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

24

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

28

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

34

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