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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
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PHARMACODYNAMIC ANALYSIS
n Statistical Analysis Plan § PD population § Handling of data § Statistical analysis
SDTM
ADaM
SAP
DB lock
Protocol
ADPD
STAT
OUTPUT
CSR
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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
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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
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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
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CREATION OF ADPD
n Analysis variable metadata
SDTM
ADaM
ADPD
SAP
DB lock
Protocol
ADaM (ADSL)
ADaM (ADPHASE)
SDTM (PD)
PD
STAT
OUTPUT
CSR
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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
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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
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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
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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
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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
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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
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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
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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
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
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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
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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
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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
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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
38
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: [email protected]
[email protected] 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
42
BACK-UP SLIDE: PAPER EXAMPLES
43
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
45
BACK-UP SLIDE: SAS VS. PD SOFTWARE
Extracted from Phoenix® WinNonLin user manual
