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>