Transcript Kawohl_CDISC-based-esubmission

CDISC based eSubmission
Key Points of the
CDISC SDTM/ADaM Pilot
Monika Kawohl
Senior Statistical Programmer
Accovion GmbH, Marburg, Germany
Outline
Coverage & Aim
Process
CDISC Model Specifics
• SDTM
• ADaM
• Define.xml
FDA Reviewers‘ Feedback
Summary and Conclusions
CDISC German UG Meeting 02-Sep-2008
2
Coverage
Legacy 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
CDISC German UG Meeting 02-Sep-2008
3
Coverage - Pilot Submission Structure
eCTD/eNDA hybrid: PDF TOCs, eCTD folders
Source: Project Report – CDISC SDTM/ADaM Pilot
CDISC German UG Meeting 02-Sep-2008
4
Aim
Verify 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
CDISC German UG Meeting 02-Sep-2008
5
Process
Source: Webcast – Results and Lessons from the CDISC SDTM/ADaM Pilot Project
CDISC German UG Meeting 02-Sep-2008
6
Process – Legacy Data Conversion
Source-centric mapping specification
QC of specifications before programming started
Mapping via ETL Tool
CDISC German UG Meeting 02-Sep-2008
7
Process – SDTM/ADaM/define.xml
SDTM “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
CDISC German UG Meeting 02-Sep-2008
8
Process – Prescriptive Use of Metadata
CDISC German UG Meeting 02-Sep-2008
9
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 German UG Meeting 02-Sep-2008
10
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 German UG Meeting 02-Sep-2008
11
CDISC SDTM Specifics
SDTM “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 German UG Meeting 02-Sep-2008
12
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
 Start
Completion Status
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 German UG Meeting 02-Sep-2008
13
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 German UG Meeting 02-Sep-2008
14
CDISC ADaM Concept Sample
Selected variables from adqsadas.xpt
Communication of analysis performed
SDTM reference
CDISC German UG Meeting 02-Sep-2008
ADSL variables
15
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 German UG Meeting 02-Sep-2008
16
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
CDISC German UG Meeting 02-Sep-2008
17
Define.xml – Analysis Metadata Sample
Link to Analysis Metadata (s.b.)
Link to CSR Table
Link to Variable Metadata of ADSL
Link to SAP
CDISC German UG Meeting 02-Sep-2008
18
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 German UG Meeting 02-Sep-2008
19
CDISC define.xml Specifics Demo
CDISC Pilot (Variable Metadata)
CDISC Draft Metadata Submission Guidelines
(Variable Metadata)
CDISC German UG Meeting 02-Sep-2008
20
CDISC define.xml Specifics Demo
CDISC Pilot (Controlled Terminology)
CDISC Draft Metadata Submission Guidelines
(Value Level Metadata)
CDISC German UG Meeting 02-Sep-2008
21
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)
CDISC German UG Meeting 02-Sep-2008
22
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
CDISC German UG Meeting 02-Sep-2008
23
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
CDISC German UG Meeting 02-Sep-2008
24
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
CDISC German UG Meeting 02-Sep-2008
25
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)
CDISC German UG Meeting 02-Sep-2008
26
Thank you!
Questions?