Monika Kawohl Senior Statistical Programmer Accovion GmbH, Marburg, Germany CDISC based eSubmission Key Points of the CDISC SDTM/ADaM Pilot

Monika Kawohl

Senior Statistical Programmer

Accovion GmbH, Marburg, Germany

CDISC based eSubmission

Key Points of the CDISC SDTM/ADaM Pilot

CDISC German UG Meeting 02-Sep-2008 2

Outline

Coverage & Aim

Process

CDISC Model Specifics

• SDTM

• ADaM

• Define.xml

FDA Reviewers‘ Feedback

Summary and Conclusions


CoverageLegacy data conversion of 1 study to SDTM

SDTM domains (SAS V5 XPT format)

Annotated CRF

ADaM datasets created from SDTM

Analysis Results based on ADaM datasets

All tied together via Metadata in define.xml

eCTD structure but PDF TOC files


Coverage - Pilot Submission StructureeCTD/eNDA hybrid: PDF TOCs, eCTD folders

Source: Project Report – CDISC SDTM/ADaM Pilot


AimVerify interoperability of CDISC standards

Obtain FDA reviewers‘ feedback

Provide implementation example

Gap analysis of single CDISC Standards

But ...

Not intended as guidance regarding

• Contents

• Process applied


Process

Source: Webcast – Results and Lessons from the CDISC SDTM/ADaM Pilot Project


Process – Legacy Data ConversionSource-centric mapping specification

QC of specifications before programming started

Mapping via ETL Tool


Process – SDTM/ADaM/define.xmlSDTM “without“ derived => ADaM => SDTM some derived

• Facilitates usage of derived data in SDTM review tools

• Lineage issue

• Explorative use - final decision pending

Definition of metadata at specification level

• Prescriptive use of metadata reduces consistency issues

(Suite of SAS macros used available to CDISC members)

• Concise computational algorithm descriptions

No programs were submitted


Process – Prescriptive Use of Metadata


Process – Quality Control (QC)

QC of specifications

QC of programming/mapping against specifications

• Option: independent re-programming

QC of Analysis Results against SAP

QC of define.xml

• Verifying links and contents

• Verifying of technical requirements via tools

Consistency via automated process based on metadata


CDISC Model Specifics

CDISC SDTM IG V3.1.1

CDISC SDTM V1.1

CDISC ADaM

• CDISC ADaM IG was not yet available (in preparation)

CDISC CRT-DDS (define.xml) V1.0

• CDISC ODM V1.3 for define.xml

define.xml V1.0 standard based on ODM V1.2

• Custom stylesheet

• Schema extension for ADaM part


CDISC SDTM SpecificsSDTM “without derived“

• Includes SDTM required derived variables,e.g., USUBJID, --BLFL, (--DY)

SDTM “with some derived“

• Purpose: viewing derived data in standard domain structures

• Includes data derived in the ADaM creation step Population Flags (SUPPDM)

AE Treatment Emergent Flag and MedDRA variables (SUPPAE)

Endpoint Flag and Result Divided by UL of Normal Range (SUPPLB)

Total Score as sum of single scores (New record in QS)

• ADaM => SDTM ensures consistency of derivation results


CDISC ADaM Specifics

Important since SDTM datasets not analysis-ready

ADSL concept of ADaM V2.0

• ADSL very helpful for all reviewers

Baseline Characteristics

Treatment Variables

Population Flags

Patient Completion Status

Start and End of Study Drug, Date Patient was Last Observed

All analysis datasets instead of datasets for key analyses At least Analysis Metadata could be limited to key results


CDISC ADaM Specifics (Continued)Tracebility and transparency of analysis datasets

• Clear lineage from CRF to analysis

Clear, unambigous metadata (computation methods)

Include all CRF data + derived data

Appropriate data selection via flags

• Facilitate reproduction of analysis results

• Allow for sensitivity analysis, test of robustness

Sponsor-specific standards, e.g. variable names, PARAMs

NOW available: Draft ADaM IG


CDISC ADaM Concept Sample

Selected variables from adqsadas.xpt

SDTM reference

Communication of analysis performed

ADSL variables


CDISC define.xml Specifics

SDTM and ADaM metadata included in 1 define.xml file

• Facilitate links between SDTM and ADaM and vice versa

• Define.xml included in tabulations and analysis eCTD folder

Navigation improved (define.pdf comparable)

• Framed version solves back button issue (IE specific)


CDISC define.xml Specifics (Continued) Valuable sample for Analysis Metadata

• List of Analysis Results

• Standardized results description incl. links to

Analysis output, underlying dataset, specifications (e.g. SAP)

Layout not 100% consistent with new Draft ADaM documents


Define.xml – Analysis Metadata Sample

Link to CSR Table

Link to Variable Metadata of ADSL

Link to SAP

Link to Analysis Metadata (s.b.)


CDISC define.xml Specifics (continued) Deviations from Draft Metadata Submission Guidelines

• All derivations described via computation methods

Separate column

• Comment column reserved for ADaM links to source datasets

• No Variable Value Level Metadata

Limited to Controlled Terminology for test codes and names

• Controlled Terminology representation subdivided in

Code Lists (Code and Decode)

Discrete Value Listings

Printing Issue


CDISC define.xml Specifics DemoCDISC Pilot (Variable Metadata)

CDISC Draft Metadata Submission Guidelines(Variable Metadata)


CDISC define.xml Specifics DemoCDISC Pilot (Controlled Terminology)

CDISC Draft Metadata Submission Guidelines(Value Level Metadata)


FDA Reviewers‘ Feedback Standard disclaimer (NOT the general FDA view)

Overall, data were suitable for reviewers‘ needs

Value of SDTM depends on reviewers‘ training status

• Use define.xml comments to explain “CDISC jargon“

Integration of Reviewer‘s Guide recommended

ADaM essential since SDTM not Analysis-Ready

• ADSL variables, e.g. treatment in each dataset

Derived variables in SDTM helpful

• Use of SDTM based review tools

• CAVEAT: Results may not be reproducible based on sole SDTM (additional analysis flags to be considered)


FDA Reviewers‘ Feedback (continued) Use of SDTM Review Tool WebSDM

• SDTM compliance check

• SDTM/define.xml consistency check

• Graphical Patient Profiles

• Merge of core variables (e.g. sex, treatment) to domains

• Merge of SUPPQUAL to parent domains

• Export of combined data to other tools

Reviewers at time of Pilot more familiar with other tools


FDA Reviewers‘ Feedback (continued) Data documentation via define.xml

• Concept, Content, Navigation, Reviewer‘s Guide

• Printing

Sample for multiple-studies submission is missing

FDA committed to standards

Success of SDTM/ADaM depends on

• Training (implementers and reviewers)

• Experience (implementers and reviewers)

• Availability of suitable review tools


Summary and Conclusions

Overall, data were suitable for reviewers‘ needs

Very helpful implementation example

No guidance => evolution of CDISC standards

Importance of ADaM when submitting SDTM

Familiarity with CDISC models is a key factor

• Implementer

• Reviewer

Watch out for next pilot: multiple-studies safety data


References

CDISC SDTM/ADaM Pilot Project – Project Report(SDTMADaMPilotProjectReport.pdf)

Slides from the CDISC Pilot Webcast(bmc_cdisc_sdtm-adam_pilot_v-2.pdf)

Cathy Barrow‘s presentation at CDISC EU IC 2008(CDISC presentations website)

Revised Pilot Submission Package as provided by CDISC(CDISC Members Only website)

Thank you!

Questions?

Documents

Monika Kawohl Senior Statistical Programmer Accovion GmbH, Marburg, Germany CDISC based eSubmission Key Points of the CDISC SDTM/ADaM Pilot