implementation of cdisc ada in the …" pharmacokinetic parameters: c max t max t 1/2 auc lst...
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IMPLEMENTATION OF CDISC ADAM IN THE PHARMACOKINETICS DEPARTMENT Presented by Joanna Magielse, SGS Life Science Services
2
OUTLINE
n Introduction
n Gain
n Pharmacokinetic analysis
n Conclusion
3
OUTLINE
n Introduction
n Gain
n Pharmacokinetic analysis
n Conclusion
4
INTRODUCTION
n 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
n Introduction
n Gain
n Pharmacokinetic analysis
n Conclusion
6
n Standardization
⇒ Efficiency ↑
⇒ Time ↓
Efficiency ↑
PK
STAT • ADaM
DM • SDTM
GAIN
7
OUTLINE
n Introduction
n Gain
n Pharmacokinetic analysis
n Conclusion
8
PHARMACOKINETIC ANALYSIS
n 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
n 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
n 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
n 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
n 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
n 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
n 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
n 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
n 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
n 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
n 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
n In SAS
n 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
n 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
n 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
n 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
n PARAM, PARAMCD
25
CREATION OF ADPC
n 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
n ADTM
Character Numeric SAS format:
is8601dt.
27
CREATION OF ADPC
n 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
n AVISIT, AVISITN
29
CREATION OF ADPC
n 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
n ATPT, ATPTN
SDTM
ADaM
ADPC
PK analysis
PP
ADPP
STAT
OUTPUT
SAP
DB lock
Protocol
CSR
31
CREATION OF ADPC
n 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
n ARELTM, ARELMTU, ANCHOR
33
CREATION OF ADPC
n 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
n ANLzzFL, ANLzzFD
35
CREATION OF ADPC
n 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
n Missing predose => 0
37
CREATION OF ADPC
n 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
n BLoQ => 0
BLoQ: Below Limit of Quantification
39
CREATION OF ADPC
n 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
n Embedded BLoQ
BLoQ: Below Limit of Quantification
41
CREATION OF ADPC
n 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
n Time deviation
43
CREATION OF ADPC
n Predose >5% Cmax
44
PHARMACOKINETIC ANALYSIS
n ADPC is imported in Phoenix® WinNonLin
n Include observations for analysis: § ANL01FL = ‘Y’
n PK analysis: § Time: ARELTM2 § Conc: AVAL
n Output file: PK parameters
SDTM
ADaM
ADPC
PK analysis
PP
ADPP
STAT
OUTPUT
SAP
DB lock
Protocol
CSR
45
CREATION OF PP
n In SAS
n Add and rename variables (SDTM IG): § DOMAIN PPSEQ PPCAT PPSPEC
n Calculate extra PK parameters: § e.g. Ratio of metabolite/parent AUC
n PPTEST, PPTESTCD: § Controlled terminology
n Relation with PC: § PPRFTDTC
SDTM
ADaM
ADPC
PK analysis
PP
ADPP
STAT
OUTPUT
SAP
DB lock
Protocol
CSR
46
CREATION OF PP
n R²adj < 0.9
AVA
L (n
g/m
L)
ARELTM2 (h)
47
CREATION OF ADPP
n In SAS
n 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
n 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
n 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
n 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
n PARAM, PARAMCD
52
CREATION OF ADPP
n 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
n AVISIT, AVISITN
54
CREATION OF ADPP
n 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
n ANLzzFL, ANLzzFD
56
CREATION OF ADPP
n 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
n AVAL = PPSTRESN
58
CREATION OF ADPP
n 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
n AUCpeo > 20% AUCifo
AVA
L (n
g/m
L)
ARELTM2 (h)
60
STATISTICAL ANALYSIS
n ADPP
n 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
n ADPC
n ADPP
n 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
n ADPC
SDTM
ADaM
ADPC
PK analysis
PP
ADPP
STAT
OUTPUT
SAP
DB lock
Protocol
CSR
63
TABLES, LISTINGS AND FIGURES
n ADPP
SDTM
ADaM
ADPC
PK analysis
PP
ADPP
STAT
OUTPUT
SAP
DB lock
Protocol
CSR
64
OUTLINE
n Introduction
n Gain
n Pharmacokinetic analysis
n Conclusion
65
CONCLUSION
n ADPC/ADPP § SDTM + ADaM § Derived variables
• Based on BDS • Modified variables (ANLzzFD, ARELTM1, ARELTM2)
n PK analysis § ARELTM2 and AVAL
n Selection observations § ANLzzFL
n Data handling § CRITy
n 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