out of cycle hl7 rcrim meeting 25 april 2006 berlin, germany
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Out of Cycle HL7 RCRIM Meeting
25 April 2006Berlin, Germany
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
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
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.
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)
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
Approach: Assumptions and Decisions (cont’d)
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
Approach: Assumptions and Decisions (cont’d)
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)
Protocol Representation - HierarchyDocument Type
Trial Objectives and Purpose
Subject Selection and Withdrawal
Efficacy Assessments
Trial Design
General Information
Background Information
Treatment of Subjects
Assessment of Safety
Subject Participation/Study Design
Statistics
Direct Access to Source Documents
Data Handling and Record Keeping
Publication Policy
Financing and Insurance
Quality Control and Quality Assurance
Ethics
Supplements
Protocol Representation – Hierarchy Sample: Sections, Sub-sections, Elements
Document Type
General Information
Clinical Trial Protocol
Protocol Identification
Protocol Contact Information
Protocol Title
Protocol Short Title
Protocol Identification Number
Sponsor
Sponsor Status
Field NameSUGGESTED ATTRIBUTES
FIELD NAME EXPLANATION
FIELD NAME DEFINITION and CITATION
FIELD SOURCE EUDRACT
CODE LIST GLOSSARY REFERENCE COMMENTS
Sect DocumentTypeSu Clinical Trial Protocol HL7 Modeling
Type of Application
GENERAL INFORMATION NA
Header for the section describing the protocol title and contacts, including information about amendments ICH E6 6.1 NA
Protocol Identification NA
Header for sub-section that contains all protocol identifying information CDISC PR Group
A.Trial Identification Appendix I NA
Protocol Title NAFull text of the protocol/study title
SDS Study Summary
ICH E6 6.1.1, EUDRACT
Appendix I A. Full title
of the protocol
Protocol Short Title NA
Name or abbreviated title of the trial wherever available EUDRACT
Appendix I A.Abbreviated title of the
trial
Protocol identifying number
Sponsor's protocol identifying number, EUDRACT clinical trial number, national number, other (e.g. cooperative group number)
Sponsor protocol number;and/or Unique EMEA code issued to sponsor by a central function within EMEA at the time of submission of clinical trial information to authorities. Any amendments will be reference this number also. The code will be used in reporti
ICH E6 6.1.1, EUDRACT
National trial # reference, EUDRACT clinical trial
number, Sponsor code = sponsor protocol number
CDISC, EUDRACT
EUDRACT stated that this was a national identificaton number and that is was issued by a central authority.
MODEL
Protocol Elements Spreadsheet
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
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
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
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
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
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
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
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
ProtocolElements
Definitions For
Elements
Code ListsTerminology
ModelingInformation
(e.g. cardinality)
HL7DevelopmentFramework
XMLSchema
PR Group and Reviewers HL7 Modeling HL7 Balloting Implementation/Tools
Human and Machine-
ExecutableProtocol(possibletemplate)
Review orManagement
Tools*
Cross-trialDatabases
Warehouses‡
ProtocolAuthoring
Tools
Data Collection
Tools(eSourceeCRF)
* e.g. Planned vs. Actual; Project Status
‡ e.g. Regulatory, Pharma Company, IRB
° e.g. Study Reports, PI Brochures
ElementRe-use-Clinical
Documents°
"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."
"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. LeeWHO Director-General
Opening Address to World Health Opening Address to World Health Assembly, May 2005Assembly, May 2005
Ida Sim, MD, PhD
Acknowledgement
Ida Sim, MD, PhD Project Coordinator Department of Research Policy and Cooperation World Health Organization Geneva, Switzerland
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
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
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
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
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
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 – 58th World Health Assembly
Ida Sim, MD, PhD
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
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
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
InternationalAdvisory Board
Ida Sim, MD, PhD
Registry Platform Overview
WH
O I
nte
rnati
on
al C
lin
ical
Tri
als
Reg
istr
y P
latf
orm
Journals
ResultsDatabases
WHO Search Portal
RegistersISRCTNclinicaltrials.gov . . .country specific
Ida Sim, MD, PhD
Responsible Registrant
GlobalDeduplication
Search Database
Central Reference Database
1
5
6
WHO Registration Data Set4
8
2
MeSH Coding
3
7
UTRN, MeSH Codes
Associate Registers
Primary Registers
Other Registers
Search Portal
Ida Sim, MD, PhD
WHO Registration Data Set (1)
1. Primary Register and Trial ID# (e.g., ISRCTN number)
2. Date of Registration in Primary Register3. Secondary ID#s4. Funding Source(s)5. Primary Sponsor6. Secondary Sponsor(s)7. Responsible Contact Person8. Research Contact Person9. Public Title10. Scientific Title Ida Sim, MD, PhD
WHO Registration Data Set (2)
11. Countries of Recruitment12. Health Condition(s) or Problem(s) Studied13. Intervention(s)14. Inclusion & Exclusion Criteria15. Study Type16. Date of First Enrollment17. Target Sample Size18. Recruitment Status19. Primary Outcome(s)20. Key Secondary Outcome(s)
Ida Sim, MD, PhD
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
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
20 Elements – WHO Table with Recommended Terminology/Codelists (from CDISC and HL7)
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
Study
GlobalVariables
BasicDefinitions
attributes
MetaDataVersion
@ OID
Study Element
GlobalVariables
StudyName
ProtocolName
GlobalVariables Element
StudyDescription
WHO Extension
<GlobalVariables><StudyName>CDISC Example Study</StudyName><StudyDescription>A simple trial to demonstrate the end-to-end
application of the CDISC Standards</StudyDescription><ProtocolName>CDISC Example Study</ProtocolName>
</GlobalVariables>
<GlobalVariables><StudyName>CDISC Example Study</StudyName><StudyDescription>A simple trial to demonstrate the end-to-end
application of the CDISC Standards</StudyDescription><ProtocolName>CDISC Example Study</ProtocolName>
<!-- WHO Trial Registry Elements Here --></GlobalVariables>
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