CDISC Production Standards Status & Plans

Transcription

1 Bay Area User Network CDISC Production Standards Status & Plans Wayne R. Kubick Sr. Vice President, Lincoln Technologies CDISC Technical Director SDS Team Leader

2 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

3 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

4 Scope of CDISC Production Standards Data Sources Site CRFs Laboratories Contract Research Organizations Development Partners Operational Data Interchange & Archive: ODM, LAB Operational Database Future Uniform Model Study Data Audit Trail Metadata Harmonized with HL7 Submission Data Interchange & Archive: SMM SDS, ADaM Submission Data CRT/Domain Datasets Analysis Datasets Metadata ODM = Operational Data Model SDS = Submission Domain Standards LAB = Laboratory Data Model ADaM = Analysis Dataset Models Glossary SEND = Std. Exch NonClin Data Protocol Representation Define.xml Terminology 4

5 Standard Description Implementation Version Release Date SDTM, SEND Ready for regulatory submission of CRT 4,000 downloads as of mid-2005 ODM CDISC Transport Standard for acquisition, 2001* exchange, submission (define.xml) and archive LAB Content standard available for transfer 2002 of clinical lab data to sponsors ADaM General Considerations document and 2004 examples of datasets for submission Protocol Representation Terminology Codelists Define.xml Collaborative effort to develop machinereadable standard protocol with data layer Developing standard terminology to support all CDISC standards Case Report Tabulation Data Definition Specification 2004* In progress * * Specification in FDA Guidance 5

6 Board Committees Executive Financial Oversight Governance Global Strategy Global Communications President & CEO CDISC Board of Directors Chief Operating Officer CDISC Coordinating Committee Leaders, Japan & Europe Industry Advisory Board 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

7 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

8 New Opportunities Alliances Communications Standards Development Production Standards Maintenance & Enhancement Implementation Support; Education Cross-organization Standards -HL7-RCRIM -ISO -WHO -HITSP Healthcare Link CDASH Protocol BRIDG Terminology NIH Projects New Stds Development (endpoints) Roadmap Tasks & Harmonization Standards Updates (SDTM, SEND, LAB, ADaM, Define.xml, Glossary) End-to-end Documentation SDTM-ADaM Pilots Submission in ODM SDTM Extensions: (Devices, Genomics, Therapeutic Areas, TDM Part 2) 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 Technical Roadmap Committee Industry Architecture Technical Advisory Committee 8

9 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

10 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

11 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 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

12 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

13 CDISC Terminology Overview Support & Provisioning Integration SDTM Terminology Harmonization 40 Team Members (5 Europe) Package-1 30 code lists 700+ terms Package-2 26 code lists terms Lab Test NCI EVS Collaboration 13

14 Collaboration - Integration Download CDISC CT NCI EVS NCI cadsr CDE CDISC Codelist Specification CDISC Codelist Values Codelist_Name SEX Codelist_Name Controlled Terms Comment Codelist_Label Sex SEX U Unknown 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: Date: Chapter Page: 36 Field Name: Controlled Terms or Format Reference_URL CDISC Codelist Specification CDISC Codelist Values Codelist_Name SEX Codelist_Name Controlled Terms Comment Codelist_Label Sex SEX U Unknown 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: Date: Chapter Page: 36 Field Name: Controlled Terms or Format Reference_URL CDISC Codelist Specification CDISC Codelist Values Codelist_Name SEX Codelist_Name Controlled Terms Comment Terms: Concept assigned Mapped to other CT Definition will be checked and added CDISC CDE re-arranged according to initial spec. & cadsr metadata requirements Codelist_Label Sex SEX U Unknown 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: Date: Chapter Page: 36 Field Name: Controlled Terms or Format Reference_URL 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

15 Protocol Representation Standard: Element Definition, BRIDG Modeling XML Schema Development Remaining Protocol Study Report Sections Trial Design Part 1 Statistical Analysis Plan Elements Time and Events Table Elements (TD Pt 2) Trial Design (all parts) Eligibility Criteria Clinical Trial Registry (CTR); Trial Tracking Machine-readable Protocol Development and Testing Jan 2006 Q1 07 Q2 07 Q3 07 Q

16 CDISC Roadmap Priorities The BRIDG Model* 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

17 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

18 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

19 Standards Applied Across the Process Protocol & SDTM SDTM ODM ODM, LAB SDTM ADaM,SDTM Define.xml ODM Study Design Data Collection Data Exchange Data Validation Analysis & Reporting Archive Standard Terminology Data Repository 19

20 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

21 Roadmap Guiding Principles Complete original missions -- harmoniously with all CDISC models Aim for a single CDISC standard: ODM XML defines format Maintain Clinical Research scope mapped to world of HL7 Remain platform-independent and platform-neutral 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 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

22 Roadmap Destinations 1. The final alignment of the LAB model with SDTM and ODM. Sponsors can now comfortably implement all 3 models and understand how they work together 2. The ability to transport all CDISC submission data using the ODM transport mechanism and ensure consistency with the protocol representation standard. Sponsors can then comfortably submit SDTM data in ODM format with Define.xml 3. 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. 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 4. 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

23 CDISC Standards Technical Roadmap CDISC harmonization milestones BRIDG (Biomedical Research Integrated Domain Group) A B C D LAB SDTM ODM DEFINE.XML ADaM LAB & SDTM ODM DEFINE.XML ADaM LAB, SDTM, ODM & DEFINE.XML ADaM LAB, SDTM, ODM, DEFINE.XML & ADaM PROTOCOL PROTOCOL PROTOCOL PROTOCOL The CDISC Standard Controlled Terminology

24 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

25 Data Flow Using CDISC Standard Linking Clinical Research and Healthcare Electronic Health Record = ODM (transport) = SDTM and Analysis Data (content) HL7 or ODM XML Patient Info Clinical Trial Data HL7 or ODM XML = Protocol information (content) = Source data (other than SDTM/CRF data) Protocol Representation Trial Design (SDTM) Analysis Plan Clinical Trial Protocol ODM XML Patient Info Clinical (CRF or ecrf) Trial Data (defined by SDTM) (e)source Document ODM XML Administrative, Tracking, Lab Acquisition Info CRF, Analysis Data Operational & Analysis Databases ODM XML Define.xml Integrated Reports SDTM Data, Analysis Data, Metadata Regulatory Submissions 25

26 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

27 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

28 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

29 SDTM is an FDA Priority 29

30 30

31 Current FDA Review Process Sponsor FDA Gateway Repository Review Environment Sponsor Document Mgmt System Sponsor Data Warehouse esub FDA Electronic Document Room Servers SDTM Data Documents CRTs Listings Patient Profiles Analysis Data WebSDM Data Load & Validation WebSDM Oracle Database Desktop Tools (Acrobat, PPV, JMP, ireview ) WebSDM Data Viewer 31

32 Future FDA Review Process Sponsor FDA Gateway Repository Review Environment Sponsor Document Mgmt System Sponsor Data Warehouse esub FDA Electronic Document Room Servers CRTs Documents CRTs Listings Patient Profiles Analysis Data WebSDM Data Load & Validation Document Share Janus Oracle Data Warehouse Database Desktop Tools (Acrobat, PPV, JMP, Excel etc.) WebSDM Data Viewer 32

33 The FDA Janus Warehouse Includes: All clinical trial data Protocol Pharm/tox Analysis plan 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 Does not include: Spontaneous reports Study reports & Reviews Real vs. planned } Support cross-study analysis Source: Norman Stockbridge 33

34 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

35 SDTM in ectd Directory structure SDTM Data 35

36 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, i- Review, 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

37 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

38 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

39 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

40 Inspecting Data 40

41 Patient Profile View 41

42 PPD Patient Profiles 42

43 ECG Viewer 43

44 Compare population safety thumbprint using Sector maps 44

45 Subgroup Analysis Used to assess safety within demographic population subsets of intended populations 45

46 Results across subgroups can identify potential associations for further exploration 46

47 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 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

48 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: A word too much always defeats its purpose. Arthur Schopenhauer ( ) 48