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: joanna.magielse@sgs.com

WHERE EXPERIENCE MEETS SPEED