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 ………………………………………………………………………………………………………………………..

PK Data Consists of two types of data 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 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 Issues: Three different data sources Three different departments Three different systems No data standards Clinical DB Management System Statistical Analysis CRF Timepoints Biostatistics Merged Concentration Data PK Parameters Clinical Study Report Concentration Results WinNonLin Pharmacokineticist Bioanalytical Lab

Logical Data Model ……………………………………………………………………………………………………………………….. 9

Logical Data Model Three entities Relationships Two SDTM domains PC and PP Relationships CRF-Timepoints to Concentration One-to-many Concentration to PK Parameters Many-to-many Requires use of RELREC in SDTM

SDTM Data Model ……………………………………………………………………………………………………………………….. 11

SDTM PK Data Model Two domains Both are Findings 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 PCTEST – Represents analyte (Usually). Long, chemical names possible. Inconsistent spellings frequent. For urine samples, can contain diffferent info, e.g. specific gravity, total volume collected. PCTESTCD – Will need to develop shortened versions of Analyte. Can be difficult for long names that are similar to one another PCCAT – If PCTEST is an Analyte, then PCCAT = “ANALYTE”. If PCTEST is a urine descriptive variable, then PCCAT = “SPECIMEN PROPERTY”. PCCAT has very different meaning than PPCAT PCGRPID – Use in conjunction with RELREC to relate PP to PC

PC Domain PCSPEC – Biological Matrix PCSPCCND, PCSTAT – useful for relating PP to PC

PC Domain PCTPT – Part of unique key for PC. Generally, VISITNUM and VISIT not as important in uniquely identifying timepoints in a crossover. PERIOD and TIMEPOINT are adequate PCTPTREF – Generally is the first dose of the period. However, some studies can have multiple doses and profiles of samples within a period. PCRFTDTC – Time in addition to date is critical for phase I crossovers. PCENDTC – Used for urine collection where there is a stop and start. Should be null for blood samples.

PP Domain PPCAT – In PP, represents Analyte. The same value represented by different types of variables in PP and PC PPCAT vs PCTEST PPORRESU – Units for the same PK parameter can be different for different analytes. Some PK parameters do not have units e.g. No of points, r-squared

PP Domain PPSPEC – Biological Matrix, same type of variable as in PC. Variable should probably be Required since it is part of unique key of PP

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 RELREC provides data needed to perform many- to-many join

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 Complexities – Analyte variable different in PP and PC, PCTESTCDs abbreviate long chemical names,

Thank You roger.landau@phaseforward.com 32 © 2009 Phase Forward Incorporated. All rights reserved. 32