1234Main
03TK
30 mg/kg C1234 TK
01
100 mg/kg C1234 Main
01TK
100 mg/kg C1234 TK
01R
100 mg/kg C1234 Recovery
4
3.
Standards, Formats, and Terminologies and their Versions
3.1
Standards Used
Standard or Dictionary
Standard or Dictionary
Versions Used
Tabulation Datasets
CDISC SEND
3.0
Controlled Terminology
CDISC SEND Controlled Terminology
2014-12-26
Data Definition file
CDISC DEFINE.XML
1.0
Validation Rules
FDA Specific SEND Validation Rules
2.0
3.2
Rationale for Selection
The standards versions used were the most current at the time of dataset creation.
3.3
Nonstandard Terminology
The following nonstandard terminology was used. It was submitted to NCI for consideration, but no
resolution was received prior to dataset creation:
Dataset
Name
Variable
Codelist
Term Used
Meaning
LB
LBTEST
LBTEST
Melamine abutyltransferfree
A measurement of the
melamine abutyltransferfree
in a biological specimen.
LB
LBTESTCD
LBTESTCD
MELTRFRE
A measurement of the
melamine abutyltransferfree
in a biological specimen.
4.
Description of Study Datasets
4.1
Dataset Summary
Dataset
Name
Supplemental
Qualifiers?
Dataset Label
TS
Trial Summary
Trial Design
TE
Trial Elements
Trial Design
TA
Trial Arms
Trial Design
TX
Trial Sets
Trial Design
CO
Comments
Special Purpose
DM
Demographics
Special Purpose
SE
Subject Elements
Special Purpose
EX
Exposure
Interventions
DS
Disposition
Events
BW
Body Weight
Findings
BG
Body Weight Gain
Findings
Observation Class
5
Dataset
Name
Dataset Label
CL
Clinical Observations
Findings
FW
Food and Water Consumption
Findings
LB
Laboratory Test Results
Findings
MA
Macroscopic Findings
X
Findings
MI
Microscopic Findings
X
Findings
OM
Organ Measurements
Findings
PC
Pharmacokinetic Concentrations
Findings
PP
Pharmacokinetic Parameters
Findings
RELREC
Related Records
Relationship
POOLDEF
Pooled Definition
Relationship
4.2
Supplemental
Qualifiers?
Observation Class
Use of Supplemental Qualifiers
Dataset
Name
Associated Dataset
Qualifiers Used
SUPPMA
Macroscopic Observations
Modifiers that were part of MAORRES which SEND
variables have not yet been developed.
SUPPMI
Microscopic Observations
Modifiers that were part of MIORRES which SEND
variables have not yet been developed.
5.
Data Standards Validation Rules, Versions, and Issues Conformance Issues
5.1
Validation Outcome Summary
There were no errors warnings or notices that impacted the reporting or interpretation of these SEND
datasets.
5.2
Validation Method Used
Rule Conformance to SEND 3.0 was evaluated using the OpenCDISC Validator version 1.7, which includes
checks for conformance against the FDA Specific SEND Validation Rules, Version 2.0.
5.3
Errors
There were no errors reported.
5.4
Warnings
The following warnings were reported:
Rule
Message
Domain(s)
Count
Explanation
SD0026
Missing value for LBORRESU
LB
3745
There are some LB variables that
6
Rule
Message
Domain(s)
Count
(unit of the original laboratory
result) when LBORRES
(laboratory result or findings
as collected) is provided
Explanation
are not associated with units, as
shown in the table following.
Many of these pertain to the
presence or absence of
substances in urine. We
therefore do not consider these
warnings to be meaningful.
SD0029
Missing value for LBSTRESU
(unit of the standardized
laboratory result) when
LBSTRESC is provided
(reference range for character
result – standard unit)
LB
3745
Data for some LB variables are
recorded as present or absent
(table following) and are
therefore not associated with
reference ranges. The rule is
incorrect in indicating that a
reference range was provided.
We therefore do not consider
these warnings to be
meaningful.
SD0006
No baseline result for subject
for PC
DM
124
This information was not
available. Baseline (prestudy)
blood samples for PC
parameters are often not
obtained in rodents because of
blood volume limitations.
SD1117
Duplicate records
LB, MA, MI,
PP
216
Rule SD1117 does not include a
sufficient number of variables to
determine uniqueness. For
example, neither –ORRES nor
any of the variables associated
with specimen collection time
are included. We therefore do
not consider these warnings to
be applicable.
7
LB Variables Not Associated with Units and/or Reference Ranges
Hyperchromasia (blood)
Anisocytosis (blood)
Hemoglobin variance (blood)
Microcytosis (blood)
Large Platelets (blood)
pH (urine)
Color (urine)
Clarity (urine)
Glucose (urine)
Bilirubin (urine)
Ketones (urine)
Blood (urine)
Spermatozoa (urine)
Amorphous Crystals (urine)
Calcium Oxylate Crystals (blood)
Triple Phosphate Crystals (blood)
Granular casts (urine)
5.5
Macrocytosis (blood)
Hypochromasia (blood)
Polychromasia (blood)
Target Cells (blood)
Howell-Jolly Bodies (blood)
Proteins (urine)
Urobilinogen (urine)
White Blood Cells (urine)
Red Blood Cells (urine)
Squamous Epithelial Cells (urine)
Transitional Epithelial Cells (urine)
Bacteria (urine)
Coarsely Granular Casts (urine)
Hyaline Casts (urine)
Finely Granular Casts (urine)
Calcium carbonate crystals (urine)
Uric acid crystals (urine)
Notices
Rule
Message
Domain(s)
Count
Explanation
SD1076
Model permissible variable
added into standard domain
CL
1
The permissible variable
included in the Cl (clinical
observations) domain was
CLREFID (clinical observations
reference identifier).
6.
Description of Sponsor Decisions Related to Data Standard Implementations
6.1
Sponsor-Defined Standardization Descriptions
The following options, as described in the SEND Implementation Guide, were



6.2
In the DM domain, RFSTDTC is the first day the animal was dosed
In the EX domain, there is one entry per animal per dose administered
Baseline flag is assigned to the last predose result for each animal for BW, FW and LB. No
baseline flag was assigned to PC since no predose TK samping was done.
Differences between SEND Datasets and Study Report
The first day of dosing in the report and protocol is Day 0. The first day of dosing in the SEND datasets is
Day 1 compliance with SEND. Accordingly, all study days in the SEND dataset are 1 day later than the
corresponding day in the protocol and study report.
8
6.3
Nonstandard Electronic Data Submitted
Ocular data was provided in a non-standard format, since there is no SEND 3.0 domain definition for this
data. Refer to the file Ocular_def.txt for format details.
6.4
Legacy Data Conversion Plan
Data was transformed from original LIMS source content terminology and format, to SEND version 3.0,
using commercial product XXXX.
9