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Converting Pharmacokinetic Data to the PP and PC Domains Roger Landau Principal Consultant, Lincoln Safety Group, Phase Forward 10 Sep 2009 Copyright © 2009 Phase Forward Incorporated. All rights reserved. Introduction Support for Pharmacokinetic (PK) data new in SDTM 3.1.2 PK data combines •CRF timing variables •Lab findings •Derived data Converting to SDTM can be difficult Will present my recommendations Interactive participation encouraged 2 Overview Typical Pharmacokinetic Data Workflow Logical Data Model SDTM Data Model Recommendations for converting data •Use of RELREC 3 Typical Pharmacokinetic Data Workflow ……………………………………………………………………………………………………………………….. 4 PK Data Consists of two types of data 1) Concentration of drug or metabolite in bodily fluid/substance Analyte – drug or metabolic product whose concentration is analyzed in biologic matrix Parent compound or metabolite produced when body metabolizes compound Biological Matrix – fluid or substance in a living being Usually plasma or urine Can also be feces, Cerebrospinal Fluid (CSF) 5 PK Data 2) PK Parameters • Derived values describing how a compound is metabolized by the body over time T1/2: Half-life AUC: Area Under the Curve C Max: maximum concentration T Max: time from drug administration to maximum concentration – Many others – – – – Phase I Crossover Studies PK analysis usually in phase I crossover studies. Some studies only include concentration No PK parameters In each period/epoch: Blood samples taken at many timepoints Urine collected over several intervals 7 Typical PK Data Workflow Clinical DB Management System CRF Timepoints Issues: • Three different data sources • Three different departments • Three different systems • No data standards Statistical Analysis Biostatistics Merged Concentration Data PK Parameters Concentration Results Bioanalytical Lab 8 WinNonLin Pharmacokineticist Clinical Study Report Logical Data Model ……………………………………………………………………………………………………………………….. 9 Logical Data Model Three entities •Two SDTM domains •PC and PP Relationships •CRF-Timepoints to Concentration CRF Timepoints PK PK PK Subject No Period Timepoint Date-Time Sample ID Sample Condition Not Done Vomited? Concentration PK PK PK PK PK Subject No Period Timepoint Matrix Analyte Concentration Conc Units Exclude – One-to-many •Concentration to PK Parameters – Many-to-many – Requires use of RELREC in SDTM PK Parameters PK PK PK PK PK Subject No Period Matrix Analyte PK Parameter Value Units Exclude SDTM Data Model ……………………………………………………………………………………………………………………….. 11 SDTM PK Data Model Two domains •PC – Concentration Data •PP – PK Parameters Both are Findings domains •PC has more timing and qualifier variables PC and PP related to one another •But relationship is complex PC Domain PC Domain PC Domain PP Domain PP Domain Recommendations for Converting PK Data ……………………………………………………………………………………………………………………….. 18 Converting PK Data - Recommendations Source Data •May be in different formats: XPT, XLS, TXT •May be one PK file per analyte •CRF Timepoint and Concentration may be in separate files – Merging/joining will probably not go smoothly • Accession number typos, missing records, etc. •Usually will need to join and/or concatenate datasets before converting Analyte •Maps to different variables in PP and PC •Compound/metabolite names may be spelled inconsistently in different datasets Converting PK Data - Recommendations Units •Can be different for different analytes: – pg/ml – ng/ml •Some PK parameters don’t have units – No of points – R-squared PK Parameter Test Codes •Develop library of PPTEST and PPTESTCD •Work with Pharmacokineticists •Encourage use of standard PPTESTCDs in WinNonLin Converting PK Data - Recommendations Status Flags •Useful for statistical analysis and relationship between PP and PC •Obtain flags in WinNonLin output indicating values not to be used in analysis •May be difficult to obtain due to WinNonLin shortcomings Epoch •Include Epoch variable in PC and PP •Represents Period in crossover •Frequently included in source data Relating PP to PC Each PK Parameter in PP calculated from set of concentrations in PC PP and PC can be joined to show related values 3.1.2 Implementation Guide •Analysis datasets may document relationship OR •RELREC used to represent how to join PP and PC RELREC method will be discussed IG – Section 6.3.10.5 Relating PP Records to PC Records Reading this section of IG will either Make you head spin Put you to sleep Logical Data Model Many-to-Many relationship • Each PK parameter calculated from several concentrations • Each Concentration used in the calculation of several PK parameters CRF Timepoints PK PK PK Subject No Period Timepoint Date-Time Sample ID Sample Condition Not Done Vomited? Concentration PK PK PK PK PK Subject No Period Timepoint Matrix Analyte Concentration Conc Units Exclude RELREC provides data needed to perform manyto-many join PK Parameters PK PK PK PK PK Subject No Period Matrix Analyte PK Parameter Value Units Exclude RELREC Can be used in one of two methods •Relating Datasets (simpler) •Relating Records (more complex) RELREC - Relating Datasets Can only be used if: •For all subjects •All concentrations at all timepoints used for all PK parameters PCGPRID, PPGRPID = Matrix + Analyte + Period This situation usually doesn’t happen •Some values excluded Acceptable if agreed that excluded values do not need to be identified in SDTM datasets RELREC – Relating Records Populate RELREC with records from both PP and PC •Use RELID to indicate related records IG provides 4 examples (1, 2, 3, 4) For each example, 4 possible methods (A, B, C, D) to populate RELREC OMG! •Less would have been more RELREC – Relating Records Recommendations Only use Method A • Use PCGRPID and PPGRPID as IDVARs in RELREC Set PPGRPID and PCGRPID to Matrix + Analyte + Period • PPGRPID = PPSPEC + PPCAT + EPOCH • PCGRPID = PCSPEC + PCTEST + EPOCH RELREC – Relating Records Recommendations Use example 2 method to indicate concentration values not used in PK parameter calculations. • Usually due to insufficient sample or subject vomited • Can be obtained from PCSPCCND and PCSTAT/PCREASND RELREC – Relating Records Recommendations (cont’d) Do not indicate concentration values not used to calculate particular PK parameters • • • • • Examples 3 and 4 in IG Documents Pharmacokineticist’s analytical methods Information in WinNonLin Difficult to obtain and document Not appropriate in SDTM tabulation datasets Has any one used any of these methods? • Which method was used? • How did it work out? Summary Converting PK data to PP and PC can be challenging • Source data from three different systems PC and PP follow Findings model • Several complexities need to be taken into account Recommendations listed for converting source data to SDTM Relating PP to PC using RELREC • Use Method A and example 2 from IG Thank You [email protected] © 2009 Phase Forward Incorporated. All rights reserved. 32