WHO International Clinical Trials
Registry Platform
Ida Sim, MD, PhD
Project Coordinator, WHO
October 14, 2005
Outline
†Background
†WHO Registry Platform Objectives, Governance, and
Structure
†WHO Registry Platform Subprojects
„ WHO Registration Data Set
„ Register Certification
„ Unique Numbering Scheme
„ Results Reporting
„ Search Portal
†Summary
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
Current Policies
†The International Committee of Medical Journal
Editors (ICMJE) now accepts only registered trials
for potential publication
†FDA Modernization Act compliance incomplete
„ Fair Access to Clinical Trials Act in US
Congress imposing broader mandates on
trial registration and reporting
†Over 50 bills pending in various jurisdictions in
the US alone
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
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
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
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
Opening Address to World Health
Assembly, May 2005
"We are ready to move
forward with an international
Dr J.W. Lee
WHO Director-General
Clinical Trials Registry. This
will do much to strengthen
the research process and its
ability to win public trust"
Outline
†Background
†WHO Registry Platform Objectives, Governance, and
Structure
†WHO Registry Platform Subprojects
„ WHO Registration Data Set
„ Register Certification
„ Unique Numbering Scheme
„ Results Reporting
„ Search Portal
†Summary
WHO Registry Platform Objectives
† Increase transparency, accessibility, accountability
† Standardize and clarify registration worldwide
„ Reduce uncertainty about expectations
„ Reduce duplication of effort
† Increase global capacity for trial registration
† Consensus-building approach to provide platform for
existing and future registers to work together
†Driving principle
„ Scientific and ethical integrity
WHO International Clinical
Trials Registry Platform
WHO Registry Platform Overview
WHO Search Portal
CT.gov
country specific
...
ISRCTN
Registries
Journals
Results
Databases
WHO Registry Platform Specific Aims
† Establish international norms and standards for trial
registration and results disclosure
† Establish international certification of registers
† Establish unique numbering system
† Provide one-stop search portal for registers worldwide
† Advocate for compliance
† Advise & help build registration capacity as needed
WHO Registry Platform
Administrative Structure
†
WHO EIP/RPC
„
International
Advisory Board
Registry
Platform
Secretariat
Registry Platform Secretariat
Scientific
Advisory Group
policy development and
implementation
International Advisory
Board
†
„
broad-based, senior
leaders
„
endorses
strategy/direction
„
leads in communication /
advocacy
† Scientific Advisory Group
„
expert group
„
advises on principles /
substantive standards
International Advisory Board (IAB)
† Chair
„
Richard Sykes, Rector, Imperial College, UK
† Members
„
Gail Cassell, Vice President Scientific Affairs, Eli Lilly, USA
„
Iain Chalmers, Editor, James Lind Library, UK
„
Heng-Leng Chee, Asia Research Institute, National University of Singapore
„
Nirmal K. Ganguly, Director General, Indian Council for Medical Research, India
„
Victoria Hale, CEO, One World Health, USA
„
Ching-Li Hu, Director, Shanghai Research Center for Care for Children, China
„
Ana Langer, Population Council, Mexico
„
Caroline Loew, Vice President, Scientific & Regulatory Affairs, PhRMA, USA
„
Pascoal Mocumbi, European Developing Countries Clinical Trials Partnership, Netherlands
„
Carlos Morel, Director, Center for Technological Development in Health, Fiocruz, Brazil
„
Kathy Redmond, European Cancer Patient Coalition (ECPC), Milan, Italy
„
Joerg Reinhardt, Head of Development, Novartis, Switzerland
„
Hideo Shinozaki, President, National Institute of Public Health, Japan
„
Hal Sox, Editor, Annals of Internal Medicine, USA
Scientific Advisory Group (SAG)
†Co-Chairs
„
Kay Dickersin, Johns Hopkins Bloomberg School of Public Health, MD, USA
„
Richard Horton, The Lancet, UK
†Members
„
Gerd Antes,
Antes, Deutsches Cochrane Zentrum,
Zentrum, Germany
„
Chris Chute,
Chute, Mayo Clinic, USA
„
Francis P. Crawley,
Crawley, European Forum for Good Clinical Practice, Belgium
„
Davina Ghersi,
Ghersi, University of Sydney, Australia
„
Anne Greenwood,
Greenwood, Current Science Group, UK
„
Karmela KrlezaKrleza-Jeric,
Jeric, Canadian Institutes of Health Research, Canada
„
Rebecca Kush,
Kush, Clinical Data Interchange Standards Consortium, USA
„
David Moher,
Moher, Children’
Children’s Hospital of Eastern Ontario, Canada
„
Philip Noguchi,
Noguchi, Director Regulatory Affairs, Amgen, USA
„
Frank Rockhold,
Rockhold, Senior Vice President, GlaxoSmithKline, USA
„
Marc Taylor,
Taylor, UK Department of Health, UK
„
Jimmy Volmink,
Volmink, University of Cape Town, South Africa
„
Liz Wager,
Wager, Sideview Consulting, UK
„
Janet Wale,
Wale, Cochrane Consumer Network, Australia
„
Deborah Zarin,
Zarin, ClinicalTrials.gov,
ClinicalTrials.gov, MD, USA
Funding
†WHO funds
„
Start-up costs
†External support
„
Department of Health, UK
„
Wellcome Trust
†In-kind support from experts and stakeholders worldwide
„
Travel, meetings, consultations
† Potential revenue sources
„
Register certification fees
„
Unique ID fees
Outline
†Background
†WHO Registry Platform Objectives, Governance, and
Structure
†WHO Registry Platform Subprojects
„ WHO Registration Data Set
„ Register Certification
„ Unique Numbering Scheme
„ Results Reporting
„ Search Portal
†Summary
Which Trials Must Register
†Any research study that prospectively assigns human
participants or groups to one or more health related
interventions to evaluate the effects on health outcomes
„ Includes all health interventions (e.g., drugs,
devices, procedures, behavioural treatments, care
process changes, etc)
†All hypothesis-testing trials
„ Marketed and not-yet-approved products
„ Primary and secondary indications
†Strongly encourage registration of exploratory trials
„ Escrow mechanism for protecting intellectual
property being developed
†If in doubt, register
WHO Registration Data Set (1)
1.
Primary Register and Trial ID# (e.g., CT.gov number)
2.
Date of Registration in Primary Register
3.
Secondary Trial 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
WHO Registration Data Set (2)
11.
Research Ethics Review
12.
Disease or Condition Studied
13.
Intervention(s)
14.
Inclusion & Exclusion Criteria
15.
Study Type
16.
Date of First Enrollment
17.
Target Sample Size
18.
Recruitment Status, at time of CT-UID request
19.
Primary Outcome(s)
20.
Secondary Outcome(s)
Reasons for Full Disclosure
† Restore public trust and confidence to clinical research
and avoid decrease in trial enrollment, by bolstering
„ scientific integrity
† public record of trial’s scientific objective
provides tracking mechanism for ensuring full,
unbiased disclosure of results
„ ethical integrity
† all results gained from human participants should
be made available to the public community
„ to avoid unnecessary duplication, harm
Chief Concern
† Selective disclosure that benefits proprietary
interests over public health
“5 Sensitive Items”
† Desire and belief that mutually acceptable
compromise on this issue is achievable
† Balance of
„ intellectual property and competitive
advantage issues
„ scientific and ethical integrity issues
Coding of Data Fields
†4 key fields describing the trial
„ Conditions, Interventions, Primary and
Secondary Outcomes
†Should be coded using a standard vocabulary to
„ Standardize description of trials
„ Support more accurate search
Proposed Coding Approach
†Assume that WHO will receive entries in free text only
„ allow trialists to enter free text
„ registers do not have to do any coding
†WHO will code free text into MeSH terms
„ Evaluate existing coding engines
„ Negotiate use for WHO
„ Obtain benchmarks on human input required
(National Library of Medicine)
„ Store MeSH terms for 4 fields, offer MeSH terms
back to registers
†Plan for transition to more granular vocabulary (e.g.,
SNOMED) when more feasible
Outline
†Background
†WHO Registry Platform Objectives, Governance, and
Structure
†WHO Registry Platform Subprojects
„ WHO Registration Data Set
„ Register Certification
„ Unique Numbering Scheme
„ Results Reporting
„ Search Portal
†Summary
Key Register Certification Criteria
†Content
„ Accepts interventional trials
„ Collects full WHO Registration Data Set
†Unique ID
„ Commits to requesting WHO unique ID for all trials
†Technical
„ Able to upload to WHO following technical standards
†Quality Assurance
„ For authenticating input, validating submitted info
†Administrative…
Administrative Criteria for Certification
†Searchable by public at no charge
†Clearly define prospective registrants and accept all
submissions from that community
†Must disclose ownership and for/non-profit status
†Must not have or receive any funds from entities with
conflict of interest
„ any entity that stands to gain financially or otherwise
from partial or selective registration of trials or trial
information
† E.g., benefiting from registering only trials it
expects to produce favourable results
† E.g., benefiting from registering only some of the
planned outcomes
Differences with ICMJE
†ICMJE requires "open to all registrants"
†ICMJE requires non-profit status
†In discussions to align our register criteria
NOT Required for Certification
†Entries can be in any language, but uploads to
WHO must be in English
†Encouraged but not required to
„ Collect or store protocol document itself
„ Collect or store protocol amendments
„ Store or link to trial results
†Encouraged to provide free or minimal cost
registration, with fee waivers for hardship cases
Outline
†Background
†WHO Registry Platform Objectives, Governance, and
Structure
†WHO Registry Platform Subprojects
„ WHO Registration Data Set
„ Register Certification
„ Unique Numbering Scheme
„ Results Reporting
„ Search Portal
†Summary
WHO CT-UID
†Globally unique ID to unambiguously identify
trial worldwide
„ WHO procedure standardizes this
worldwide, promotes integrity entire system
†A 10 character string with appropriate formal
technical properties
„ E.g., WHOCT-1064000005
†Only Certified Registers can apply for a CT-UID
Key Features
† PI/Sponsor registers with a Certified Register
when final IRB approval obtained
†Certified Register submits WHO Registration
Data set to WHO for WHO CT-UID
† WHO determines uniqueness of trial
„ Semi-automated method, to be developed
with existing registers
† PI/Sponsor responsible for informing other
registers, if any, of the trial’s WHO CT-UID
Outline
†Background
†WHO Registry Platform Objectives, Governance, and
Structure
†WHO Registry Platform Subprojects
„ WHO Registration Data Set
„ Register Certification
„ Unique Numbering Scheme
„ Results Reporting
„ Search Portal
†Summary
Results Reporting
‰Remains a top concern, although registration is current priority
†Assumptions
„
Report results for use by multiple constituencies
„
Complements, does not replace, peer-reviewed journal publication
„
At least in International Conference on Harmonization ICH E3
format in English
†
with WHO CT-UID added and Conclusions removed
„
Mutual links between results database and the trial register(s)
„
General standard: trial results should be disclosed within one year
of study completion
„
The sponsor/funder is responsible for reporting the results. If the
trial is unfunded, the primary investigator is responsible
Outline
†Background
†WHO Registry Platform Objectives, Governance, and
Structure
†WHO Registry Platform Subprojects
„ WHO Registration Data Set
„ Register Certification
„ Unique Numbering Scheme
„ Results Reporting
„ Search Portal
†Summary
Open Access One-Stop Search Portal
†Searches registers worldwide
„
All certified registers
„
Other registers uploading data to WHO using data
interchange standard
† Search by
„
WHO CT-UID
„
All items of WHO Registration Data Set
„
Conditions, interventions, outcomes coded in MeSH to
improve retrieval accuracy
„
Escrow status (if mechanism agreed upon)
† Anticipate that over time most registers will be certified and
searched through the WHO Registry Platform
Outline
†Background
†WHO Registry Platform Objectives, Governance, and
Structure
†WHO Registry Platform Subprojects
„ WHO Registration Data Set
„ Register Certification
„ Unique Numbering Scheme
„ Results Reporting
„ Search Portal
†Summary
WHO Registry Platform Will…
†Finalize required registration items
†Define criteria for certifying registers (to be recognized by
ICMJE)
†Issue globally unique IDs to trials in certified registers
†Code conditions, interventions, outcomes in MeSH
†Define data interchange standards among registers, WHO,
and results databases
†Launch one-stop search portal of registers worldwide
Approximate Project Timeline
Q4 2005
„ Finalization of the WHO Registration Data Set
„ Establishment of a universal unique clinical trial identifier (WHO CTUID) and a process for assigning the WHO CT-UID
„ Finalization of registry certification criteria
„ Scientific Advisory Board Meeting: Advice on WHO Registration Data
Set, register certification, and other norms and standards
Q1 2006
„ First version of register certification
„ International Advisory Board Meeting
Q2 2006
„ WHO CT-UID assignment and MeSH coding
„ Launch of the WHO Registry Platform Search Portal
Conclusion
† Clinical trials transparency and public trust is a
global issue
† WHO taking lead on policy and technical
platform for coordinated trial registration and
reporting worldwide
† Overriding principle is to promote scientific and
ethical integrity
† Invite comments and consultation as WHO
Registry Platform develops
WHO Registry Platform Team
† Project Coordinator
„ Ida Sim
† Staff
„ Ghassan Karam
„ Patrick Unterlerchner
† Other WHO
„ Metin Gulmezoglu
„ Tikki Pang
„ Luis Gabriel Cuervo
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http://www.who.int/ictrp