Meeting 070108 - Wayne Kubick

Bay Area User Network
CDISC Production
Standards Status & Plans
Wayne R. Kubick
Sr. Vice President, Lincoln Technologies
CDISC Technical Director
SDS Team Leader
Agenda Topics
• The role and work of the CDISC technical
committee
• The CDISC Technical Roadmap and priorities
and plans for 2007
• Implementation of CDISC standards and
WebSDM at FDA
• Smart strategies for using production standards
• Lingering Questions.
2
CDISC Experience
•
•
Founding Board Member
CDISC Committees:
–
–
–
–
–
•
Technical Advisory Committee
Board of Directors Meetings
BRIDG Advisory Committee
Janus Change Control Board
HL7 RCRIM founding member and participant
Team Activities:
– SDS Team founder and leader and primary editor of SDTM
– ODM 1.1 leader
– Observer and occasional kibbutzer on other teams
•
Roadmap and Production Standards Committee
– Primary responsibility for development, maintenance and harmonization of all
CDISC Production standards: SDTM, ODM, LAB, ADaM, Define.xml, SEND
•
Team Leadership
• Wayne Kubick leads the SDS/SDTM Team
• Sally Cassells leads ODM and Define.xml
•
Phase Forward/Lincoln are CDISC Registered Solution Providers
3
Scope of CDISC Production Standards
Data Sources
• Site CRFs
•Laboratories
•Contract
Research
Organizations
•Development
Partners
Operational Submission
Operational
Data
Database
Data
Future Uniform Model
Interchange
Interchange
& Archive:
•Study Data
& Archive:
SMM
•Audit
Trail HL7
ODM,
LAB
Harmonized
with
SDS, ADaM
•Metadata
ODM = Operational Data Model
LAB = Laboratory Data Model
Glossary
Protocol Representation
Terminology
Submission
Data
•CRT/Domain
Datasets
•Analysis
Datasets
•Metadata
SDS = Submission Domain Standards
ADaM = Analysis Dataset Models
SEND = Std. Exch NonClin Data
Define.xml
4
Standard
Description
Implementation
Version Release
Date
SDTM, SEND
Ready for regulatory submission of CRT
4,000 downloads as of mid-2005
2004*
ODM
CDISC Transport Standard for acquisition,
exchange, submission (define.xml) and
archive
2001*
LAB
Content standard – available for transfer
of clinical lab data to sponsors
2002
ADaM
General Considerations document and
examples of datasets for submission
2004
Protocol
Representation
Collaborative effort to develop machinereadable standard protocol with data layer
In progress
Terminology
Codelists
Developing standard terminology to
support all CDISC standards
2006
Define.xml
Case Report Tabulation Data Definition
Specification
2005*
* Specification in FDA Guidance
5
Board Committees
•Executive
•Financial Oversight
•Governance
•Global Strategy
•Global Communications
CDISC
Board of Directors
CDISC Coordinating Committee
Leaders, Japan & Europe
Industry Advisory
Board
President &
CEO
Chief Operating
Officer
CDISC Regional
User Networks
R-CCC
Communications
& Alliances
Global Operations
Technical Advisory Committee
Technical Roadmap Committee
New
Opportunities
Standards
Development
Production
Standards
Implementation
Services
CDISC Teams
6
Technical Advisory Committee
• Purpose:
– To provide oversight and guidance by the Board of Directors for
CDISC’s core work and processes
– To ensure effective planning, management and harmonization of
technical activities relevant to CDISC standards.
• Responsibilities:
– Reviewing proposed plans, budgets and progress for technical
and project teams, including education and implementation
activities
– Setting annual priorities for the work of the technical and project
teams
– Preparing an annual technical plan
– Reviewing proposals for new technical projects for funding
consideration and make recommendations to the Board
– Issue resolution involving teams, maintenance or harmonization
• TAC meeting in early Feb. to prepare 2007 plan.
7
New Opportunities
Alliances
Communications
Standards
Development
Production Standards
Maintenance
& Enhancement
•Standards Updates
(SDTM, SEND, LAB,
ADaM, Define.xml,
Glossary)
Cross-organization
Standards
-HL7-RCRIM
-ISO
-WHO
-HITSP
•Terminology
•Healthcare Link
•New Stds
Development
(endpoints)
•Submission in ODM
•Roadmap
Tasks &
Harmonization
SDTM Extensions:
(Devices, Genomics,
Therapeutic Areas,
TDM Part 2)
•CDASH Æ
•Protocol Æ
• BRIDG
•End-to-end
Documentation
•NIH Projects
•SDTM-ADaM Pilots
Technical Roadmap Committee
Technical Advisory Committee
Implementation
Support;
Education
•Courses
•Collaboration
Portals
•User Networks
•Global CCC
•Certification
•Help Desk
•Tools (e.g. ODM
Stylesheet for
FDA)
•FDA /Regulatory
Implementation
Support Training
& Support, incl.
CRIX, ERS
•Industry
Architecture
8
Production Standards Mission
• Enhance, maintain, and support CDISC production
standards for more effective use by CDISC
constituencies, while ensuring both model stability and
backward compatibility.
• Ensure all changes to production standards are
approved by a representative standards review board.
• Work to maintain harmonization and improve
interoperability among all CDISC production standards
• Ensure that all critical terms are declared to the
glossary group, that terminology standards are
developed through the Terminology Group, that
education is coordinated thru the CDISC Education
Group, and that production standards are properly
represented in the CDISC clinical research information
model (BRIDG).
9
Operational Standards Status & Plans
•
ODM (Sally Cassells, Jozef Aerts):
– 1.3 Draft posted for comment early in 2006; Production version imminent
• Typed data transmission – allows for schema level validation of data
• New data types (partial dates, incomplete dates, durations, binary floating point
and Boolean
• Support for representation of conditional data collection elements (Study Events,
Forms, ItemGroups and Items)
• Support for transmission of computable expressions
– Supporting Define.xml update, Submission in XML, BRIDG harmonization,
protocol registration and trial design representation, eDCI/eCRF projects
•
LAB (Phil Pochon):
– Version 1.1 imminent
• SAS Name and concept updates for consistency with SDTM LB domain
• Other documentation corrections and clarifications
– Microbiology extension
• Two pilot projects completed
• Harmonization with SDTM Microbiology Domain
– HL7 CTLab Release 1 Implementation Guide produced
• HL7 CTLab Release 2 (with Pharmacogenomics extension) passed as DSTU
– Working with HL7 and CDISC Cross-team initiatives (SDTM Harmonization,
BRIDG, Terminology
10
Submission Standards Status & Plans (1):
•
SDTM (Wayne Kubick, Fred Wood):
– Production Versions1.1/3.1.1
• >7 FDA submissions to date; many in progress
– Finalizing 3.1.2 draft to be posted for comment in Spring
• New domains (PK, MB, CE, CF) some previously posted
• Corrections, clarifications, new business rules to improve consistency
–
–
–
–
–
•
Metadata Implementation Guide due in Q2 (Define, annotated CRFs)
SDTM Controlled Terminology Package 2
Operational SDTM Implementation Guide planned for 2007
Trial Design Model version 2 scheduled for 2007
Ensuring harmonization with CDASH CRF standards.
SEND (Seema Handu, Fred Wood):
– Production version 2.3
– Planning pilot projects at FDA for SEND and Genomics data
– Updates for safety pharmacology prepared (domains for cardiovascular
and respiratory tests)
– New domains planned for reproductive data (including mutligenerational
studies)
– Planning implementation guide for operational use (CRO data exchange)
11
Submission Standards Status & Plans (2)
•
ADaM (Susan Kenny, Jack Shostak):
– General Considerations 2.0 final version published
• Incorporates Subject-level analysis model & analysis-level metadata
• To be referenced in forthcoming FDA guidance on analysis dataset
submissions
– New v. 3 IG in process to include standard variable names for common
derived variables, methods for representing derived records (such as
endpoint & LOCF) and a standard structure to support a variety of
analysis types
• Will include linear (categorical and change from baseline), Adverse Events,
and Time to Event models
– Follow-up actions as a result of initial FDA SDTM/ADaM Pilot
– Supporting cross-team efforts (Define.xml, protocols)
•
Define.xml: (Sally Cassells):
– Updates to address feedback from initial SDTM/ADaM pilot project
– Developing proposed format for XML SDTM data transmission – builds
on ODM 1-3 improvements.
– Defining requirements for representing ADaM metadata
•
Glossary annual update published in December 2006.
12
CDISC Terminology Overview
Support & Provisioning
Integration
Package-1
30 code lists
700+ terms
SDTM
Terminology
40 Team Members
(5 Europe)
Harmonization
Package-2
26 code lists
1000+ terms
Lab Test
NCI EVS Collaboration
13
Collaboration - Integration
CDISC CT
CDISC Codelist Specification
CDISC Codelist Values
Codelist_Name
SEX
Codelist_Name Controlled Terms Comment
Codelist_Label
Sex
SEX
U
Upper_Case
Y
SEX
M
Male
Restriction_8char
N
SEX
F
Female
Extensible_NY
N
SEX
UN
Undifferentiated
Reference_Description
Organization Name: CDISC
Document Title: Study Data Tabulation Model Implementation Guide: Human Clinical
Trials
Document Version: 3.1.1
Date: 2005-08-26
Chapter 5.1.1
Page: 36
Field Name: Controlled Terms or Format
Reference_URL
http://www.cdisc.org/models/sdtm/v1.1/index.html
CDISC Codelist Values
Codelist_Name
SEX
Codelist_Name Controlled Terms Comment
Codelist_Label
Sex
SEX
U
Upper_Case
Y
SEX
M
Male
Restriction_8char
N
SEX
F
Female
Extensible_NY
N
SEX
UN
Undifferentiated
Reference_Description
Organization Name: CDISC
Document Title: Study Data Tabulation Model Implementation Guide: Human Clinical
Trials
Document Version: 3.1.1
Date: 2005-08-26
Chapter 5.1.1
Page: 36
Field Name: Controlled Terms or Format
Unknown
Terms:
• Concept assigned
• Mapped to other CT
• Definition will be
checked and added
CDISC CDE
re-arranged according
to initial spec. &
caDSR metadata
requirements
http://www.cdisc.org/models/sdtm/v1.1/index.html
CDISC Codelist Specification
CDISC Codelist Values
Codelist_Name
SEX
Codelist_Name Controlled Terms Comment
Codelist_Label
Sex
SEX
U
Upper_Case
Y
SEX
M
Male
Restriction_8char
N
SEX
F
Female
Extensible_NY
N
SEX
UN
Undifferentiated
Reference_Description
Organization Name: CDISC
Document Title: Study Data Tabulation Model Implementation Guide: Human Clinical
Trials
Document Version: 3.1.1
Date: 2005-08-26
Chapter 5.1.1
Page: 36
Field Name: Controlled Terms or Format
Reference_URL
NCI EVS
NCI caDSR CDE
Unknown
CDISC Codelist Specification
Reference_URL
Download
Unknown
http://www.cdisc.org/models/sdtm/v1.1/index.html
CT=Controlled Terminology
NCI= National Cancer Institute
EVS= Enterprise Vocabulary Services
caDSR= Cancer Data Standards Repository
CDE= Common Data Element
ISO= International Standards Organization
14
Protocol Representation Standard:
Element Definition, BRIDG Modeling
XML Schema Development
Remaining Protocol –
Study Report Sections
Trial Design (all parts)
Statistical Analysis
Plan Elements
Time and Events
Table Elements (TD Pt 2)
Trial Design Part 1
Eligibility Criteria
Clinical Trial Registry
(CTR); Trial Tracking
Machine-readable Protocol Development and Testing
Jan 2006
Q1 07
Q2 07
Q3 07
Q4 07
2008
2008
2008-09
15
The BRIDG Model*
CDISC Roadmap Priorities
• Progress on Roadmap is top 2007 priority
• Using the BRIDG to guide the roadmap
harmonization
– All current models in BRIDG
– Future model updates represented in BRIDG to help
ensure harmonization and consistency
• Production standards being actively harmonized
into BRIDG
– LAB, ODM and SDTM, Trial Design nearing
completion
– SEND, ADaM and Protocol planned for 2007
*Biomedical Research Integrated Domain Group (BRIDG) Model
16
Implementation Services Priorities
• Online Training
• ODM Certification
• Implementation Enabler tools (Stylesheets and
utilities)
• Improved tools for team and user network
collaborations
• Expanded HELP desk
17
What’s wrong with this picture?
Data Sources
• Site CRFs
•Laboratories
•Contract
Research
Organizations
•Development
Partners
Operational
Data
Interchange
& Archive:
ODM, LAB
Operational
Database
•Study Data
•Audit Trail
•Metadata
Submission
Data
Interchange
& Archive:
SMM
SDS, ADaM
Submission
Data
•CRT/Domain
Datasets
•Analysis
Datasets
•Metadata
18
Standards Applied Across the Process
Protocol &
SDTM
Study
Design
SDTM
ODM
ODM, LAB
SDTM
ADaM,SDTM
Define.xml
Data
Data
Data
Collection Exchange Validation
ODM
Analysis
&
Archive
Reporting
Standard Terminology
Data Repository
19
The CDISC Roadmap
• Purpose:
– To provide a concise, common specification of all technical
products to be developed by CDISC.
• Endpoint:
– By 2010, there will be a single CDISC standard for the full lifecycle of a clinical trial for protocol representation, capture of
source data, submission and archive
• Using a set of fully integrated and consistent models evolving
logically and organically from our current set.
• Success Criteria
– The CDISC standard is used for all submissions to the FDA
– CDISC used across the full life-cycle of clinical trials
– Global adoption of the CDISC standard.
20
Roadmap Guiding Principles
•
•
Complete original missions -- harmoniously with all CDISC models
Aim for a single CDISC standard:
–
ODM XML defines format
•
•
–
–
Define.xml describes common submission metadata
SDTM, LAB and ADaM define content
•
•
•
•
Standard ItemGroups and Items
Standard business rules and code lists
Metadata and information needed to support analysis
Alignment with the BRIDG model
–
•
Bridging CDISC to HL7 as portal to healthcare
Leverage cross-functional teams
–
–
–
•
•
•
Maintain Clinical Research scope – mapped to world of HL7
Remain platform-independent and platform-neutral
Fund projects, but assign teams as stewards and maintainers
Strive to achieve stability and maturity for current standards
More frequent meetings of team leaders under Roadmap Committee
Prioritize processes over separate, individual models
Support sites, sponsors and FDA as stakeholders.
Expand goals to include: Improving patient safety, process optimization,
facilitating scientific and regulatory data review.
21
Roadmap Destinations
1.
The final alignment of the LAB model with SDTM and ODM.
•
2.
Sponsors can now comfortably implement all 3 models and understand
how they work together
The ability to transport all CDISC submission data using the ODM
transport mechanism and ensure consistency with the protocol
representation standard.
•
3.
Sponsors can then comfortably submit SDTM data in ODM format with
Define.xml
The addition of the appropriate analysis datasets and analysis
programs into the CDISC submission model and alignment with the
protocol representation standard and the statistical analysis plan.
•
4.
Sponsors can then submit both tabulation and analysis data as well as
analysis programs in a standardized format using SDTM, AdaM, ODM and
define.xml
Final harmonisation of the models and the full protocol representation
standard.
•
Sponsors can then use standard structured protocols to plan, conduct and
submit trials using the CDISC standard
22
CDISC Standards Technical Roadmap
CDISC harmonization milestones
BRIDG (Biomedical Research Integrated Domain Group)
A
LAB
B
C
SDTM
LAB &
SDTM
ODM
ODM
DEFINE.XML
DEFINE.XML
ADaM
ADaM
ADaM
PROTOCOL
PROTOCOL
PROTOCOL
LAB,
SDTM,
ODM &
DEFINE.XML
D
LAB,
SDTM,
ODM,
DEFINE.XML
& ADaM
The
CDISC
Standard
PROTOCOL
Controlled Terminology
2006
2007
2008
2009-2010
23
Roadmap Milestone 1 Status
• Harmonization of LAB, SDTM LB, and ODM
XML for Lab data transfers
• Outputs
–
–
–
–
Flow diagrams
LAB->LB and LB->LAB Mappings
Implementation Guide
LAB/ODM XML conversion guidelines
• Findings to presented at 2006 US Interchange
– Publication pending.
24
Data Flow Using CDISC Standard Linking Clinical
Research and Healthcare
= ODM (transport)
Electronic
Health Record
= SDTM and Analysis Data (content)
= Protocol information (content)
Patient Info
HL7 or
ODM XML
HL7 or
ODM XML
= Source data
(other than SDTM/CRF data)
Clinical Trial
Data
Protocol
Representation
Trial Design
(SDTM)
Analysis Plan
Clinical Trial
Protocol
ODM
XML
Clinical
(CRF or eCRF)
Trial Data
(defined by
SDTM)
(e)Source
Document
Integrated
Reports
Administrative,
Tracking, Lab
Acquisition Info
Patient Info
ODM
XML
CRF, Analysis
Data
Operational &
Analysis
Databases
ODM XML
Define.xml
SDTM Data,
Analysis
Data,
Metadata
Regulatory
Submissions
25
Conclusions: Production Standards and
CDISC Roadmap Objectives
•
•
•
Keep production standards stable and backward compatible to
promote implementation
Support terminology team efforts to improve semantic
interoperability
Prioritize cross-team interactions focused on harmonization
– Define.XML, Trial Design, Submission in XML, Roadmap
Harmonization, Pilot projects
•
•
Complete End-2-End Traceability
Support the needs of existing users
– Education, support, implementation and evolution
•
Follow the path of the roadmap
– All submissions to the FDA use the CDISC standard
– CDISC models in use across the full life-cycle of clinical trials
– The CDISC standard is globally adopted.
26
Agenda Topics
• The role and work of the CDISC technical
committee
• The CDISC Technical Roadmap and priorities
and plans for 2007
• Implementation of CDISC standards and
WebSDM at FDA
• Smart strategies for using production standards.
27
Current State: Industry Implementation of
SDTM
• Many sponsors are preparing first SDTM submissions by
mapping existing data
• Large sponsor company status varies
– Planning stages thru early implementation
– Most SDS member companies planning partial SDTM
submissions for 2007/2008
• CDISC SDS team is working on guidelines for using
SDTM upstream in an operational database
– Applying SDTM in an operational database presents some
challenges
– Goal is to encourage adoption of SDTM concepts throughout the
data collection, management, analysis and review process.
• Some companies – large and small – are already using
SDTM standards beginning with study design
28
SDTM is an FDA Priority
29
30
Current FDA Review Process
FDA
Sponsor
Gateway
Sponsor
Document
Mgmt System
Sponsor
Data
Warehouse
eSub
FDA
Electronic
Document
Room
Servers
SDTM
Data
Repository
Documents
CRTs
Listings
Patient Profiles
Analysis Data
WebSDM
Data
Load &
Validation
Review
Environment
Desktop Tools
(Acrobat, PPV,
JMP, iReview…)
WebSDM
Oracle
Database
WebSDM
Data
Viewer
31
Future FDA Review Process
FDA
Sponsor
Gateway
Sponsor
Document
Mgmt System
Sponsor
Data
Warehouse
eSub
FDA
Electronic
Document
Room
Servers
CRTs
Repository
Documents
Document
CRTs
Share
Listings
Patient Profiles
Analysis Data
WebSDM
Data
Load &
Validation
Janus
Oracle
Data
Database
Warehouse
Review
Environment
Desktop Tools
(Acrobat, PPV,
JMP, Excel etc.)
WebSDM
Data
Viewer
32
The FDA Janus Warehouse
•
Includes:
–
–
–
–
•
•
All clinical trial data
Protocol
Pharm/tox
Analysis plan
Does not include:
– Spontaneous reports
– Study reports & Reviews
Actual Data (submitted in standard SDS format):
– Findings (LB, EG, VS, QS, PE, etc.)
– Events (AE, MH, DS)
– Interventions (EX, CM)
•
Planned Protocol Definition (to support cross-study analysis):
–
–
–
–
Trial structure
Planned assessments
Planned interventions
Analytic plan
}
Real vs. planned
Support cross-study
analysis
Source: Norman Stockbridge
33
Planned Uses with Janus
• Janus Phase 1 – testbed server environment
with data for 1 sample study and DB QBE tools
• Janus Phase 2 – Activities in progress include:
• Integration of WebSDM with FDA eDocument Room for
automated loading, validation and notification
• Development of a process to move and load validated data
from WebSDM into the JANUS repository
• Designing framework for integration with software tools
(WebSDM, iReview, SAS, ToxVision) for a production system
to be used by FDA reviewers
• Links to ECG warehouse and potentially other viewing tools
• Phase 2 pilot will include additional demo/sample data
• Use with live review data possible in 2007.
34
SDTM in eCTD Directory structure
SDTM Data
35
FDA Submission Acceptance Use Case
• Data loaded into EDR
• Data loaded and checked by WebSDM
– Possible queries to sponsor: errors, MedDRA
– Data accessed thru WebSDM or directly by JMP, iReview, etc.
• Many reviewers prepare customized datasets in WebSDM for
JMP or S-Plus
– Reporting, hypothesis testing, drilldown
• Future plans to load into Janus
– Would allow cross-submission analysis
– Likely to result in tighter requirements (checks, trial
design define.xml, terminology)
36
SDTM Error Checking
• Structural Errors
– Dataset structure doesn’t
match requirements in SDTM
specification
– Priorities linked to Core SDS
attribute: Required, Expected,
Permitted
• Consistency Errors
– Within domain checks
• No duplicate USUBJIDs in
DM
• AEDECOD not in specified
MedDRA version
• Date comparisons
• Range comparisons
– Cross domain checks
• Unexpected values for
Subject and Visit (based
on Trial Design)
• Missing IDVAR/IDVARVAL
values for SUPPQUALS
• Referential integrity checks
37
Error Review
• Readable error
messages
• Identifies actual and
expected values
• Drill down to rule
definition or subject data
• Built-in annotation utility
or download to Excel
• Filter and sort capabilities
• FDA Business process
for error review response
still in development
38
CDISC SDTM Standards Enable
Standard FDA Tools
• FDA reviewers typically struggle with non-standard
submission data
– Many medical reviewers work only with pdfs
• Reviewers lack programming support and need tools
– But tools must be reconfigured for each non-standard data
submission
• The emergence of data standards has allowed FDA to
acquire or develop standard tools under Cooperative
Research and Development Agreements (CRADAs)
• Standard tools used by FDA may also be of interest to
sponsors.
39
Inspecting Data
40
Patient Profile View
41
PPD Patient Profiles
42
ECG Viewer
43
• Compare population
safety thumbprint using
Sector maps
44
Subgroup Analysis
• Used to assess
safety within
demographic
population
subsets of
intended
populations
45
•
Results across subgroups can
identify potential associations
for further exploration
46
Current State: Government Implementation
• FDA CDER encouraging sponsors to submit in SDTM
format
– Several FDA working groups for PK, MB, SEND, Genomics
– OBPS support staff ramping up
– Many reviewers anxious to work with SDTM data
• FDA validation, training and support processes are still
evolving
– Always check with review division before submitting any data
– WebSDM 1.5 (with 3.1.1 support) now in production at FDA
• Submit separate analysis files and programs
– But consider how you may derive these from SDTM
• FDA/NCI Phase 2 Janus pilot in process
– NCI expected to host current FDA applications and Janus along
with Project Firebird beginning in 2007.
47
Agenda Topics
• The role and work of the CDISC technical committee
• The CDISC Technical Roadmap and priorities and plans
for 2007
• Implementation of CDISC standards and WebSDM at
FDA
• Smart strategies for using production standards
• Lingering Questions.
Jeers, Cheers and Inquiries:
Wayne.Kubick@LincolnTechnologies.com
A word too much always defeats its purpose.
Arthur Schopenhauer (1788-1860)
48