WHO International Clinical Trials Registry Platform

WHO International Clinical Trials Registry Platform Ida Sim, MD, PhD Project Coordinator Department of Research Policy and Cooperation World Health Organization Geneva, Switzerland March 16, 2006

Outline Background Objectives, Governance, and Structure WHO Registry Platform Overview Disclosure Timing Future Work 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 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

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 58 th World Health Assembly

Opening Address to World Health Assembly, May 2005 Dr J.W. Lee WHO Director-General "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"

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

Outline Background Objectives, Governance, and Structure WHO Registry Platform Overview Disclosure Timing Future Work Summary

Goal Goal and Objectives 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.

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

International Advisory Board (IAB) Chair Richard Sykes,, Rector, Imperial College, UK Members Alan Bernstein, President, Canadian Institutes of Health Research, Canada Jose Carvalheiro, President, Fiocruz,, Brazil Gail Cassell,, Vice President Scientific Affairs, Eli Lilly, USA Iain Chalmers,, Editor, James Lind Library, UK 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 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-chair) Kay Dickersin Dickersin,, Johns Hopkins Bloomberg School of Public Health, MD, USA (Co-chair) Richard Horton,, The Lancet, UK Gerd Antes, Deutsches Cochrane Zentrum,, Germany Allan Breier,, Eli Lilly & Co. Chris Chute,, Mayo Clinic, USA Francis P. Crawley,, European Forum for Good Clinical Practice, Belgium Pierre Ducimetiere,, INSERM Research Director, France Davina Ghersi,, University of Sydney, Australia Anne Greenwood,, Current Science Group, UK Michael Gropp,, VP Global Regulatory and Public Policy, Guidant Corp., Belgium Karmela Krleza-Jeric Jeric, Canadian Institutes of Health Research, Canada Rebecca Kush,, Clinical Data Interchange Standards Consortium, USA David Moher,, Children s s Hospital of Eastern Ontario, Canada Frank Rockhold,, Senior Vice President, GlaxoSmithKline, USA C. Marc Taylor,, UK Department of Health, UK Toshiro Tango,, National Institute of Public Health, Japan Prathap Tharyan,, Christian Medical College, Velore,, India Jimmy Volmink,, University of Cape Town, South Africa Liz Wager, Sideview Consulting, UK Janet Wale,, Cochrane Consumer Network, Australia Deborah Zarin, ClinicalTrials.gov,, MD, USA

Funding Internal Support WHO start-up and operational funds External Support English Department of Health Japanese Ministry of Health Wellcome Trust Canadian Institutes of Health Research In-kind support from experts and stakeholders Travel, meetings, consultations

Outline Background Objectives, Governance, and Structure WHO Registry Platform Overview Disclosure Timing Future Work Summary

Registry Platform Overview country specific clinicaltrials.gov... ISRCTN Registers

Registry Platform Overview country specific clinicaltrials.gov... ISRCTN Registers Journals

Registry Platform Overview country specific clinicaltrials.gov... ISRCTN Registers Journals Results Databases

Registry Platform Overview WHO International Clinical Trials Registry Platform country specific clinicaltrials.gov... ISRCTN Registers Journals Results Databases

Registry Platform Overview WHO International Clinical Trials Registry Platform WHO Search Portal country specific clinicaltrials.gov... ISRCTN Registers Journals Results Databases

Which Trials Must Register The registration of all interventional trials is a scientific, ethical, and moral responsibility Any research study that prospectively assigns humans or groups of humans to one or more health related interventions to evaluate the effects on health outcomes Includes all health interventions (e.g., drugs, devices, cells and biological products, procedures, behavioural treatments, care process changes, etc) early and late phase studies studies on healthy volunteers marketed and not-yet yet-approved products primary and secondary indications randomized and non-randomized, etc.

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

Responsible Registrant Either the principal investigator (PI) or the primary sponsor, to be decided by an agreement between the parties primary sponsor is "the individual, organization, group or other legal person taking on responsibility for securing the arrangements to initiate, manage and finance a study primary sponsor is ultimately accountable for ensuring that the trial is properly registered for multi-centre and multi-sponsor trials, lead PI or lead sponsor has responsibility for registration Responsible registrant should make every reasonable effort to ensure that a trial is registered once and only once in any one register, and that the trial is registered in the fewest number of registers necessary to meet applicable regulations

Register Network Structure Two-tiered system Primary Registers (relatively few) should be national, regional, or international maximum of one per country must be open access perform quality assurance, deduplication, accountability, data interchange submit Registration Data Set directly to WHO Associate Registers (relatively many) serve diverse constituents and objectives must be affiliated with a Primary Register submit Registration Data Set to that register

NOT Required for Primary Registers 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

Register Network and Criteria Registers Working Group major national and international registers share best practices, develop standards, etc. Register Criteria Primary Register criteria in final draft form now will be posted on Registry Platform website for Open Comments soon Associate Register criteria to be defined WHO encourages fewest number of Primary Registers necessary to serve global needs

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

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)

Coding of Data Fields 44 key fields describe the trial s s scientific nature conditions, Interventions, Primary and Secondary Outcomes Should be coded using a standard vocabulary to standardize description of trials support more accurate search WHO plans to code 4 key fields in MeSH some registers already code some of these fields assume that most submissions will be in free text

Local and Global Deduplication Trials may be registered in more than one register (e.g., to meet regulatory requirements, to promote enrollment) Duplicate registrations can falsely inflate the apparent volume of global research activity Need to deduplicate trial registrations Local deduplication Individual registers identifying duplicate entries within their own register Global deduplication WHO will coordinate the identification of duplicates across registers worldwide

Universal Trial Reference Number (UTRN) New number to be issued by WHO to each trial deemed unique across registers unique trial: conducted according to a single document (the protocol) that describes the objective(s), design, methodology, statistical considerations, and organization of a trial. A multi- center trial is one that is conducted according to a single protocol but carried out at more than one site. Used to cross-reference reference entries for same trial across multiple registers each single, unique trial will have one UTRN each UTRN will related to a single unique trial worldwide no current trial ID number performs this function, promotes integrity of entire system

Open Access One-Stop Search Portal Searches all Primary Registers Search by provides gateway to trial information worldwide UTRN All items of WHO Registration Data Set Conditions, interventions, outcomes coded in MeSH to improve retrieval accuracy Will have patient and scientist versions

Data Interchange Standard Currently defining XML standard for data interchange of 20 item WHO Registration Data Set CDISC is leading the effort, working with HL7, BRIDG, etc. using existing standards as much as possible no decision yet on target vocabulary for coding key scientific fields condition, interventions, outcomes WHO will provide technical assistance to national or regional registers as needed to use data interchange standard

Registry Platform Overview WHO International Clinical Trials Registry Platform WHO Search Portal country specific CT.gov... ISRCTN Registers Journals Results Databases

Outline Background Objectives, Governance, and Structure WHO Registry Platform Overview Disclosure Timing Future Work Summary

Disclosure Timing In public interest of transparency to disclose all 20 items at initial registration Concern that such disclosure will allow competitors to copy ideas, esp. for early trials concern voiced by industry and academia delaying disclosure could protect competitive advantage WHO considering whether to implement some form of delayed disclosure for a 1-21 2 year trial period non-disclosure (never submitting data or never disclosing it) is not acceptable

Consultation Process Open Comments (see link from www.who.int/ictrp) WHO calling for best arguments for and against delayed disclosure First round closed Jan. 17, 2006 12 submissions, from industry, patient group, bioethics Second round open till March 31, 2006 Formal Consultation session in Geneva, 26 Apr high level consultation involving strategic thinkers, key players from all stakeholder groups to significantly inform the WHO decision

Outline Background Objectives, Governance, and Structure WHO Registry Platform Overview Disclosure Timing Future Work Summary

Results Reporting Standards A top concern, although registration is current priority Assumptions Report results for use by multiple constituencies Complements,, does not replace, peer-reviewed reviewed journal publication At least in International Conference on Harmonization ICH E3 format in English with UTRN 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

Research Need for better evidence to guide registration and reporting policies Research topics under consideration registration compliance rates extent of and nature of duplicate registration consequences of duplicate registration patterns of mis-reporting and consequences evidence supporting various recommendations for trial reporting

Outline Background Objectives, Governance, and Structure WHO Registry Platform Overview Disclosure Timing Future Work Summary

WHO Registry Platform Has finalized required registration items Is establishing a network of Primary and Associate registers to coordinate registration worldwide Will perform global deduplication of trials and issue UTRNs to globally unique trials Will launch one-stop search portal of Primary Registers Is definingd standards for minimum reporting of results Is pursuing compliance mechanisms for registration and reporting

Approximate Project Timeline Q1 2006 International Advisory Board meeting Finalization of WHO Registration Data Set Creation of Registers Working Group Q2 2006 Formal Consultation on Disclosure Timing Scientific Advisory Group meeting Launch of Register Network Q3-4 4 2006 First version of UTRN assignment Launch of the WHO Registry Platform Search Portal 1st Annual Registry Platform Meeting (SAG and Member Registers), WHO Kobe Center, Kobe, Japan Expansion of Register Network

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 Input from all stakeholders welcome

WHO Registry Platform Team Project Coordinator Staff Ida Sim Esther Awit Other WHO An-Wen Chan Ghassan Karam Patrick Unterlerchner Metin Gülmezoglu Tikki Pang Luis Gabriel Cuervo (PAHO)

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