implementation of cdisc ada in the …" pharmacokinetic parameters: c max t max t 1/2 auc lst...

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  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  Conclusion

6

n  Standardization

⇒  Efficiency ↑

⇒  Time ↓

Efficiency ↑

PK

STAT • ADaM

DM • SDTM

GAIN

7

OUTLINE

n  Introduction

n  Gain


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


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


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


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



•  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



•  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



•  Time deviations >10% => exclude from descriptive statistics

SDTM

ADaM

ADPC

PK analysis

PP

ADPP

STAT

OUTPUT

SAP

DB lock

Protocol

CSR

15


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


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


Database lock SDTM

ADaM

ADPC

PK analysis

PP

ADPP

STAT

OUTPUT

SAP

DB lock

Protocol

CSR

18


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


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


§  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


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




SDTM

ADaM

ADPC

PK analysis

PP

ADPP

STAT

OUTPUT

SAP

DB lock

Protocol

CSR

38

CREATION OF ADPC

n  BLoQ => 0


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




SDTM

ADaM

ADPC

PK analysis

PP

ADPP

STAT

OUTPUT

SAP

DB lock

Protocol

CSR

40

CREATION OF ADPC

n  Embedded BLoQ


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


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


•  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


n  ADPC

SDTM

ADaM

ADPC

PK analysis

PP

ADPP

STAT

OUTPUT

SAP

DB lock

Protocol

CSR

63


n  ADPP

SDTM

ADaM

ADPC

PK analysis

PP

ADPP

STAT

OUTPUT

SAP

DB lock

Protocol

CSR

64

OUTLINE

n  Introduction

n  Gain


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

implementation of cdisc ada in the …" pharmacokinetic parameters: c max t max t 1/2 auc lst...

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