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CONFIDENTIAL © 2015 PAREXEL INTERNATIONAL CORP.

TRACEABILITY OF DATA – FROM EDC TO TLF’S

HOW DATA ARE MAPPED AND MODIFIED FROM COLLECTION OVER SDTM AND ADAM TO TLF OUTPUTS

03-MAR-2015, 20th German CDISC User Network Meeting

Silke Hochstädter & Stefan Bordasch

© 2015 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL 2

AGENDA 03-MAR-2015 20TH GERMAN CDISC USER NETWORK MEETING

TRACEABILITY OF DATA – FROM EDC TO TLF’S

• Introduction – lifecycle of clinical studies

• Wording problems

• Transformation problems

• Data structures


BERLIN, GERMANY

TRACEABILITY OF DATA – FROM EDC TO TLF’S INTRODUCTION – LIFECYCLE OF CLINICAL STUDIES


TRACEABILITY OF DATA – FROM EDC TO TLF’S INTRODUCTION – LIFECYCLE OF CLINICAL STUDIES (1)

Clinical Studies contain different documents • Study protocol

• Statistical Analysis Plan (SAP)

...plus derived documents / tools • Case Report Form (CRF) – reflects the study design of the protocol

• Clinical Database – based on paper or eDC CRF, plus external data

• SDTM datasets – needs a SDTM mapping description, standartization of the DB

• TFL shells – reflects the statistical output based on the SAP

• ADaM datasets – needs a ADaM specification, based on the SAP

• Final outputs: Tables, Listings; Figures (TLFs) – based on ADaM datasets



FDA and CDISC expectation: traceablity of data from source to final outputs

SAP & TFL shells

eDC SDTM

ADaM

CRF Study Protocol

TFL Output

CSR

CDISC



Different requirements needed for each step • CRF contains clinical requirements

• Database has to reflect the CRF and all procedures, designed by programmer

• SDTM datasets have to follow SDTM definitions and the Controlled Terminologies (CT)

• ADaM datasets have to support the statistical analyis and therefore they are driven by the SAP and the TFL shells

Multiple parties are involved in the process • ...but not all might be trained on CDISC requirements

• Best practice for CRF design: CDASH and using CTs – but you‘re not able to create a CRF in the same way as the SDTM structure (e.g. DS, SUPPs)


TRACEABILITY OF DATA – FROM EDC TO TLF’S INTRODUCTION – WORDING PROBLEMS (1)

The different study modules based on different terminology requirements:

• CRF: based on the wording given in the protocol and the medical terminolgy

• Clinical Database: based on the CRF wording

• SDTM: based on the CDISC SDTM terminology

• ADAM: based on the wording in the Mock TFL shells/CRF and the CDISC ADaM terminology

• TFL output: based on the wording of the CRF and SAP/Protocol

This different sources lead to problems in the wording in case the CRF do not take the CDISC terminolgy into account.


TRACEABILITY OF DATA – FROM EDC TO TLF’S INTRODUCTION – WORDING PROBLEMS (2)

Add here some examples like:

• Sex

• AE outcome

CRF SDTM ADaM/TFLs

CRF SDTM ADaM/TFLs

Add additional information in SUPPAE


TRACEABILITY OF DATA – FROM EDC TO TLF’S INTRODUCTION – TRANSFORMATION PROBLEMS (1)

Dates are handled in a different way across the documents • CRF collects the date as any person would expect to enter it: Day, Month and Year as

DD-MMM-YYYY, e.g. 03-MAR-2015

• SDTM has to use the ISO8601 format to list date information – so 2015-03-03

• For ADaM the date will be converted to numberic and is used to calculate periods or durations. Therefore impution of incomplete data are in place e.g. 03MAR2015 (date9.)

• In the TLFs dates are only listed and need to be a character again, e.g. 03-MAR-2015. Listings should be created based on SDTM normally.



Visits • Protocol defines the visit terms and structures

• Only planned visits are mentioned in the protocol

• In eDC there are structures for unscheduled visits too

• For SDTM you define additional VISITNUM and VISIT terms, close to eDC structure, in the TV domain

• SV domain reflects the visits done per subject – planned and unscheduled , having extra rules to sort the unscheduled visits in chronological order

• For ADaM you often define analysis visits AVISIT and the corresponding AVISITN. Unscheduled visits will be sorted to the analysis visits.

• In the TLFs the analysis visits used for the statical analysis in tables. In Listings SDTM visits and the analysis visits are used.



Baseline Flags • Baseline flag has to flag the last meassurement before the first treatment

• Sometimes the baseline is defined in the Protocol

• The eDC never collects that information

• For SDTM this is a derived information, expected to be in place for all Finding domains

• For ADaM for BDS datasets there is a need of a baseline flag ABLFL when baseline has to be used for analysis. The definiton is given in the SAP.

• In the TLFs baseline is driven from AVIST=“Baseline” and in listings is often given as a marker is given for the SDTM visit.



Test Codes and PARAM terms • In SDTM the TEST and TESTCD variables are the required topic variables for all Finding

domains

• Additional information like record qualifier have to be listed in extra variables

• Most of these terms have to use CTs – units, position, location and the test terms themself

• For ADaM PARAM and PARAMCD are required in the BDS datasets. PARAM must include test, units, location, position, and any other applicable qualifying information needed. No CT terminology is given, the description should be directly useable in TFLs and CSR.

• In the TLF output the ADaM analysis parameter has to be taken directly.



Units for test parameter • For some test parameter the units are defined in the study protocol

• The CRF reflects that units

• In SDTM there are two sections to deal with units – the „original“ result, unit and ranges, and the „standarized“ section following the CT terminology

• The „standarized“ unit has to be the same per parameter across all entries in the domain

• For ADaM the units defined in the SAP has to be used.

• In the TLFs listings should reflect the data collected in the unit given in the CRF and the one used in the analysis.


TRACEABILITY OF DATA – FROM EDC TO TLF’S WHAT WOULD BE POSSIBLE SOLUTIONS?

Main problem: the protocol and the CSR outputs are from and for medical people – in the middle is the clinical and statistical programming, and biostatistics • Medical staff uses different terms and expects different output as a programmer would

design it.

• More communication between all parties are needed – when the protocol, the SAP and the expected outputs would be „harmonized“, transformation could be reduced

• Better education necessary

Submission process is forced mainly by the FDA • Benefit of standardization – minimization of training for FDA Reviewer

• Expectations for certain terms are reflected in the CTs

CDISC contains extra rules and CT which are different to the rest • ...but has been defined first


TRACEABILITY OF DATA – FROM EDC TO TLF’S WHO IS INVOLVED IN THE CLINICAL STUDY LIFECYCLE

Medical

Biostatistics

Programmer

SAP & TFL shells

eDC SDTM

ADaM

CRF Study Protocol

TFL Output

CSR

Study Protocol

CSR

SAP & TFL shells

CRF


TRACEABILITY OF DATA – FROM EDC TO TLF’S INTRODUCTION – DATA STRUCTURES (1)

eDC design is different to the SDTM structure • The clinical database has most times one line per information per subject

• Measurements are listed in one line per visit per subject

• Depending on the eDC system there might be duplicated structures, e.g. for log forms

SDTM has a fix set of variables to contain data

SDTM lists information as one line per parameter per visit per subject (if needed per time point, per parameter) • Having 20 entries in a questionsnaire you have to create 20 lines in the QS domain

Non-SDTM data have to be stored in SUPPLEMENTAL domains • List each non-SDTM information in one line, linked to the parent domain entry


TRACEABILITY OF DATA – FROM EDC TO TLF’S INTRODUCTION – DATA STRUCTURES (2)

The structure of ADaM datasets is similar to the structure of SDTM datasets: • One observation per parameter per timepoint per subject

• One datset for one topic and has to be analysis ready

... but • Not all varaiabels captured in the CRF and SDTM has to be part of ADaM

• Data could come from more than one CRF page and also from more tham one SDTM domain

• Information from SUPPxx has to be joined together with their parent domian.


TRACEABILITY OF DATA – FROM EDC TO TLF’S WHAT TOPICS WE HAVEN’T TOUCHED

• DS domain

• Inclusion/Exclusion criteria

• Time points

• AE action taken to study drug or other than study drug

• End date of event and ONGOING

• Reason for medication

• USUBJID for patient rolled over from an other study

• Drug Dispensed at visit if YES vs. NOT DONE

• Comments

• …


TRACEABILITY OF DATA – FROM EDC TO TLF’S CSHARE VIEW OF LIFECYCLE OF CLINICAL STUDIES

• By the way... that‘s how in a CDISC webinar the world looks like (SHARE Research Concepts, Rene Dahlheimer about Research Concepts in Practice, at 26-FEB-2015):


THANK YOU


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