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

OUTLINE

n  Introduction

n  Gain

n  Pharmacokinetic analysis

n  Conclusion

OUTLINE

n  Introduction

n  Gain

n  Conclusion

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

PK analysis

OUTPUT

DB lock

Protocol

OUTLINE

n  Introduction

n  Gain

n  Conclusion

n  Standardization

⇒  Efficiency ↑

⇒  Time ↓

Efficiency ↑

STAT • ADaM

DM • SDTM

OUTLINE

n  Introduction

n  Gain

n  Conclusion

PHARMACOKINETIC ANALYSIS

n  Protocol: §  Pharmacokinetic parameters: Cmax tmax t1/2 AUClst AUCifo

ARELTM2 (h)

Slope for t1/2

AUCifo

•  Min 3 points after Cmax •  R²adj>0.9

•  Only if t1/2 can be estimated

ARELTM2 (h)

AVAL: Analysis value ARELTM: Analysis relative time

AUClst

PK analysis

OUTPUT

DB lock

Protocol

n  Statistical Analysis Plan §  PK population §  Handling of data §  Statistical analysis

PK analysis

OUTPUT

DB lock

Protocol

n  Statistical Analysis Plan §  PK population

•  Co medication: §  Drug/drug interactions §  Drug with motility interference

•  Adverse events: §  Vomiting / diarrhea

PK analysis

OUTPUT

DB lock

Protocol

n  Statistical Analysis Plan §  Handling of data:

•  If predose missing => AVAL = 0 for PK analysis

AVAL: Analysis Value

PK analysis

OUTPUT

DB lock

Protocol

•  If BLoQ => AVAL = 0

BLoQ: Below Limit of Quantification AVAL: Analysis Value

PK analysis

OUTPUT

DB lock

Protocol

•  If embedded BLoQ => exclude from PK analysis

BLoQ: Below Limit of Quantification

PK analysis

OUTPUT

DB lock

Protocol

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

PK analysis

OUTPUT

DB lock

Protocol

n  Statistical Analysis Plan §  Statistical analysis:

•  AUCpeo > 20% => exclude AUCifo from statistical analysis

AUCifo

ARELTM2 (h)

AUClst AV

ARELTM2 (h)

AUCpeo: AUC %extrapolation AUCifo: AUC infinity

PK analysis

OUTPUT

DB lock

Protocol

n  Statistical Analysis Plan §  Statistical analysis:

•  Bioequivalence studies: If quantifiable concentration at pre-dose > 5% Cmax => subject will be excluded

PK analysis

OUTPUT

DB lock

Protocol

Database lock SDTM

PK analysis

OUTPUT

DB lock

Protocol

n  SDTM datasets §  DM (Demographics) §  EX (Exposure) §  PC (Pharmacokinetic concentrations) §  CM (Concomitant medications) §  AE (Adverse events) §  DV (Protocol deviations) §  CO (Comments)

PK analysis

OUTPUT

DB lock

Protocol

n  ADaM datasets §  ADSL (Subject-level Analysis Dataset) §  ADAPER (Subject Analysis periods Dataset) §  (ADEX) (Analysis Dataset containing Exposure Data)

PK analysis

OUTPUT

DB lock

Protocol

n  In SAS

n  Based upon define.xml

CREATION OF ADPC

ADPC ADSL ADAPER

Add. variables

PK analysis

OUTPUT

DB lock

Protocol

CREATION OF ADPC

n  Analysis variable metadata

PK analysis

OUTPUT

DB lock

Protocol

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

PK analysis

OUTPUT

DB lock

Protocol

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

PK analysis

OUTPUT

DB lock

Protocol

CREATION OF ADPC

n  PARAM, PARAMCD

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

PK analysis

OUTPUT

DB lock

Protocol

CREATION OF ADPC

n  ADTM

Character Numeric SAS format:

is8601dt.

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

PK analysis

OUTPUT

DB lock

Protocol

CREATION OF ADPC

n  AVISIT, AVISITN

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

PK analysis

OUTPUT

DB lock

Protocol

CREATION OF ADPC

n  ATPT, ATPTN

PK analysis

OUTPUT

DB lock

Protocol

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

PK analysis

OUTPUT

DB lock

Protocol

CREATION OF ADPC

n  ARELTM, ARELMTU, ANCHOR

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

PK analysis

OUTPUT

DB lock

Protocol

CREATION OF ADPC

n  ANLzzFL, ANLzzFD

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

PK analysis

OUTPUT

DB lock

Protocol

CREATION OF ADPC

n  Missing predose => 0

CREATION OF ADPC

n  Additional/derived variables §  PARAM, PARAMN, PARAMCD §  ADTM, ASTDTM, AENDTM §  AVISIT, AVISITN §  ATPT, ATPTN §  ARELTM, ARELTMU, ANCHOR §  ANLzzFL, ANLzzFD §  AVAL, AVALC

PK analysis

OUTPUT

DB lock

Protocol

CREATION OF ADPC

n  BLoQ => 0

CREATION OF ADPC

n  Additional/derived variables §  PARAM, PARAMN, PARAMCD §  ADTM, ASTDTM, AENDTM §  AVISIT, AVISITN §  ATPT, ATPTN §  ARELTM, ARELTMU, ANCHOR §  ANLzzFL, ANLzzFD §  AVAL, AVALC

PK analysis

OUTPUT

DB lock

Protocol

CREATION OF ADPC

n  Embedded BLoQ

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)

PK analysis

OUTPUT

DB lock

Protocol

CREATION OF ADPC

n  Time deviation

CREATION OF ADPC

n  Predose >5% Cmax

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

PK analysis

OUTPUT

DB lock

Protocol

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

PK analysis

OUTPUT

DB lock

Protocol

CREATION OF PP

n  R²adj < 0.9

ARELTM2 (h)

CREATION OF ADPP

n  In SAS

n  Based upon define.xml

ADSL ADAPER

Add. variables

PK analysis

OUTPUT

DB lock

Protocol

CREATION OF ADPP

n  Analysis variable metadata

PK analysis

OUTPUT

DB lock

Protocol

CREATION OF ADPP

n  Additional/derived variables: BDS §  PARAM, PARAMN, PARAMCD §  AVISIT, AVISITN §  ANLzzFL, ANLzzFD §  AVAL, AVALC §  CRITy, CRITyFL, CRITyFN

PK analysis

OUTPUT

DB lock

Protocol

CREATION OF ADPP

•  PARAM: PK parameter with unit •  PARAMCD: abbreviation •  PARAMN: numeric version of PARAM

§  AVISIT, AVISITN §  ANLzzFL, ANLzzFD §  AVAL, AVALC §  CRITy, CRITyFL, CRITyFN

PK analysis

OUTPUT

DB lock

Protocol

CREATION OF ADPP

n  PARAM, PARAMCD

CREATION OF ADPP

n  Additional/derived variables §  PARAM, PARAMN, PARAMCD §  AVISIT, AVISITN

•  Analogue to AVISIT in ADPC §  ANLzzFL, ANLzzFD §  AVAL, AVALC §  CRITy, CRITyFL, CRITyFN

PK analysis

OUTPUT

DB lock

Protocol

CREATION OF ADPP

n  AVISIT, AVISITN

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

PK analysis

OUTPUT

DB lock

Protocol

CREATION OF ADPP

n  ANLzzFL, ANLzzFD

CREATION OF ADPP

n  Additional/derived variables §  PARAM, PARAMN, PARAMCD §  AVISIT, AVISITN §  ANLzzFL, ANLzzFD §  AVAL, AVALC

•  AVAL = PPSTRESN §  CRITy, CRITyFL, CRITyFN

PK analysis

OUTPUT

DB lock

Protocol

CREATION OF ADPP

n  AVAL = PPSTRESN

CREATION OF ADPP

n  Additional/derived variables §  PARAM, PARAMN, PARAMCD, PARAMTYP §  AVISIT, AVISITN §  ANLzzFL, ANLzzFD §  AVAL, AVALC §  CRITy, CRITyFL, CRITyFN

•  Criteria evaluation §  AUCpeo > 20%

PK analysis

OUTPUT

DB lock

Protocol

CREATION OF ADPP

n  AUCpeo > 20% AUCifo

ARELTM2 (h)

STATISTICAL ANALYSIS

n  ADPP

n  Include observations from inferential statistical analysis: §  ANL01FL = ‘Y’

PK analysis

OUTPUT

DB lock

Protocol

TABLES, LISTINGS AND FIGURES

n  ADPC

n  ADPP

n  Include observations from descriptive statistical analysis: §  ANL02FL = ‘Y’

PK analysis

OUTPUT

DB lock

Protocol

n  ADPC

PK analysis

OUTPUT

DB lock

Protocol

n  ADPP

PK analysis

OUTPUT

DB lock

Protocol

OUTLINE

n  Introduction

n  Gain

n  Conclusion

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

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

IMPLEMENTATION OF CDISC ADA IN THE …" Pharmacokinetic parameters: C max t max t 1/2 AUC lst...

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