IMPLEMENTATION OF CDISC ADAM IN
THE PHARMACOKINETICS DEPARTMENT
Presented by Joanna Magielse, SGS Life Science Services
2
OUTLINE
Introduction
Gain
Pharmacokinetic analysis
Conclusion
3
OUTLINE
Introduction
Gain
Pharmacokinetic analysis
Conclusion
4
INTRODUCTION
Steps of PK study:
Protocol
Statistical Analysis Plan
Database Lock
• SDTM datasets
• ADaM datasets
Creation of ADPC dataset
PK analysis
Creation of PP dataset
Creation of ADPP dataset
Statistical analysis
Creation Tables, Listings, Figures
Clinical report
SDTM
ADaM
ADPC
PK analysis
PP
ADPP
STAT
OUTPUT
SAP
DB lock
Protocol
CSR
5
OUTLINE
Introduction
Gain
Pharmacokinetic analysis
Conclusion
6
Standardization
Efficiency
Time
Efficiency
PK
STAT
•
STAT
• ADaM
DM
•
DM
• SDTM
GAIN
7
OUTLINE
Introduction
Gain
Pharmacokinetic analysis
Conclusion
8
PHARMACOKINETIC ANALYSIS
Protocol:
Pharmacokinetic parameters: Cmax tmax t1/2 AUClst AUCifo
AV
AL
(ng
/mL
)
ARELTM2
(h)
Cmax
tmax
Slope for t1/2
AUCifo
• Min 3 points
after Cmax
• R²adj>0.9
• Only if t1/2
can be
estimated
AV
AL
(ng
/mL
)
ARELTM2
(h)
AVAL: Analysis value
ARELTM: Analysis relative time
AUClst
SDTM
ADaM
ADPC
PK analysis
PP
ADPP
STAT
OUTPUT
SAP
DB lock
Protocol
CSR
9
PHARMACOKINETIC ANALYSIS
Statistical Analysis Plan
PK population
Handling of data
Statistical analysis
SDTM
ADaM
ADPC
PK analysis
PP
ADPP
STAT
OUTPUT
SAP
DB lock
Protocol
CSR
10
PHARMACOKINETIC ANALYSIS
Statistical Analysis Plan
PK population
• Co medication: Drug/drug interactions
Drug with motility interference
• Adverse events: Vomiting / diarrhea
SDTM
ADaM
ADPC
PK analysis
PP
ADPP
STAT
OUTPUT
SAP
DB lock
Protocol
CSR
11
PHARMACOKINETIC ANALYSIS
Statistical Analysis Plan
Handling of data:
• If predose missing => AVAL = 0 for PK analysis
AVAL: Analysis Value
SDTM
ADaM
ADPC
PK analysis
PP
ADPP
STAT
OUTPUT
SAP
DB lock
Protocol
CSR
12
PHARMACOKINETIC ANALYSIS
Statistical Analysis Plan
Handling of data:
• If BLoQ => AVAL = 0
BLoQ: Below Limit of Quantification
AVAL: Analysis Value
SDTM
ADaM
ADPC
PK analysis
PP
ADPP
STAT
OUTPUT
SAP
DB lock
Protocol
CSR
13
PHARMACOKINETIC ANALYSIS
Statistical Analysis Plan
Handling of data:
• If embedded BLoQ => exclude from PK analysis
BLoQ: Below Limit of Quantification
SDTM
ADaM
ADPC
PK analysis
PP
ADPP
STAT
OUTPUT
SAP
DB lock
Protocol
CSR
14
PHARMACOKINETIC ANALYSIS
Statistical Analysis Plan
Handling of data:
• Time deviations >10% => exclude from descriptive
statistics
SDTM
ADaM
ADPC
PK analysis
PP
ADPP
STAT
OUTPUT
SAP
DB lock
Protocol
CSR
15
PHARMACOKINETIC ANALYSIS
Statistical Analysis Plan
Statistical analysis:
• AUCpeo > 20% => exclude AUCifo from statistical
analysis
AUCifo
AV
AL
(ng
/mL
)
ARELTM2
(h)
AUClst A
VA
L
(ng
/mL
)
ARELTM2
(h)
AUCpeo: AUC %extrapolation
AUCifo: AUC infinity
SDTM
ADaM
ADPC
PK analysis
PP
ADPP
STAT
OUTPUT
SAP
DB lock
Protocol
CSR
16
PHARMACOKINETIC ANALYSIS
Statistical Analysis Plan
Statistical analysis:
• Bioequivalence studies: If quantifiable
concentration at pre-dose > 5% Cmax => subject
will be excluded
SDTM
ADaM
ADPC
PK analysis
PP
ADPP
STAT
OUTPUT
SAP
DB lock
Protocol
CSR
17
PHARMACOKINETIC ANALYSIS
Database lock
SDTM
ADaM
ADPC
PK analysis
PP
ADPP
STAT
OUTPUT
SAP
DB lock
Protocol
CSR
18
PHARMACOKINETIC ANALYSIS
SDTM datasets
DM (Demographics)
EX (Exposure)
PC (Pharmacokinetic concentrations)
CM (Concomitant medications)
AE (Adverse events)
DV (Protocol deviations)
CO (Comments)
SDTM
ADaM
ADPC
PK analysis
PP
ADPP
STAT
OUTPUT
SAP
DB lock
Protocol
CSR
19
PHARMACOKINETIC ANALYSIS
ADaM datasets
ADSL (Subject-level Analysis Dataset)
ADAPER (Subject Analysis periods Dataset)
(ADEX) (Analysis Dataset containing Exposure Data)
SDTM
ADaM
ADPC
PK analysis
PP
ADPP
STAT
OUTPUT
SAP
DB lock
Protocol
CSR
20
In SAS
Based upon define.xml
CREATION OF ADPC
ADPC ADSL ADAPER
EX PC
Add. variables
SDTM
ADaM
ADPC
PK analysis
PP
ADPP
STAT
OUTPUT
SAP
DB lock
Protocol
CSR
SDTM
ADAM
PK
21
CREATION OF ADPC
Analysis variable metadata
SDTM
ADaM
ADPC
PK analysis
PP
ADPP
STAT
OUTPUT
SAP
DB lock
Protocol
CSR
SDTM
ADAM
PK
ADAM
22
CREATION OF ADPC
Additional/derived variables: BDS
PARAM, PARAMN, PARAMCD
ADTM, ASTDTM, AENDTM
AVISIT, AVISITN
ATPT, ATPTN
ARELTM, ARELTMU, ANCHOR
ANLzzFL, ANLzzFD
AVAL, AVALC
CRITy, CRITyFL, CRITyFN
SDTM
ADaM
ADPC
PK analysis
PP
ADPP
STAT
OUTPUT
SAP
DB lock
Protocol
CSR
23
CREATION OF ADPC
Additional/derived variables
PARAM, PARAMN, PARAMCD
• PARAM: based upon PCTEST and PCSTRESU
• PARAMCD: abbreviation
• PARAMN: numeric version of PARAM
ADTM, ASTDTM, AENDTM
AVISIT, AVISITN
ATPT, ATPTN
ARELTM, ARELTMU, ANCHOR
ANLzzFL, ANLzzFD
AVAL, AVALC
CRITy, CRITyFL, CRITyFN
SDTM
ADaM
ADPC
PK analysis
PP
ADPP
STAT
OUTPUT
SAP
DB lock
Protocol
CSR
24
CREATION OF ADPC
PARAM, PARAMCD
25
CREATION OF ADPC
Additional/derived variables
PARAM, PARAMN, PARAMCD
ADTM, ASTDTM, AENDTM
• Derived from PCDTC
• ASTDTM and AENDTM: in case of interval (e.g.
urine)
AVISIT, AVISITN
ATPT, ATPTN
ARELTM, ARELTMU, ANCHOR
ANLzzFL, ANLzzFD
AVAL, AVALC
CRITy, CRITyFL, CRITyFN
SDTM
ADaM
ADPC
PK analysis
PP
ADPP
STAT
OUTPUT
SAP
DB lock
Protocol
CSR
26
CREATION OF ADPC
ADTM
Character Numeric
SAS format:
is8601dt.
27
CREATION OF ADPC
Additional/derived variables
PARAM, PARAMN, PARAMCD
ADTM, ASTDTM, AENDTM
AVISIT, AVISITN
• Derived from VISIT and VISITNUM
• PK conc that refer to same exposure
ATPT, ATPTN
ARELTM, ARELTMU, ANCHOR
ANLzzFL, ANLzzFD
AVAL, AVALC
CRITy, CRITyFL, CRITyFN
SDTM
ADaM
ADPC
PK analysis
PP
ADPP
STAT
OUTPUT
SAP
DB lock
Protocol
CSR
28
CREATION OF ADPC
AVISIT, AVISITN
29
CREATION OF ADPC
Additional/derived variables
PARAM, PARAMN, PARAMCD
ADTM, ASTDTM, AENDTM
AVISIT, AVISITN
ATPT, ATPTN
• Derived from PCTPT and PCTPTNUM
ARELTM, ARELTMU, ANCHOR
ANLzzFL, ANLzzFD
AVAL, AVALC
CRITy, CRITyFL, CRITyFN
SDTM
ADaM
ADPC
PK analysis
PP
ADPP
STAT
OUTPUT
SAP
DB lock
Protocol
CSR
30
CREATION OF ADPC
ATPT, ATPTN
SDTM
ADaM
ADPC
PK analysis
PP
ADPP
STAT
OUTPUT
SAP
DB lock
Protocol
CSR
31
CREATION OF ADPC
Additional/derived variables
PARAM, PARAMN, PARAMCD
ADTM, ASTDTM, AENDTM
AVISIT, AVISITN
ATPT, ATPTN
ARELTM, ARELTMU, ANCHOR
• ANCHOR: EXSTDTC / PCRFTDTC / PCDTC / ADTM
• ARELTM1: PCDTC – EXSTDTC
• ARELTM2: if ARELTM1 < 0 (predose): ARELTM2 = 0
others: ARELTM2 = ARELTM1
ANLzzFL, ANLzzFD
AVAL, AVALC
CRITy, CRITyFL, CRITyFN
SDTM
ADaM
ADPC
PK analysis
PP
ADPP
STAT
OUTPUT
SAP
DB lock
Protocol
CSR
32
CREATION OF ADPC
ARELTM, ARELMTU, ANCHOR
33
CREATION OF ADPC
Additional/derived variables
PARAM, PARAMN, PARAMCD
ADTM, ASTDTM, AENDTM
AVISIT, AVISITN
ATPT, ATPTN
ARELTM, ARELTMU, ANCHOR
ANLzzFL, ANLzzFD
• Select set of records for analysis:
PK analysis
Descriptive statistics
Inferential statistical analysis
Steady state analysis
AVAL, AVALC
CRITy, CRITyFL, CRITyFN
SDTM
ADaM
ADPC
PK analysis
PP
ADPP
STAT
OUTPUT
SAP
DB lock
Protocol
CSR
34
CREATION OF ADPC
ANLzzFL, ANLzzFD
35
CREATION OF ADPC
Additional/derived variables
PARAM, PARAMN, PARAMCD
ADTM, ASTDTM, AENDTM
AVISIT, AVISITN
ATPT, ATPTN
ARELTM, ARELTMU, ANCHOR
ANLzzFL, ANLzzFD
AVAL, AVALC
• AVAL= PCSTRESN
Missing predose: AVAL = 0
BLoQ: AVAL = 0
Embedded BLoQ: exclude from PK analysis
CRITy, CRITyFL, CRITyFN
BLoQ: Below Limit of Quantification
SDTM
ADaM
ADPC
PK analysis
PP
ADPP
STAT
OUTPUT
SAP
DB lock
Protocol
CSR
36
CREATION OF ADPC
Missing predose => 0
37
CREATION OF ADPC
Additional/derived variables
PARAM, PARAMN, PARAMCD
ADTM, ASTDTM, AENDTM
AVISIT, AVISITN
ATPT, ATPTN
ARELTM, ARELTMU, ANCHOR
ANLzzFL, ANLzzFD
AVAL, AVALC
• AVAL= PCSTRESN
Missing predose: AVAL = 0
BLoQ: AVAL = 0
Embedded BLoQ: exclude from PK analysis
CRITy, CRITyFL, CRITyFN
BLoQ: Below Limit of Quantification
SDTM
ADaM
ADPC
PK analysis
PP
ADPP
STAT
OUTPUT
SAP
DB lock
Protocol
CSR
38
CREATION OF ADPC
BLoQ => 0
BLoQ: Below Limit of Quantification
39
CREATION OF ADPC
Additional/derived variables
PARAM, PARAMN, PARAMCD
ADTM, ASTDTM, AENDTM
AVISIT, AVISITN
ATPT, ATPTN
ARELTM, ARELTMU, ANCHOR
ANLzzFL, ANLzzFD
AVAL, AVALC
• AVAL= PCSTRESN
Missing predose: AVAL = 0
BLoQ: AVAL = 0
Embedded BLoQ: exclude from PK analysis
CRITy, CRITyFL, CRITyFN
BLoQ: Below Limit of Quantification
SDTM
ADaM
ADPC
PK analysis
PP
ADPP
STAT
OUTPUT
SAP
DB lock
Protocol
CSR
40
CREATION OF ADPC
Embedded BLoQ
BLoQ: Below Limit of Quantification
41
CREATION OF ADPC
Additional/derived variables
PARAM, PARAMN, PARAMCD
ADTM, ASTDTM, AENDTM
AVISIT, AVISITN
ATPT, ATPTN
ARELTM, ARELTMU, ANCHOR
ANLzzFL, ANLzzFD
AVAL, AVALC
CRITy, CRITyFL, CRITyFN
• Criteria evaluation
Time deviation > 10%
Predose > 5% Cmax (cross over studies)
SDTM
ADaM
ADPC
PK analysis
PP
ADPP
STAT
OUTPUT
SAP
DB lock
Protocol
CSR
42
CREATION OF ADPC
Time deviation
43
CREATION OF ADPC
Predose >5% Cmax
44
PHARMACOKINETIC ANALYSIS
ADPC is imported in Phoenix® WinNonLin
Include observations for analysis:
ANL01FL = ‘Y’
PK analysis:
Time: ARELTM2
Conc: AVAL
Output file: PK parameters
SDTM
ADaM
ADPC
PK analysis
PP
ADPP
STAT
OUTPUT
SAP
DB lock
Protocol
CSR
45
CREATION OF PP
In SAS
Add and rename variables (SDTM IG):
DOMAIN PPSEQ PPCAT PPSPEC
Calculate extra PK parameters:
e.g. Ratio of metabolite/parent AUC
PPTEST, PPTESTCD:
Controlled terminology
Relation with PC:
PPRFTDTC
SDTM
ADaM
ADPC
PK analysis
PP
ADPP
STAT
OUTPUT
SAP
DB lock
Protocol
CSR
46
CREATION OF PP
R²adj < 0.9
AV
AL
(ng
/mL
)
ARELTM2
(h)
47
CREATION OF ADPP
In SAS
Based upon define.xml
ADSL ADAPER
PP
Add. variables
ADPP
SDTM
ADaM
ADPC
PK analysis
PP
ADPP
STAT
OUTPUT
SAP
DB lock
Protocol
CSR
SDTM
ADAM
PK
48
CREATION OF ADPP
Analysis variable metadata
SDTM
ADaM
ADPC
PK analysis
PP
ADPP
STAT
OUTPUT
SAP
DB lock
Protocol
CSR
SDTM
ADAM
ADAM
PK
49
CREATION OF ADPP
Additional/derived variables: BDS
PARAM, PARAMN, PARAMCD
AVISIT, AVISITN
ANLzzFL, ANLzzFD
AVAL, AVALC
CRITy, CRITyFL, CRITyFN
SDTM
ADaM
ADPC
PK analysis
PP
ADPP
STAT
OUTPUT
SAP
DB lock
Protocol
CSR
50
CREATION OF ADPP
Additional/derived variables
PARAM, PARAMN, PARAMCD
• PARAM: PK parameter with unit
• PARAMCD: abbreviation
• PARAMN: numeric version of PARAM
AVISIT, AVISITN
ANLzzFL, ANLzzFD
AVAL, AVALC
CRITy, CRITyFL, CRITyFN
SDTM
ADaM
ADPC
PK analysis
PP
ADPP
STAT
OUTPUT
SAP
DB lock
Protocol
CSR
51
CREATION OF ADPP
PARAM, PARAMCD
52
CREATION OF ADPP
Additional/derived variables
PARAM, PARAMN, PARAMCD
AVISIT, AVISITN
• Analogue to AVISIT in ADPC
ANLzzFL, ANLzzFD
AVAL, AVALC
CRITy, CRITyFL, CRITyFN
SDTM
ADaM
ADPC
PK analysis
PP
ADPP
STAT
OUTPUT
SAP
DB lock
Protocol
CSR
53
CREATION OF ADPP
AVISIT, AVISITN
54
CREATION OF ADPP
Additional/derived variables
PARAM, PARAMN, PARAMCD
AVISIT, AVISITN
ANLzzFL, ANLzzFD
• Select set of records for analysis:
Statistical analysis
Descriptive statistics
AVAL, AVALC
CRITy, CRITyFL, CRITyFN
SDTM
ADaM
ADPC
PK analysis
PP
ADPP
STAT
OUTPUT
SAP
DB lock
Protocol
CSR
55
CREATION OF ADPP
ANLzzFL, ANLzzFD
56
CREATION OF ADPP
Additional/derived variables
PARAM, PARAMN, PARAMCD
AVISIT, AVISITN
ANLzzFL, ANLzzFD
AVAL, AVALC
• AVAL = PPSTRESN
CRITy, CRITyFL, CRITyFN
SDTM
ADaM
ADPC
PK analysis
PP
ADPP
STAT
OUTPUT
SAP
DB lock
Protocol
CSR
57
CREATION OF ADPP
AVAL = PPSTRESN
58
CREATION OF ADPP
Additional/derived variables
PARAM, PARAMN, PARAMCD, PARAMTYP
AVISIT, AVISITN
ANLzzFL, ANLzzFD
AVAL, AVALC
CRITy, CRITyFL, CRITyFN
• Criteria evaluation
AUCpeo > 20%
SDTM
ADaM
ADPC
PK analysis
PP
ADPP
STAT
OUTPUT
SAP
DB lock
Protocol
CSR
59
CREATION OF ADPP
AUCpeo > 20% AUCifo
AV
AL
(ng
/mL
)
ARELTM2
(h)
60
STATISTICAL ANALYSIS
ADPP
Include observations from inferential statistical analysis:
ANL01FL = ‘Y’
SDTM
ADaM
ADPC
PK analysis
PP
ADPP
STAT
OUTPUT
SAP
DB lock
Protocol
CSR
61
TABLES, LISTINGS AND FIGURES
ADPC
ADPP
Include observations from descriptive statistical analysis:
ANL02FL = ‘Y’
SDTM
ADaM
ADPC
PK analysis
PP
ADPP
STAT
OUTPUT
SAP
DB lock
Protocol
CSR
62
TABLES, LISTINGS AND FIGURES
ADPC
SDTM
ADaM
ADPC
PK analysis
PP
ADPP
STAT
OUTPUT
SAP
DB lock
Protocol
CSR
63
TABLES, LISTINGS AND FIGURES
ADPP
SDTM
ADaM
ADPC
PK analysis
PP
ADPP
STAT
OUTPUT
SAP
DB lock
Protocol
CSR
64
OUTLINE
Introduction
Gain
Pharmacokinetic analysis
Conclusion
65
CONCLUSION
ADPC/ADPP
SDTM + ADaM
Derived variables
• Based on BDS
• Modified variables (ANLzzFD, ARELTM1, ARELTM2)
PK analysis
ARELTM2 and AVAL
Selection observations
ANLzzFL
Data handling
CRITy
Guidance from CDISC needed
66
THANK YOU FOR YOUR ATTENTION
Joanna Magielse
Life Science Services
Pharmacokineticist
SGS Belgium NV
Vieux Chemin du Poète10
1301 Wavre - Belgium
Phone: + 32(0)15 44 01 33
Email: [email protected]
WHERE EXPERIENCE MEETS SPEED