1. Out of Cycle HL7 RCRIM Meeting 25 April 2006 Berlin, Germany

2. Initial Associate Charter Agreement 2001 Formed Clinical Trial Special Interest Group Elevated to Regulated Clinical Research Information Management (RCRIM) Technical Committee Renewed Associate Charter between CDISC and HL7 in 2004 Organizational Memberships and Collaborations Outreach Committee for Clinical Research (OCCR) Commitment to harmonize the HL7 and CDISC standards

3. Protocol Representation: Project Scope Project Description Protocol Representation will identify standard elements of a clinical trial protocol that can be further elucidated and codified to facilitate study design, regulatory compliance, project management, trial conduct and data interchange among consumers and systems. This work will be based upon the needs of protocol consumers, which may include regulatory authorities, IRBs, statisticians, project managers, site personnel and users of any downstream systems for the management of clinical trial information. Project Objective(s): Publication of a standard, machine-readable model for protocol representation that will enable interchange of this data among systems and stakeholders. PR Group April 2002

4. Protocol Representation (PR) Group A volunteer organization of domain experts representing the stakeholders of the biopharmaceutical industry, NCI/NIH, and FDA with specific expertise in developing and/or conducting regulated clinical trials with regulated protocols.

5. PR Group is both: – A CDISC team – A Project Team of the Health Level 7 (HL7) Regulated Clinical Research and Information Management (RCRIM) Technical Committee PR Group (cont d)

6. Approach: Assumptions and Decisions Development should concentrate on content first and implementation second. – PR Elements Spreadsheet Elements: – a data item or a block of text representing a unique piece of information

7. Approach: Assumptions and Decisions (contd) Elements must be defined in a glossary, since the industry uses multiple definitions for the majority of protocol elements – CDISC Glossary Applied Clinical Trials, Dec 2004

8. Approach: Assumptions and Decisions (contd) Identify core set of elements initially, and expand with further details, as needed – Initial set of elements based on ICH E6 & ICH E3 documents, which focus on efficacy and safety trials, but can be applied to other types of studies. ICH E6 – Basis for the development and organization of the PR Element Spreadsheet ICH E3 – Terms & definitions EUDRACT (EMEA) – Key words and Protocol description Specific topics (e.g. IRB, SAP-E9)

11. Protocol Elements Spreadsheet

12. CDISC Reviews and HL7 Ballots Comments received through CDISC website (spreadsheet, glossary) Comments received through HL7 initial ballot (CDA of element subset, with SPL modeling aspects included) – 33 Negative; 18 Affirmative Votes Achieved goal of obtaining feedback on work of PR Group, but were not yet ready to do next ballot for September WGM

13. Recommendations from HL7 Meeting (RCRIM TC, Structured Documents TC, RIM developers, others) Use comments for team education (and also to educate reviewers); team should go through all comments Better define scope and use cases and communicate these; focus on limited number of use cases, but not just one Review others work in more depth and ensure compatibility with existing models (prior DMIM and emerging DMIM should be useful); link with SDTM and other CDISC models Approach the work as a structured document but not necessarily a Clinical Document Architecture At some point, identify core elements and/or required elements Approach the protocol as the plan, not the database over the course of the trial, i.e. should not include items that are tracked over time … model will accommodate that Better communicate the broader scope of the use of the protocol elements and the potential linkages

14. PR Group Objective To develop a standard structured protocol representation that supports the entire life-cycle of clinical research protocols to achieve semantic interoperability (the exchange of content and meaning) amongst systems and stakeholders. - As of 2005

15. Use Case Re-Prioritization Use Case 1: (Priority #3) Develop machine-readable Protocol Document – Score 10. Use Case 2: IRB – Score 0 Use Case 3: Submission to Regulators – Score 3 Use Case 4: (Priority #2) Use Case 4: Study Tracking Database – Score 17 –This use case will include the Study Summary/Synopsis dataset that the SDS has started. Use Case 5: Clinical Trial Data Collection / Database Setup – Score 8 Use Case 6: (Priority #1) Support SDS V3.1 Submission (SDTM) – Top Priority (especially: Planned Assessments/Interventions, Study Design, Statistics, Inclusion/Exclusion) Use Case 7: Cross trial search and data mining – Score 3

16. Protocol Use Case Priorities 1. To support CDISC Study Data Tabulation Model (SDTM) V3.1.1 -Trial Design-Planned Assessments -Planned Interventions-Inclusion/Exclusion criteria -Statistical Analysis Plan 2. To support study tracking databases, e.g. EudraCT, clinicaltrials.gov, the protocol/trial tracking aspect of trial registry or results databases, or databases that support project management tools 3. To support the development of the clinical trial protocol document

17. Trial Design Model Led by Diane Wold, GSK - from SDTM Team Allows description of key aspects of the planned conduct of a clinical trial in a standardized way – The planned arms of the trial – What happens to a subject in each arm – The planned schedule of visits – The inclusion and exclusion criteria for the trial Status – Version 1 published as part of SDTM V3.1 – Version 2 : Draft, with incorporation into SDTM planned for Spring 2006

18. Trial Registry Use Case Originally a separate project of RCRIM – now a sub-project of PR Group Sub-group of PR Group led by Lakshmi Grama (of NCI, clinicaltrials.gov, PDQ, CDE) Identified subset of elements (~65) for trial registration and trial tracking/project management Modeled these in BRIDG in April 2006

19. BRIDG Modeling PR Group, including CDISC, NCI, HL7, FDA representation, modeled Protocol Elements and Trial Design, Adverse Events and Statistics into the existing BRIDG – modeling sub-group of ~10 (CDISC, NCI, others) – several multi-day sessions over ~ 7 month period Continue to ensure representation of the protocol elements in the existing BRIDG, beginning with Trial Registry subset

20. Protocol Elements Definitions For Elements Code Lists Terminology Modeling Information (e.g. cardinality) HL7 Development Framework XML Schema PR Group and Reviewers HL7 Modeling HL7 Balloting Implementation/Tools Human and Machine- Executable Protocol (possible template) Review or Management Tools* Cross-trial Databases Warehouses Protocol Authoring Tools Data Collection Tools (eSource eCRF) * e.g. Planned vs. Actual; Project Status e.g. Regulatory, Pharma Company, IRB ° e.g. Study Reports, PI Brochures Element Re-use- Clinical Documents°

21. "We are ready to move forward with an international Clinical Trials Registry. This will do much to strengthen the research process and its ability to win public trust." Dr J.W. Lee WHO Director-General Opening Address to World Health Assembly, May 2005 Ida Sim, MD, PhD

22. Acknowledgement Ida Sim, MD, PhD Project Coordinator Department of Research Policy and Cooperation World Health Organization Geneva, Switzerland

23. World Health Organization Premise: Need for Trial Registration and Reporting Clinical trials one of the most valuable sources of evidence about safety and efficacy of health interventions Extensive media coverage of several cases of selective reporting of results Trial registration and full reporting of trial results would help ensure a full and unbiased public record on safety and effectiveness Ida Sim, MD, PhD

24. Current Policies Many journals in addition to International Committee of Medical Journal Editors (ICMJE) now accept only registered trials for potential publication Patchwork of regulations worldwide – Fair Access to Clinical Trials Act in US Congress, over 50 bills pending in various jurisdictions in the US alone – Increasing numbers of trials are multi-country, resulting in risk of legislative overload Ida Sim, MD, PhD

25. Worldwide Proliferation of Registers Fragmented, inaccessible, duplicated, varying in – constituency country-, disease- and/or funder-specific – purposes participant enrollment administrative tracking scientific analysis Need for standardization and coordination Ida Sim, MD, PhD

26. Why World Health Organization? Global, neutral, independent body with convening capacity (i.e. World Health Assembly resolutions) Authoritative; Role in setting norms and standards in research, policy and practice – Good Clinical Practice, Ethics guidelines, Classification standards (e.g., ICD) Contributes to capacity building (i.e. in developing countries) Political legitimacy, accountable to 192 member States Commitment to achieving equity in health Ida Sim, MD, PhD

27. Leading up to WHO Registry Platform Oct 2003 – WHO Director-General highlighted trial registration in global health research Oct 2004 –Rockefeller Foundation meeting, NY – Need for global approach to trial registration – WHO should establish formal process on a global approach Ida Sim, MD, PhD

28. Leading up to WHO Registry Platform Nov 2004 – Ministerial Summit on Health Research, Mexico City – Ministers of Health and others from 52 countries called on WHO to establish network of clinical trial registers ensure unambiguous identification of trials ensure a single point of access April 2005 – Technical Consultation, Geneva – Meeting of diverse stakeholders to build consensus policies May 2005 – 58 th World Health Assembly Ida Sim, MD, PhD

29. WHO Registry Platform Registry Platform project is now a major force in trial registration – have received support and participation from all relevant stakeholder groups Some early accomplishments – defined 20 item WHO Trial Registration Data Set – defined a coordinated global "platform" for trial registration But much more needs to be done to make trial registration a widespread and routine reality Ida Sim, MD, PhD

30. Goal and Objectives Goal – strengthen public trust in clinical research by promoting transparency and accountability Objectives – ensure that all trials worldwide are registered and thus publicly declared and identifiable – ensure that a minimum set of results are publicly reported for all registered trials – support use of trial registration information for recruitment, research planning, etc. Ida Sim, MD, PhD

31. Registry Platform Administrative Structure International Advisory Board – broad-based, 15 senior leaders – advise on strategy/direction – lead in communication/ advocacy Scientific Advisory Group – 21 experts – advise on principles/ substantive standards Registry Platform Secretariat WHO EIP/RPC Scientific Advisory Group International Advisory Board Ida Sim, MD, PhD

32. Registry Platform Overview WHO International Clinical Trials Registry Platform Journals Results Databases WHO Search Portal Registers ISRCTN clinicaltrials.gov... country specific Ida Sim, MD, PhD

33. Responsible Registrant Global Deduplication Search Database Central Reference Database 1 5 6 WHO Registration Data Set 4 8 2 MeSH Coding 3 7 UTRN, MeSH Codes Associate Registers Primary Registers Other Registers Search Portal Ida Sim, MD, PhD

34. WHO Registration Data Set (1) 1. Primary Register and Trial ID# (e.g., ISRCTN number) 2. Date of Registration in Primary Register 3. Secondary ID#s 4. Funding Source(s) 5. Primary Sponsor 6. Secondary Sponsor(s) 7. Responsible Contact Person 8. Research Contact Person 9. Public Title 10. Scientific Title Ida Sim, MD, PhD

35. WHO Registration Data Set (2) 11. Countries of Recruitment 12. Health Condition(s) or Problem(s) Studied 13. Intervention(s) 14. Inclusion & Exclusion Criteria 15. Study Type 16. Date of First Enrollment 17. Target Sample Size 18. Recruitment Status 19. Primary Outcome(s) 20. Key Secondary Outcome(s) Ida Sim, MD, PhD

36. Role of CDISC and HL7 Terminology/coding recommendations for 20 elements Standard for the transfer of information on the 20 elements NOT the political aspects related to clinical trial registration

37. Progress to Date Terminology recommended CDISC ODM XML schema developed 20 elements mapped into BRIDG model Comparison of 20 elements with work in progress in Protocol Representation Group – Sub-team focusing on Clinical Trial Registration- Clinical Trial Tracking

38. 20 Elements – WHO Table with Recommended Terminology/Codelists (from CDISC and HL7)

39. ODM Study AdminData @ FileOID attributes ClinicalData Association ds:signature @ CreationDateTime @ Description @ FileType @ Granularity @ Archival @ PriorFileOID @ AsOfDateTime @ ODMVersion @ Originator @ SourceSystem @ SourceSystemVersion @ ID ODM Element ReferenceData Dave Iberson-Hurst

40. Study GlobalVariables BasicDefinitions attributes MetaDataVersion @ OID Study Element

41. GlobalVariables StudyName ProtocolName GlobalVariables Element StudyDescription WHO Extension CDISC Example Study A simple trial to demonstrate the end-to-end application of the CDISC Standards CDISC Example Study CDISC Example Study A simple trial to demonstrate the end-to-end application of the CDISC Standards CDISC Example Study