Post on 28-Feb-2018
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 • ADaM
DM • SDTM
GAIN
7
OUTLINE
Introduction
Gain
Pharmacokinetic analysis
Conclusion
8
PHARMACOKINETIC ANALYSIS
Protocol: Pharmacokinetic parameters: Cmax tmax t1/2 AUClst AUCifo
AVA
L (n
g/m
L)
ARELTM2 (h)
Cmax
tmax
Slope for t1/2
AUCifo
• Min 3 points after Cmax • R²adj>0.9
• Only if t1/2 can be estimated
AVA
L (n
g/m
L)
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
• 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
10
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
11
PHARMACOKINETIC ANALYSIS
Statistical Analysis Plan Handling of data:
• If BLoQ => AVAL = 0 for PK analysis and descriptive statistics
BLoQ: Below Limit of Quantification 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 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
AVA
L (n
g/m
L)
ARELTM2 (h)
AUClst AV
AL
(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 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
18
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
19
In SAS
Based upon define.xml
CREATION OF ADPC
ADSL ADAPER
EX PC
Add. variables
ADPC
SDTM
ADaM
ADPC
PK analysis
PP
ADPP
STAT
OUTPUT
SAP
DB lock
Protocol
CSR
SDTM
ADAM
PK
20
CREATION OF ADPC
Analysis variable metadata
SDTM
ADaM
ADPC
PK analysis
PP
ADPP
STAT
OUTPUT
SAP
DB lock
Protocol
CSR
SDTM
ADAM
PK
ADAM
21
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
22
CREATION OF ADPC
Additional/derived variables PARAM, PARAMN, PARAMCD
• PARAM: pharmacokinetic concentration used for PK analysis
• PARAMCD: PKCONC 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
PARAM, PARAMCD
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CREATION OF ADPC
Additional/derived variables PARAM, PARAMN, PARAMCD ADTM, ASTDTM, AENDTM
• Derived from PCDTC 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
25
CREATION OF ADPC
ADTM
Character Numeric SAS format:
is8601dt.
26
CREATION OF ADPC
Additional/derived variables PARAM, PARAMN, PARAMCD ADTM, ASTDTM, AENDTM AVISIT, AVISITN
• Derived from VISIT and VISITNUM • all 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
27
CREATION OF ADPC
AVISIT, AVISITN
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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
29
CREATION OF ADPC
ATPT, ATPTN
SDTM
ADaM
ADPC
PK analysis
PP
ADPP
STAT
OUTPUT
SAP
DB lock
Protocol
CSR
30
CREATION OF ADPC
Additional/derived variables PARAM, PARAMN, PARAMCD ADTM, ASTDTM, AENDTM AVISIT, AVISITN ATPT, ATPTN ARELTM, ARELTMU, ANCHOR
• ANCHOR: PCRFTDTC / EXSTDTC / PCDTC • 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
31
CREATION OF ADPC
ARELTM, ARELMTU, ANCHOR
32
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
AVAL, AVALC CRITy, CRITyFL, CRITyFN
SDTM
ADaM
ADPC
PK analysis
PP
ADPP
STAT
OUTPUT
SAP
DB lock
Protocol
CSR
33
CREATION OF ADPC
ANLzzFL, ANLzzFD
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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
35
CREATION OF ADPC
Missing predose => 0
36
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
37
CREATION OF ADPC
BLoQ => 0
BLoQ: Below Limit of Quantification
38
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
39
CREATION OF ADPC
Embedded BLoQ
BLoQ: Below Limit of Quantification
42
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
43
CREATION OF ADPC
Time deviation
44
CREATION OF ADPC
Predose >5% Cmax
45
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
46
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
47
CREATION OF PP
R²adj < 0.9
AV
AL
(n
g/m
L)
ARELTM2 (h)
48
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
49
CREATION OF ADPP
Analysis variable metadata
SDTM
ADaM
ADPC
PK analysis
PP
ADPP
STAT
OUTPUT
SAP
DB lock
Protocol
CSR
SDTM
ADAM
ADAM
PK
50
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
51
CREATION OF ADPP
Additional/derived variables PARAM, PARAMN, PARAMCD
• PARAM: Pharmacokinetic parameter used for statistical analysis
• PARAMCD: PKPARAM AVISIT, AVISITN ANLzzFL, ANLzzFD AVAL, AVALC CRITy, CRITyFL, CRITyFN
SDTM
ADaM
ADPC
PK analysis
PP
ADPP
STAT
OUTPUT
SAP
DB lock
Protocol
CSR
52
CREATION OF ADPP
PARAM, PARAMCD
53
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
54
CREATION OF ADPP
AVISIT, AVISITN
55
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
56
CREATION OF ADPP
ANLzzFL, ANLzzFD
57
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
58
CREATION OF ADPP
AVAL = PPSTRESN
59
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
60
CREATION OF ADPP
AUCpeo > 20% AUCifo
AV
AL
(n
g/m
L)
ARELTM2 (h)
62
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
63
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
64
TABLES, LISTINGS AND FIGURES
ADPC
SDTM
ADaM
ADPC
PK analysis
PP
ADPP
STAT
OUTPUT
SAP
DB lock
Protocol
CSR
65
TABLES, LISTINGS AND FIGURES
ADPP
SDTM
ADaM
ADPC
PK analysis
PP
ADPP
STAT
OUTPUT
SAP
DB lock
Protocol
CSR
66
OUTLINE
Introduction
Gain
Pharmacokinetic analysis
Conclusion
67
CONCLUSION
ADPC/ADPP SDTM + ADaM Derived variables
• Based on BDS • Modified variables (ANLzzFD, ARELTM1, ARELTM2)
PK analysis ARELTM2 and AVAL
Data handling CRITy and ANLzzFL
Guidance from CDISC needed
68
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: joanna.magielse@sgs.com
WHERE EXPERIENCE MEETS SPEED