Out of Cycle HL7 RCRIM Meeting
25 April 2006
Berlin, 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 (cont’d)

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
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
–

ICH E3
–

Terms & definitions
EUDRACT (EMEA)
–

Basis for the development and organization of the PR
Element Spreadsheet
Key words and Protocol description
Specific topics (e.g. IRB, SAP-E9)
Protocol Representation - Hierarchy
Document Type
General Information
Background Information
Trial Objectives and Purpose
Trial Design
Subject Selection and Withdrawal
Subject Participation/Study Design
Treatment of Subjects
Efficacy Assessments
Assessment of Safety
Statistics
Direct Access to Source Documents
Quality Control and Quality Assurance
Ethics
Data Handling and Record Keeping
Financing and Insurance
Publication Policy
Supplements
Protocol Representation – Hierarchy
Sample: Sections, Sub-sections, Elements
Document Type
Clinical Trial Protocol
General Information
Protocol Identification
Protocol Title
Protocol Short Title
Protocol Identification Number
Protocol Contact Information
Sponsor
Sponsor Status
Protocol Elements Spreadsheet
MODEL
S
e
c
t
S
u
Field Name
SUGGESTED
ATTRIBUTES
FIELD NAME
EXPLANATION
FIELD NAME
DEFINITION and FIELD
CITATION
SOURCE
EUDRACT
CODE LIST
GLOSSARY
REFERENCE
COMMENTS
DocumentType
Clinical Trial Protocol
Type of
Application
NA
HL7 Modeling
Header for the section
describing the protocol
title and contacts,
including information
about amendments
NA
Header for sub-section
that contains all protocol
identifying information
CDISC
NA
Full text of the
protocol/study title
SDS Study
Summary
Protocol Short Title
NA
Name or abbreviated title
of the trial wherever
available
A.Trial
Identification
PR Group
Appendix I NA
Appendix I
A. Full title
ICH E6 6.1.1,
of the
EUDRACT
protocol
Appendix I
A.Abbreviate
d title of the
EUDRACT
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
National trial
# reference,
EUDRACT
clinical trial
number,
Sponsor
code =
sponsor
ICH E6 6.1.1,
protocol
CDISC,
EUDRACT
number
EUDRACT
GENERAL INFORMATION
Protocol Identification
Protocol Title
ICH E6 6.1
NA
EUDRACT stated that this was a
national identificaton number and
that is was issued by a central
authority.
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 Interventions
-Statistical Analysis Plan
2.
3.
-Planned Assessments
-Inclusion/Exclusion criteria
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
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
Element
Re-useClinical
Documents°
Review or
Management
Tools*
Protocol
Elements
Definitions
For
Elements
HL7
Development
Framework
XML
Schema
Code Lists
Terminology
Cross-trial
Databases
Warehouses‡
Human and
MachineExecutable
Protocol
(possible
template)
Protocol
Authoring
Tools
Data
Collection
Tools
(eSource
eCRF)
Modeling
Information
(e.g. cardinality)
PR Group and Reviewers

HL7 Modeling
 HL7 Balloting

Implementation/Tools
* e.g. Planned vs. Actual; Project Status
‡ e.g. Regulatory, Pharma Company, IRB
° e.g. Study Reports, PI Brochures
Opening Address to World Health
Assembly, May 2005
"We are ready to move
forward with an
international Clinical Trials
Dr J.W. Lee
WHO Director-General
Registry. This will do much
to strengthen the research
process and its ability to win
public trust."
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

–
Need
country-, disease- and/or funder-specific
purposes

participant enrollment

administrative tracking

scientific analysis
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
•
•
•

April 2005 – Technical Consultation, Geneva
–

establish network of clinical trial registers
ensure unambiguous identification of trials
ensure a single point of access
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
–

Some early accomplishments
–
–

have received support and participation from all
relevant stakeholder groups
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

WHO EIP/RPC
–
–
International
Advisory Board
Registry
Platform
Secretariat
International Advisory Board
–

Scientific
Advisory Group
broad-based, 15 senior leaders
advise on strategy/direction
lead in communication/
advocacy
Scientific Advisory Group
–
–
21 experts
advise on principles/
substantive standards
Ida Sim, MD, PhD
Registry Platform Overview
WHO International Clinical
Trials Registry Platform
Ida Sim, MD, PhD
WHO Search Portal
clinicaltrials.gov
country specific
...
ISRCTN
Registers
Journals
Results
Databases
8
5
Global
Deduplication
6
MeSH Coding
Central
Reference
Database
7
UTRN, MeSH Codes
Search Portal
Search
Database
4 WHO Registration Data Set
2
Responsible
1 Registrant
Primary Registers
3
Associate Registers
Other Registers
Ida Sim, MD, PhD
WHO Registration Data Set (1)
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
Primary Register and Trial ID# (e.g., ISRCTN
number)
Date of Registration in Primary Register
Secondary ID#s
Funding Source(s)
Primary Sponsor
Secondary Sponsor(s)
Responsible Contact Person
Research Contact Person
Public Title
Scientific Title
Ida Sim, MD, PhD
WHO Registration Data Set (2)
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
Countries of Recruitment
Health Condition(s) or Problem(s) Studied
Intervention(s)
Inclusion & Exclusion Criteria
Study Type
Date of First Enrollment
Target Sample Size
Recruitment Status
Primary Outcome(s)
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 RegistrationClinical Trial Tracking

20 Elements – WHO Table with
Recommended Terminology/Codelists (from
CDISC and HL7)
ODM Element
attributes
ODM
@ Description
Study
@ FileType
AdminData
@ Archival
@ Granularity
@ FileOID
ReferenceData
@ CreationDateTime
@ PriorFileOID
ClinicalData
Association
ds:signature
@ AsOfDateTime
@ ODMVersion
@ Originator
@ SourceSystem
@ SourceSystemVersion
@ ID
Dave Iberson-Hurst
Study Element
attributes
Study
@ OID
GlobalVariables
BasicDefinitions
MetaDataVersion
GlobalVariables Element
GlobalVariables
StudyName
StudyDescription
ProtocolName
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>
<!-- WHO Trial Registry Elements Here -->
</GlobalVariables>
Descargar

Protocol Representation - Health Level Seven International