IMPLEMENTATION OF CDISC ADAM IN ...IMPLEMENTATION OF CDISC ADAM IN PHARMACODYNAMICS Françoise...

IMPLEMENTATION OF CDISC ADAM IN PHARMACODYNAMICS Françoise Frérart

Pharmacokineticist

SGS Life Sciences

PhUSE 2017 – 11th October

2

OUTLINE

n  Introduction

n  CDISC ADaM in PD

n  Conclusion

3

OUTLINE

n  Introduction

n  CDISC ADaM in PD

n  Conclusion

4

INTRODUCTION

n  Steps of PD study analysis: §  Protocol §  Statistical Analysis Plan §  Database Lock

•  SDTM datasets •  ADaM datasets

§  Creation of ADPD dataset §  Statistical analysis (descriptive / inferential) §  Creation Tables, Listings, Figures §  Clinical Study Report

SDTM

ADaM

STAT

OUTPUT

SAP

DB lock

Protocol

CSR

ADPD

5

INTRODUCTION

n  Steps of PD study analysis: §  Protocol §  Statistical Analysis Plan §  Database Lock

•  SDTM datasets •  ADaM datasets

§  Creation of ADPD dataset Estimation of PD parameters

§  Statistical analysis (descriptive / inferential) §  Creation Tables, Listings, Figures §  Clinical Study Report

SDTM

ADaM

SAP

DB lock

Protocol

ADPD

STAT

OUTPUT

CSR

PD parameters

in SAS

in PD software

6

OUTLINE

Approach to: §  Create the ADPD dataset §  Capture the PD parameters

n  Introduction

n  CDISC ADaM in PD

n  Conclusion

7

PHARMACODYNAMIC ANALYSIS

n  Protocol / SAP: §  PD marker to be monitored §  PD measurement

•  Values already available in SDTM PD dataset (e.g., receptor occupancy)

•  Or need to calculate (%) change from baseline (e.g., marker serum conc.)

§  PD parameters : Emax tEmax AUEC SDTM

ADaM

ADPD

STAT

OUTPUT

SAP

DB lock

Protocol

CSR

8

PHARMACODYNAMIC ANALYSIS

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

SDTM

ADaM

SAP

DB lock

Protocol

ADPD

STAT

OUTPUT

CSR

9

PHARMACODYNAMIC ANALYSIS

n  Database lock

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

SDTM

ADaM

SAP

DB lock

Protocol

ADPD

STAT

OUTPUT

CSR

10

PHARMACODYNAMIC ANALYSIS

n  ADaM datasets §  ADSL (Subject-level Analysis Dataset) §  ADPHASE (Analysis of Subject Phases and Periods)

SDTM

ADaM

SAP

DB lock

Protocol

ADPD

STAT

OUTPUT

CSR

11

n  In SAS

n  Based upon define.xml

CREATION OF ADPD

ADPD ADSL ADPHASE

EX PD

Derived BDS

variables

SDTM

ADaM

ADPD

SAP

DB lock

Protocol

SDTM

ADaM

PD

STAT

OUTPUT

CSR

12

CREATION OF ADPD

n  Analysis variable metadata

SDTM

ADaM

ADPD

SAP

DB lock

Protocol

ADaM (ADSL)

ADaM (ADPHASE)

SDTM (PD)

PD

STAT

OUTPUT

CSR

13

CREATION OF ADPD

n  Additional/derived variables: BDS §  PARAM(N), PARAMCD §  AVISIT, AVISITN §  ATPT, ATPTN §  AVAL, BASE, CHG, PCHG §  AVALCATy(N), CHGCATy(N), PCHGCATy(N) §  ANLzzFL, ANLzzFD §  CRITy, CRITyFL

SDTM

ADaM

ADPD

SAP

DB lock

Protocol

STAT

OUTPUT

CSR

14

n  Additional/derived variables §  PARAM(N), PARAMCD

•  PARAM: based upon PDTEST and PDSTRESU •  PARAMCD: abbreviation

§  AVISIT, AVISITN §  ATPT, ATPTN §  AVAL, BASE, CHG, PCHG §  AVALCATy(N), CHGCATy(N), PCHGCATy(N) §  ANLzzFL, ANLzzFD §  CRITy, CRITyFL

CREATION OF ADPD

SDTM

ADaM

ADPD

SAP

DB lock

Protocol

STAT

OUTPUT

CSR

15

n  Additional/derived variables §  PARAM(N), PARAMCD §  AVISIT, AVISITN

•  Derived from VISIT and VISITNUM •  PD measurements that refer to same exposure

§  ATPT, ATPTN §  AVAL, BASE, CHG, PCHG §  AVALCATy(N), CHGCATy(N), PCHGCATy(N) §  ANLzzFL, ANLzzFD §  CRITy, CRITyFL

CREATION OF ADPD

SDTM

ADaM

ADPD

SAP

DB lock

Protocol

STAT

OUTPUT

CSR

16

n  Additional/derived variables §  PARAM(N), PARAMCD §  AVISIT, AVISITN §  ATPT, ATPTN

•  Derived from PDTPT and PDTPTNUM •  If estimation of PD parameters

§  AVAL, BASE, CHG, PCHG §  AVALCATy(N), CHGCATy(N), PCHGCATy(N) §  ANLzzFL, ANLzzFD §  CRITy, CRITyFL

CREATION OF ADPD

SDTM

ADaM

ADPD

SAP

DB lock

Protocol

STAT

OUTPUT

CSR

17

n  Additional/derived variables §  PARAM(N), PARAMCD §  AVISIT, AVISITN §  ATPT, ATPTN §  AVAL, BASE, CHG, PCHG

•  AVAL= PDSTRESN (with possible imputations) •  BASE= AVAL at baseline •  CHG= AVAL-BASE •  PCHG= ((AVAL-BASE)/BASE)*100

§  AVALCATy(N), CHGCATy(N), PCHGCATy(N) §  ANLzzFL, ANLzzFD §  CRITy, CRITyFL

CREATION OF ADPD

SDTM

ADaM

ADPD

SAP

DB lock

Protocol

STAT

OUTPUT

CSR

Percentage reduction change from baseline 100-(AVAL/BASE)*100

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n  Additional/derived variables §  PARAM(N), PARAMCD §  AVISIT, AVISITN §  ATPT, ATPTN §  AVAL, BASE, CHG, PCHG §  AVALCATy(N), CHGCATy(N), PCHGCATy(N) §  ANLzzFL, ANLzzFD §  CRITy, CRITyFL

CREATION OF ADPD

SDTM

ADaM

ADPD

SAP

DB lock

Protocol

STAT

OUTPUT

CSR

•  Change from baseline / percent change from baseline

•  Percentage reduction from baseline

19

CREATION OF ADPD

n  Additional/derived variables §  PARAM(N), PARAMCD §  AVISIT, AVISITN §  ATPT, ATPTN §  AVAL, BASE, CHG, PCHG §  AVALCATy(N), CHGCATy(N), PCHGCATy(N) §  ANLzzFL, ANLzzFD

•  Select set of records for analyses: §  Descriptive statistical analysis (ANL01FL)

§  Inferential statistical analysis (ANL02FL)

§  PD analysis (estimation of PD parameters) (ANL03FL)

§  CRITy, CRITyFL

SDTM

ADaM

ADPD

SAP

DB lock

Protocol

STAT

OUTPUT

CSR

20

CREATION OF ADPD

n  ANLzzFL, ANLzzFD

21

CREATION OF ADPD

n  Additional/derived variables §  PARAM(N), PARAMCD §  AVISIT, AVISITN §  ATPT, ATPTN §  AVAL, BASE, CHG, PCHG §  AVALCATy(N), CHGCATy(N), PCHGCATy(N) §  ANLzzFL, ANLzzFD §  CRITy, CRITyFL

•  Criteria evaluation

SDTM

ADaM

ADPD

SAP

DB lock

Protocol

STAT

OUTPUT

CSR

22

OUTLINE

Approach to: §  Create the ADPD dataset §  Capture the PD parameters

n  Introduction

n  CDISC ADaM in PD

n  Conclusion

23

ESTIMATION OF PD PARAMETERS IN SAS WITHIN THE ADPD

n  For not complex calculations

n  Include observations for PD analysis: §  PD ANALYSIS => ‘Y’ (ANL03FL)

n  Estimation of PD parameters, using: §  Time: ATPTN §  Measurement: AVAL / CHG / PCHG

SDTM

ADaM

ADPD

SAP

DB lock

Protocol

STAT

OUTPUT

CSR

PD parameters

24

ESTIMATION OF PD PARAMETERS IN SAS WITHIN THE ADPD

SDTM

ADaM

ADPD

SAP

DB lock

Protocol

STAT

OUTPUT

CSR

PD parameters

Additional/derived variables §  PARAM(N), PARAMCD §  AVISIT, AVISITN §  AVAL §  ANLzzFL, ANLzzFD §  CRITy, CRITyFL

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ESTIMATION OF PD PARAMETERS IN PD SOFTWARE WITH ADPD AS INPUT FILE

n  For more complex calculations

n  ADPD1 is imported in Phoenix® WinNonLin

n  Include observations for PD analysis: §  PD ANALYSIS => ‘Y’ (ANL03FL)

n  Estimation of PD parameters, using: §  Time: ATPTN §  Measurement: AVAL / CHG / PCHG

n  Output file: PD parameters

n  ADPD2 is created (in SAS)

SDTM

ADaM

ADPD

SAP

DB lock

Protocol

STAT

OUTPUT

CSR

PD parameters

26

ESTIMATION OF PD PARAMETERS IN PD SOFTWARE WITH ADPD AS INPUT FILE

n  For more complex calculations

n  ADPD1 is imported in Phoenix® WinNonLin

n  Include observations for PD analysis: §  PD ANALYSIS => ‘Y’ (ANL03FL)

n  Estimation of PD parameters, using: §  Time: ATPTN §  Measurement: AVAL / CHG / PCHG

n  Output file: PD parameters

n  ADPD2 is created (in SAS)

SDTM

ADaM

ADPD1

SAP

DB lock

Protocol

STAT

OUTPUT

CSR

ADPD2

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CREATION OF ADPD2

n  In SAS

n  Based upon define.xml

ADSL ADPHASE

Derived BDS

variables

ADPD2 ADaM

PD

SDTM

ADaM

ADPD1

SAP

DB lock

Protocol

STAT

OUTPUT

CSR

ADPD2

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CREATION OF ADPD2

n  Analysis variable metadata (same as ADPD1)

SDTM

ADaM

ADPD1

SAP

DB lock

Protocol

STAT

OUTPUT

CSR

ADPD2

ADaM (ADSL)

ADaM (ADPHASE)

PD

29

CREATION OF ADPD2

ADPD1

ADPD2

SDTM

ADaM

ADPD1

SAP

DB lock

Protocol

STAT

OUTPUT

CSR

ADPD2

30

OUTLINE

n  Introduction

n  CDISC ADaM in PD

n  Conclusion

Approach to: §  Create the ADPD dataset §  Capture the PD parameters

31

STATISTICAL ANALYSIS

Include observations for statistical analysis: §  DESCR STAT => ‘Y’ (ANL01FL)

§  INFER STAT => ‘Y’ (ANL02FL)

SDTM

ADaM

ADPD1

SAP

DB lock

Protocol

STAT

OUTPUT

CSR

ADPD2

ADPD

PD parameters

or

32

TABLES, LISTINGS AND FIGURES

Example: Percentage receptor occupancy

AVALCAT1 => categorization of AVAL

SDTM

ADaM

ADPD1

SAP

DB lock

Protocol

STAT

OUTPUT

CSR

ADPD2

ADPD

PD parameters

33

TABLES, LISTINGS AND FIGURES

Example: Percentage receptor occupancy: Frequency Tabulation

AVALCAT1 => categorization of AVAL

SDTM

ADaM

ADPD1

SAP

DB lock

Protocol

STAT

OUTPUT

CSR

ADPD2

ADPD

PD parameters

34

TABLES, LISTINGS AND FIGURES

SDTM

ADaM

ADPD1

SAP

DB lock

Protocol

STAT

OUTPUT

CSR

ADPD2

ADPD

PD parameters

Example: Emax: Maximum Percentage receptor occupancy

AVALCAT1 => categorization of AVAL

35

TABLES, LISTINGS AND FIGURES

SDTM

ADaM

ADPD1

SAP

DB lock

Protocol

STAT

OUTPUT

CSR

ADPD2

ADPD

PD parameters

Example: Emax: Maximum Percentage receptor occupancy: Frequency Tabulation

AVALCAT1 => categorization of AVAL

36

OUTLINE

n  Introduction

n  CDISC ADaM in PD

n  Conclusion

37

CONCLUSION

n  ADaM ADPD dataset §  SDTM + ADaM §  Derived variables

•  Based on BDS •  Modified variables (ANLzzFD)

§  Capture of PD parameters

Standardized

Flexible

In SAS

Outside SAS

Traceability

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THANK YOU FOR YOUR ATTENTION

Françoise Frérart Life Sciences Pharmacokineticist SGS Belgium NV Generaal de Wittelaan 19A b5 2800 Mechelen - Belgium Phone: + 32(0)473 84 74 63 Email: francoise.frerart@sgs.com

clinicalresearch@sgs.com EUROPE: +32 15 27 32 45 AMERICAS: + 877 677 2667 www.sgs.com/cro

Meet us at the PhUSE Booth 2

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BACK-UP SLIDE: PAPER EXAMPLES

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BACK-UP SLIDE: PAPER EXAMPLES

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BACK-UP SLIDE: PAPER EXAMPLES

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BACK-UP SLIDE: PAPER EXAMPLES

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n  Handling of data: •  If <LLoQ => AVAL = LLoQ value

SDTM

ADaM

SAP

DB lock

Protocol

ADPD

STAT

OUTPUT

CSR

LLoQ: Lower Limit of Quantification AVAL: Analysis Value

<LLoQ LLoQ

BACK-UP SLIDE: STATISTICAL ANALYSIS PLAN

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BACK-UP SLIDE: SAS VS. PD SOFTWARE

Extracted from Phoenix® WinNonLin user manual