CDISC Standards: Connecting Clinical Research and Healthcare NCBO Meeting Signs, Symptoms and Findings 3 September 2008, Dallas TX Bron Kisler (CDISC) Gary Walker (Quintiles)

Strength through collaboration. CDISC operates to advance the continued improvement of public health by enabling efficiencies in medical research and related areas of healthcare. Strength through collaboration. As a catalyst for productive collaboration, CDISC brings together individuals spanning the healthcare continuum to develop global, open, consensus-based medical research data standards. 2

CDISC Standards Description 2004* 2001* 2005* 2002 2004 Fall 2008 Implementation Version Release Date SDTM, SEND Ready for regulatory submission of CRT Over 10,000 downloads as of late-2007 2004* ODM CDISC Transport Standard for data interchange (acquisition, exchange, documentation and archive) 2001* Define.xml Case Report Tabulation Data Definition Specification (submission documentation) 2005* LAB Content standard – available for transfer of clinical lab data to sponsors 2002 ADaM Analysis data for submissions - general considerations document and examples 2004 Protocol Representation Collaborative effort to develop machine-readable standard protocol with data layer Fall 2008 Terminology Codelists Developing standard terminology to support all CDISC standards 2006-07 Package1 2007-08 Package2 CDASH Data acquisition (CRF) standards Sept. 2008 * Specification referenced via FDA Final Guidance

Data Flow Using CDISC Standards = ODM - Operational Data Model (transport of data and metadata…”the message”) = SDTM - Study Data Tabulation Model and ADaM - Analysis Dataset Model (content) SEND for Non-clinical Data = Protocol Representation Standard (content) = Source data (other than SDTM/CRF data) = LAB – Laboratory Data Standard Protocol Representation Integrated Reports Patient Info Lab Data CDASH-eCRF Study Data (defined by SDTM) Study & Analysis Data Study & Analysis Data Trial Design Analysis Plan ODM XML ODM XML ODM XML Define.xml Study Protocol (e)Source Document Operational & Analysis Databases Reporting or Regulatory Submissions Warehouse 4

Submissions – SDTM version 3.1.2 Interventions Exposure Conmeds SubstUse Events AE Deviations Disposition MedHx Clinical Findings Vitals Labs ECG Incl/Excl SubjChar Ques’aire Micro MS Micro MB DrugAcct PhysExam PK Param PK Conc Demog Special Purpose Comments SUPPQUAL Trial Design (5 Tables) RELREC SubjElements SubjVisits SDTM = Study Data Tabulation Model

SDTM General Observation Classes Interventions class captures investigational, therapeutic and other treatments that are administered to the subject (with some actual or expected physiological effect) either as specified by the study protocol (e.g., “exposure”), coincident with the study assessment period (e.g., “concomitant medications”), or self-administered by the subject (such as alcohol, tobacco, or caffeine) Events class captures planned protocol milestones such as randomization and study completion (“disposition”), and occurrences, conditions or incidents independent of planned study evaluations occurring during the trial (e.g., “adverse events”) or prior to the trial (e.g., “medical history”) Findings class captures the observations resulting from planned evaluations to address specific tests or questions such as laboratory tests, histopathology, ECG testing, and questions listed on questionnaires. Most findings are measurements, tests, assessments, or examinations performed on a subject in the clinical trial

CDISC Terminology Snapshot Formalized CDISC Terminology Initiative in 2005 Primary Objective: to define and support the terminology needs of the CDISC models across the clinical trial continuum (SDTM → CDASH) Focus on “standard” terminology development and publication, beginning with SDTM ver3.1.1 Key partnership with US National Cancer Institute Enterprise Vocabulary Services (NCI EVS) External harmonization: ISO, HL7 RCRIM, FDA, HITSP, NCI, etc. Controlled Terminology represents one of CDISC’s broadest and most ambitious initiatives. We formalized… Primary Objective…across the clinical trial continuum from the point of data collection through to eSubmissions

CDISC Controlled Terminology LOINC SNOMED MedDRA MeSH ICD’s . 60+ Controlled Vocabularies NCI Thesaurus

Clinical Data Acquisition Standards Harmonization CDISC-led Project (initiated by ACRO) to address FDA Critical Path Initiative Opportunity #45 Mission: To develop a set of ‘content standards’ (element name, definition, metadata) for a core set of global data collection fields that will support clinical research studies. Scope: The initial scope is focused on the ‘safety data/domains’ common across all therapeutic areas Process: Begin with and map to SDTM version 3.1.1; focus on ‘CRF content’ not layout; collect CRF samples and id commonalities; work with Terminology Team on terminology proposals; follow CDISC consensus process 9 9

CDASH Collaborative Group American Medical Informatics Association (AMIA) Association of Clinical Research Organizations (ACRO) Association of Clinical Research Professionals (ACRP) Baylor College of Medicine Biotechnology Industry Organization (BIO) Clinical Data Interchange Standards Consortium (CDISC) Clinical Research Forum Critical Path Institute Duke Clinical Research Institute (DCRI) Food & Drug Administration (FDA) NIH - NCI - caBIG NIH - Clinical Research Policy Analysis & Coordination Program National Clinical Research Resources (NCRR) NIH - National Institute of Child Health & Human Development (NICHD) National Library of Medicine (NLM) Pharmaceutical Research and Manufacturers Association (PhRMA) Society for Clinical Data Management (SCDM) 10 10

CDASH-ODM Connection

Creating CDASH-ODM Template <Study> <Meta … </Meta </Study> </ODM> CDASH–ODM Template CDASH Content SDTM - Study Data Tabulation Model Terminology Codelists Presentation Extended ODM ODM - Operational Data Model (Database Content and Structure) 12

ODM Building Blocks How does CDASH Relate? Clinical Database Variable Name CDASH CRF Label/Question CDASH Core (Highly Recommended) Controlled Terminology

Optimal Solution from Standardized Content to any EDC System I have an alternative to this diagram – this is new. Good because it brings in libraries ……

Multi-Vendor Visualizations – PhaseForward 15

Multi-Vendor Visualizations - Medidata 16

CDISC ‘Healthcare Link’

Data Flow Using CDISC Standards linking clinical research & healthcare Electronic Health Record = SDTM and Analysis Data (content) = ODM (transport) = Protocol information (content) = Source data (other than SDTM/CRF data) Patient Info HL7 and/or ODM XML HL7 and/or ODM XML Clinical Trial Data Integrated Reports Protocol Representation Patient Info Lab Data CDASH-eCRF) Study Data (defined by SDTM) Study & Analysis Data Study & Analysis Data Study Design Analysis Plan ODM XML ODM XML Define.xml ODM XML Operational & Analysis Databases Study Protocol (e)Source Document Regulatory Submissions 18 18

Workflow Integration: RFD Clinical Research Sponsor Data Receiver Receives the data instance from the Form Filler. Forms Manager Serves up the form to the Form Filler. Case Report Form (CRF) CDASH ODM Forms Filler Displays the form for completion in an EHR session EHR Data Archiver Stores the electronic source document Primary Use RFD = Retrieve Form for Data Capture 19

RFD Proof of Concept Lilly/Quintiles RFD 20 3. Form Manager pre-populates Lilly S001 form and returns to Form Filler who completes and submits the form 4. Data Receiver Receives and inserts data into Phase Forward’s Clintrial CDMS. Lilly/Quintiles Form Manager Data Receiver CDASH data elements (demographics, AE, meds) hit 25/33 slots in Lilly CRF. ODM + XForms allowed 4 EHRs to render the form on the first try! RFD 2. Form Filler forwards CDASH data elements to the Form Manager (to retrieve a pre-populated form) Form Filler 5. Data Archiver stores the electronic source document. Data Archiver Cerner Millennium 1. Site Investigator uses Cerner Millenium to retrieve an electronic case report form. 20

Other Healthcare Links

CDISC Standards & BRIDG Model (Biomedical Research Information Domain Group) Submissions Analysis Data SDTM / SEND Glossary ODM LAB ADaM CDASH Data Collection Protocol BRIDG is a mechanism for standards integration 22

BRIDG as a portal to Healthcare Submissions CDASH Data Collection B R I D G Glossary Healthcare SDTM / SEND Protocol B R I D G ODM ADaM HL7 RIM LAB Analysis Data 23

BRIDG Domain Analysis Model (implementation independent) The value of the BRIDG model is in the disambiguation Forces the semantics into a visual representation Models the “problem space” of protocol-driven clinical research This is an example of a class diagram for BRIDG that depicts classes, relationships, etc.

FDA IT Plan (CDISC-HL7 Message) Site Sponsor CDISC Content and Interchange Interchange: HL7 output file CDISC Content Trial Design CDASH Data Checker and Loader Sponsor Data Warehouse (ODM) FDA Reviewers SDTM ADaM Janus FDA/NCI Analytical Data Warehouse Review Tools Site Data Archive (ODM) MedWatch AE Reports (ICSR)