The caBIG/HL7/CDISC Structured Protocol Representation

1. The caBIG/HL7/CDISC Structured Protocol Representation John Speakman Douglas B. Fridsma, MD, PhD Center for Biomedical Informatics Center for Pathology and Oncology Informatics University of Pittsburgh

2. Agenda for today • A short history of the model and what it does • (aka caSPR, aka Problem Space Model, aka DAM, aka DSAM) • CaPRI and the Development Framework • How this workspace could/should get involved

3. A Team Effort Core modeling team: • Christo Andonyadis (NCICB) • Greg Anglin (Eli Lilly) • Lisa Chatterjee (Digital Infuzion / NIAID) • Julie Evans (CDISC) • Doug Fridsma (UPCI) • Smita Hastak (ScenPro / NCICB) • Ray Heimbuch (Novartis) • Charlie Mead (Oracle / HL7) • Joyce Niland (City of Hope) • John Speakman (Memorial Sloan-Kettering) • Cara Willoughby (Eli Lilly) • Diane Wold (Glaxo SmithKline) Leadership: Sue Dubman (NCI), Becky Kush (CDISC), Charlie Mead (HL7 RCRIM / Oracle), Linda Quade (HL7 RCRIM / Eli Lilly), Barbara Tardiff (HL7 RCRIM / Merck), Randy Levin (HL7 RCRIM / FDA)

4. Clinical Data Interchange Consortium (www.cdisc.org) • Protocols • SEND Operational Data Interchange & Archive: ODM, LAB Submission Data Interchange & Archive: SDM, ADaM • Data Sources • Site CRFs • Laboratories • Contract • Research • Organizations • Development • Partners • Operational • Database • Study Data • Audit Trail • Metadata • Submission • Data • CRT/Domain Datasets • Analysis Datasets • Metadata One harmonized CDISC standard/model ODM = Operational Data Model SDM = Submission Data Model LAB = Laboratory Data Model ADaM = Analysis Data Models

5. Operational Data Modeling Submission Data Modeling Regulatory Reviewers ODM values can be expressed via SDS metadata Data Sources • ODM • Operational Data Model • XML format for clinical study • data and metadata • Supports regulatory-compliant • e-Archive format • SDS • Submission Data Standards *Describes content, structure and attributes of data for regulatory submissions *Defines metadata content for standard domains *Facilitates regulatory reviews define.xml • LAB • Laboratory • Data Model • Defines standard content for • transferring clinical laboratory • data from labs to sponsors • ASCII, SAS, XML, and • HL7 implementations available LAB data can be mapped into ODM XML Applies submission model for analysis datasets • ADaM • Analysis • Dataset Models • Provides models for commonly used statistical analyses. ODM can be used to represent and archive submission data

6. Health Level Seven (www.hl7.org) • The world’s leading standard for the electronic interchange of healthcare information • >20 Global affiliates • 16 years of operation • ANSI-accredited SDO, acknowledged by the DHHS as the standard for healthcare information exchange • RIM (Reference Information Model) • RCRIM (Regulated Clinical Research Information Management) Technical Committee

8. CDISC and HL7 Relationship • 2001-2002: • Early CDISC attempts to map CDISC ODM (Operational Data Model) to the HL7 RIM failed • 2003: • CDISC-HL7 joint study group to assess how CDISC standards might become RIM compliant and be grafted onto HL7 RIM • Plan developed for creating domain-space ‘business’ model for clinical research • 2004: Modeling starts

9. Domain Space Analysis Model: Timeline 2001-2002 2003 Jan 2004 Mar-Aug 2004 Aug-Oct 2004 Dec 2004 Nov 2004 ... Dr. Mead’s Report to CDISC Board of Directors Initial DSAM Development, led by Dr.Mead Feedback Review of DSAM with Focus Groups Initial Modeling of Protocol Elements in DSAM Begin Mapping CDISC ODM to HL7 V3 RIM Early attempts to map ODM to HL7 RIM • Involvement from: • CDISC • NCI • RCRIM inv. • Reps from: • CDISC Board • CDISC Teams • HL7 RCRIM • TCC • NCI • Reps from: • NIH/NCI • FDA • EHR/eSource • TCC • HL7 RCRIM • CDISC teams • CDISC IAB • Reps from: • CDISC • HL7 • Reps from: • CDISC • NCI/caBIG • HL7 RCRIM HL7 V3 RIM Implementation of CDISC LAB Model -> ANSI Accreditation; Assistance for ODM sought from L.Bain, C.Mead SDTM Announced by HHS/FDA; eSubmission made w/ define.xml ODM Production V1.2 (XML Schema) - Industry Adoption and Tool Development 

10. Interchange Standards: Long-term Desired Outcomes • A holistic approach to standards, facilitating data interchange from sites through regulatory submission, utilizing XML • Standards for data acquisition supporting the population of a cross-trial warehouse within FDA • HL7-CDISC models harmonized to yield value for both clinical research and healthcare – sharing of information between EMR and clinical trials • Global adoption of CDISC data standards CDISC Meeting with FDA Commissioner, April 2003

11. CDISC Plans • Today, CDISC is working to ensure interoperability among its own standards. • CDISC has committed to using the HL7 Development Framework (HDF) as a process through which the CDISC standards are to be harmonized with the HL7 RIM in the long term. • The ultimate goal is one overarching model to support interoperability between healthcare and clinical research systems.

12. International Conference on Harmonization (ICH) U.S. Dept. of Health and Human Services (HHS) EFPIA JPMA PhRMA NIH CDC EMEA MHLW KIKO U.S. FDA NIAID NCI NLM DICOM caBIG CDISC Health Level 7 (HL7) ISO/ANSI ADaM SDS ODM Reference Information Model RIM LAB MedDRA LOINC SNOMED Clinical Document Architecture eCTD The “World of Clinical Trial Standards” Source: Becky Kush, mod.Cara Willoughby TC: RCRIM Protocol Std = Dictionary, Codelist = Document Standard, or Architecture = Organization = Standard = Model

13. Vision of the SPR SIG (July 2004) • To: • Define a computable protocol representation that supports the entire life-cycle of a clinical trial protocol • Developtools that use this protocol representation. • The protocol representation will serve as a foundation for caBIG modules that support all phases of the clinical trials life cycle (including protocol authoring)

14. PDF Full-text protocol RTF paper Today’s Clinical Trial Protocol One full-text source presented several ways Source: Greg Anglin, Eli Lilly

15. Full-text protocol Database Tomorrow’s Clinical Trial Protocol A data layer in the full-text source Data layer

16. Semanticinteroperability Syntacticinteroperability (interchange) Interchange vs. Interoperability • interoperability: ability of two or more systems or components toexchange information and to predictably use the information that has been exchanged. Source: IEEE Standard Computer Dictionary: A Compilation of IEEE Standard Computer Glossaries, IEEE, 1990] Syntax  Structure Semantics  Meaning Source: Charlie Mead, HL7

17. (Concept) Symbol “Shark” Thing Concept 1 Concept 2 “Delicious with cabernet.” “A guy who hustled me.” Concept Thing 1 Symbol “Shark” Symbol “Shark” Thing Thing 2 The Semiotic Triangle:How Humans Communicate Source: Charlie Mead, HL7

18. Concept 1 Concept 2 “We need to sign off on the protocol by Friday” • “Protocol XYZ has enrolled 73 patients” Thing 1 Thing 2 Study Document Concept 3 Thing 3 “Per the protocol, you must be at least 18 to be enrolled” Plan “Protocol” and the Semiotic Triangle Symbol “Protocol”

19. Some HL7 Terms • Mood: • Lifecycle of a concept through a business process • State: • Lifecycle of an instance

20. New Final Draft Review Study Concept Business Process Propose Plan Execute Report Protocol Document Instance

21. New Draft Final Review Protocol:A document that contains study information in the planning mood. Intent Study Report Document Plan Execute MOOD:Lifecycle of a research concept through a business process STATE: Lifecycle of an instance

22. Basis of the Model • CDISC Protocol Elements Spreadsheet • Contains definitions of ~200 concepts deemed important to clinical research • But no structure (i.e., no representation of their relationships) • Job #1: build a model that includes all the concepts in the speadsheet

23. The iterative process of creating the SPR: Stage I HL7v3 RIM Domain elements (drawn from CDISC PR elements) * at this stage there are granular ideas that we know we need to represent, but relationships not clear Business Inputs

24. CDISC protocol elements

25. The iterative process of creating the SPR: Stage II HL7v3 RIM Strawman model of structure of domain elements * at this stage we describe the relationships between domain elements, without regard for the RIM Business Inputs

28. The iterative process of creating the SPR: Stage III [now] HL7v3 RIM reductionist model of structure of domain elements * at this stage we analyze the model to boil it down to its primitive data structure. It gets close to RIM, but very abstract … loses some meaning to domain experts Business Inputs

29. The Model: Stage II-III

30. The iterative process of creating the SPRStage Two  Stage Three  Stage Four

31. The iterative process of creating the SPR: Stage IV RIM integrated model(s) of structure of domain elements Explode back to domain concepts, through instance diagrams, storyboards,vocabularies, and other tools; check that the initial elements still hold in the model Business Inputs

32. ECOG 2190 Schema

33. ECOG 2190 Protocol Activity

34. Internal Tracking and Protocol Registration caSPR forms the foundation for interoperable module development

35. caPRI < ---------- > < ------ > < ----------- > < --------- > < ----------- > < ------ > ----------------- ----------------- ------------ ------------ ---------------- ----------------- ----------------- ----------------- ----------------- ------------ ------------ ---------------- ----------------- ----------------- ----------------- ----------------- ------------ ------------ ---------------- ----------------- ----------------- caSPR CDE < ---------- > < ------ > < ----------- > < --------- > < ----------- > < ------ > < ---------- > < ------ > < ----------- > < --------- > < ----------- > < ------ > < ---------- > < ------ > < ----------- > < --------- > < ----------- > < ------ > < ---------- > < ------ > < ----------- > < --------- > < ----------- > < ------ > Protocol Database Legacy data specification Task context information BusinessRules Layout specification Proposed caPRI System Description

36. caPRI < ---------- > < ------ > < ----------- > < --------- > < ----------- > < ------ > ----------------- ----------------- ------------ ------------ ---------------- ----------------- ----------------- ----------------- ----------------- ------------ ------------ ---------------- ----------------- ----------------- ----------------- ----------------- ------------ ------------ ---------------- ----------------- ----------------- caSPR CDE < ---------- > < ------ > < ----------- > < --------- > < ----------- > < ------ > < ---------- > < ------ > < ----------- > < --------- > < ----------- > < ------ > < ---------- > < ------ > < ----------- > < --------- > < ----------- > < ------ > < ---------- > < ------ > < ----------- > < --------- > < ----------- > < ------ > Protocol Database BusinessRules Legacy data specification Task context information Layout specification Portions currently implemented EAV database

39. The Importance of Process • We need processes to develop interoperable applications • Can use the HL7 Development framework • We need processes to develop interchange standards • Again can use the HL7 Development Framework • We need processes to maintain the Model • Collaboration • Versioning control • Model harmonization

40. A example development process—caPRI Application Development Functional Requirements caSPR module analysis model caSPR CDE caPRI input module (module specification) caPRI CT management framework Semantic connector & UML loader caDSR candidate CDEs caSPR = CDISC DSAM = HL7 DAM RCRIM DMIM RMIM (interchange requirements) HL7 XSD (Interchange specification) HL7 compliant framework Interchange Specification Increasing specificity and computability

41. The people processes – Desiderata for a collaboration web-board-type thing • Open access, open communication, discussion forums • Mechanisms for proposing changes • Mechanisms for harmonization • Levels of access (readers, modelers, stewards) • Tightly controlled versioning with tracking • Integration of model packages, application code, documentation, and user groups

42. What have we accomplished? • caSPR • Established excellent collaboration with CDISC, HL7 and other caBIG modelers • Constructed the initial pieces of a comprehensive model • still much to do • Established this model as the HL7 Domain analysis model • Have established Enterprise Architect as the tool of choice, and moved the model from Rational Rose XDE into EA

43. What have we accomplished? • caPRI • Demonstrated a caBIG compliant application that is modular, extensible, flexible, and driven from the SPR model • Set the stage for collaborative development of new modules and features • Process • Proposed a model development, collaboration, and version control process

44. The caFuture

45. What we need Ask not what the structured protocol representation can do for you, Ask what you can do for the structured protocol representation

46. Current caBIG/HL7/CDISC SPR needs • Developing Instance diagrams, examples, and testing the model using the ECOG 2190 protocol as our initial test • The model is “static” heavy • Develop the behavioral portions of the model • The people processes around clinical trials • Calendars • Activities • Behaviors • Study execution

47. Next steps in the SPR project – our tasks • caSPR • Dissemination and presentation—road shows • caBIG April 10th, HL7 May 2nd, CDISC middle/end of May • Development and implementation of model versioning control and collaboration processes • People and technical processes to be finalized • Incorporation of informal comments and correction of known model problems • Next core modeling session next week!

48. Next steps in the SPR project • Model development needs • Review class and attribute definitions • Assistance with instance diagrams and examples • Requirements gathering for new functionality and subdomains • Application development needs • Adopters of caPRI – testing and improvement • Developers of new modules

49. Next steps in the SPR project • Integration within CTMS and across caBIG • SIGs should be the leads in the requirements and testing of the parts of the model that they have expertise in • Other workspaces activities will touch on the SPR • Tissue banking and pathology tools • i.e., us

50. TBPT involvement Include a stub to the caTISSUE OM? • How big is the stub? • Or just include the whole caTISSUE OM within it? • When is a tissue protocol something we “care” about? • When is it just another “protocol” like the IRB protocols we know and love? • What does it depend on? • Consent type? • IRB involvement? • Assignment of an IRB number? • Annotation of specimens? *shrug*