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Information and software requirements for assembling and accessing information on ongoing controlled trials
Meeting held at UK Cochrane Centre, Oxford
Wednesday July 29 1998
Participants:
Association of the British Pharmaceutical Industry (ABPI), Richard Tiner
British Medical Journal, Richard Smith
Cardiovascular Clinical Trials Forum, Desmond Julian
Centre for Statistics in Medicine (Oxford), Doug Altman
Clinical Trial Service Unit (Oxford), Mike Clarke
Current Science Group, Ian Tarr and Vitek Tracz
GlaxoWellcome (now GlaxoSmithKline), Trevor Gibbs and Chris Haigh
The Lancet, Richard Horton
Medical Editors' Trials Amnesty, Ian Roberts
Medical Research Council, Tony Helm and Frances Rawle
National Research Register, Kevin Hall
Schering Health Care, Peter Longthorne
UKCCCR Cancer Trials Register, Lesley Stewart
UK Cochrane Centre, Iain Chalmers and Cath Milwain
Update Software, Mark Starr and John Yisa
Zeneca, Hamish Cameron
Welcome and introduction
After welcoming participants to the meeting and mutual introductions among those present, Iain Chalmers (UK Cochrane Centre) outlined the rationale for prospective registration of information about ongoing controlled trials. This is needed because:
 people using evidence from controlled trials want to be confident that they are aware of all of the trial evidence relevant to a particular question;
research funding agencies (public, commercial and charitable) want to take their funding decisions in the light of information about relevant ongoing research, both to avoid duplication of effort and to promote collaboration; and
patients and other decision-makers wish to be informed about trials in which they can participate or to which they can contribute in other ways.
Iain Chalmers paid tribute to Schering Health Care and GlaxoWellcome (now GlaxoSmithKline) for having taken the initiative, within the pharmaceutical industry, in disclosing information about ongoing trials (see the Editorial in the British Medical Journal from Richard Sykes, Chairman GlaxoWellcome [now GlaxoSmithKline]). Following GlaxoSmithKline's announcement last November that the company wishes to work with him and the UK Cochrane Centre in taking this initiative forward, a joint meeting was held at the company's headquarters in Greenford in March. This provided an opportunity for Iain Chalmers to make clear that the UK Cochrane Centre:
does not want actual trial data
thinks peer reviewed publication is the best method for disseminating results
is not interested in Phase I data
It had been agreed at the meeting that:
it would be acceptable for information about randomized Phase II and III studies to be made available at the time of regulatory approval;
information about randomized Phase IV (post-licensing) studies should be registered prospectively; and
trial information could be transferred directly to a central register or accessed from a GlaxoWellcome (now GlaxoSmithKline) website.
Professor Julian expressed regret that studies would not be registered prior to licensing because he felt that this would result in missed opportunities to encourage collaboration and reduce duplication among researchers. Iain Chalmers noted that there was no bar to registering pre-licensing studies, but that the practicalities of registration for drug companies could be accomplished more easily if registration was based on the portfolio that they had to assemble anyway for licence applications.
Participants from industry explained that the conduct of registration programmes means that duplication among researchers is very unlikely. In addition, recruitment of patients is conducted through very careful quality controlled centres and for the purpose of this exercise, the industry's prime focus is to provide information so that people are aware of all the trial evidence relevant to a particular question. Therefore providing Phase II/III information at the time of registration would be logical.
Although the nature of Phase III studies meant that their existence was almost always public knowledge (within the industry and more widely), it is important to acknowledge that the initiatives taken by Schering Health Care and GlaxoWellcome (now GlaxoSmithKline) had not been universally welcomed even within those companies, let alone more widely within the industry. In promoting and establishing prospective registration of controlled trials and greater openness, guidance on strategy from those within industry who are committed to these principles will be important.
Richard Tiner (ABPI) suggested that while UK subsidiaries of companies might be happy to actively contribute to a register of ongoing trials, internationally it may be more difficult to persuade companies to contribute. Iain Chalmers emphasised that the initiative which was being explored in this meeting related to ways that UK-based decision makers could help make progress in promoting and establishing prospective registration of controlled trials.
Which core items of information about an ongoing or completed but unpublished controlled trial should be made available?
As a basis for discussing which core items of information were necessary for registration, Iain Chalmers presented a table comparing data items submitted by Schering Health Care for inclusion in The Cochrane Controlled Trials Register, and data items in the Medical Research Council's trials directory and the National Research Register. Desmond Julian presented the information available on the website of the Cardiovascular Clinical Trials Forum.
It was felt that when considering which data should be made available it would be important to consider the potential users of the data and to make searching as easy as possible. There was disagreement, for example, about whether potential participants in controlled trials (patients) should be seen as a target, some expressing enthusiasm for this, others expressing scepticism.
After discussion it was unanimously agreed that to begin with at least, the aim should be to register completely and accurately a minimum amount of data for each trial, with electronic links to more detailed information to try to ensure that those providing the core data did not become overwhelmed with enquiries. It was agreed that the data submitted would need managing to keep it as accurate as possible, and that quality control would be important. The possibility of adding terms to indicate subject area or keywords was raised.
While it was agreed that the minimum data possible would be collected, which data items should be collected was not agreed. The area which caused most debate was 'current status'. It was suggested that it would be very useful to know the planned start and finish dates of trials, but as this information changed frequently it would be difficult to keep up to date. More concrete information that could be included would be if the trial had stopped and where it had been published/presented. It was thought users of the information would want to know if the trial was ongoing, and if so, if it was still recruiting and also, if the trial had finished.
Although it may need to be modified in future, it was agreed that the Cochrane Collaboration's definition of a controlled trial should be used, namely, a study in which 'the participants (or other units) were definitely or possibly assigned prospectively to one of two (or more) alternative forms of care using a process of random or quasi-random allocation'.
Which organisations based in the UK would be prepared to make this core set of data items available?
So far, the following organisations have indicated willingness to register information about ongoing and unpublished trials: Schering Health Care, GlaxoWellcome (now GlaxoSmithKline), the Medical Research Council, the National Research Register, and the UK Coordinating Committee on Cancer Research (provisionally). Other organisations (some represented at the meeting) are known to be actively considering doing
so. It was noted that approaching research funders might be a more efficient way to collect information, rather than urging investigators to register trials, but it was agreed that these two approaches need not be mutually exclusive.
What practical arrangements are needed to make these core data accessible through the world wide web?
Vitek Tracz and Ian Tarr (Current Science Group) introduced the practicalities of creating and managing data submitted for registration and offered to create a website through which a register could be made available. They emphasised that the information on the register would need careful managing and that the Current Science Group has extensive relevant experience and the facilities to prepare and maintain a register.
They envisaged a central 'metaRegister' of minimum data, accessible free of charge, and providing links to other sites where further information could be obtained (it is likely that charges would be levied for access to some of these sites). The metaRegister would provide facilities for people to register new trial information and a variety of search and browse functions would be available.
Lesley Stewart (UKCCCR) asked whether there was a possibility of developing web-searching software to search all relevant databases, on a distributed basis, rather than creating one metaRegister. Vitek Tracz (Current Science Group) said that although this might be a possibility for the future, the limitation of existing technology suggested that the metaRegister approach was likely to offer the best means of making rapid progress.
There was agreement that the proposals presented by Vitek Tracz and Ian Tarr provided an excellent basis for making rapid progress, and the meeting encouraged them to proceed along the lines outlined. Ian Tarr would convene a series of meetings with Tony Helm (Medical Research Council), Mark Starr and Kevin Hall (National Research Register), and Ian Roberts (Medical Editors' Trials Amnesty) to discuss the practicalities of taking the proposals forward. Peter Longthorne (Schering Health Care) and Trevor Gibbs (GlaxoWellcome, now GlaxoSmithKline) will ensure that input is made to these discussions from their respective companies.
Vitek Tracz and Ian Tarr would plan to launch the register at the British Medical Journal meeting 'Randomised Controlled Trials: 50 Years of Clinical Trials - Past, Present and Future' on 29/30 October 1998.
Any other business
Ad hoc group
Iain Chalmers suggested the meeting could form the foundation for an ad hoc group to explore and take forward prospective registration of trials within the UK. In the light of the support for this initiative recently pledged to the UK Cochrane Centre by the Medical Research Council, he offered to provide the secretariat for such a group. This idea was well received by those present, although participants from the pharmaceutical industry felt it would be prudent to clear the idea with their respective companies before agreeing to participate.
It was agreed that Iain Chalmers should draft a report of the meeting, making clear the aims and objectives of the initiative, particularly because it was felt that this would allay some of the fears that exist within industry. Richard Tiner (ABPI) said the chief executives of member companies of the ABPI wished to invite Iain Chalmers to discuss prospective registration with them. Such a report would provide helpful background material for that discussion.
Other potential contributors
It was noted that some organisations that could have an important role in promoting prospective registration of trials were not represented at the meeting, in particular, research ethics committees, medical research charities and the Medicines Control Agency.
All ethics committees are required to produce an annual report, but there is wide variation in the information conveyed in these reports. It was suggested that research ethics committees, even if they were not permitted for reasons of confidentiality to submit the information themselves, could be encouraged to ask investigators to register their trials.
Iain Chalmers reported that he had approached Diana Garnham, the General Secretary of the Association of Medical Research Charities, about prospective registration of trials. She had indicated that member charities of the Association appeared not to support many trials: a total of only 17 were identified when the former Director of NHS Research and Development (Michael Peckham) had asked her for this information a few years ago. Desmond Julian (Cardiovascular Clinical Trials Forum) and others present felt that although this might be the case for some charities, others, such as the British Diabetic Association, the British Heart Foundation and the cancer charities, did support trials and they might be willing to contribute information for inclusion in the metaRegister envisaged. Richard Horton (The Lancet) offered to contact Professor Leslie Turnberg, scientific adviser to the Association of Medical Research Charities, to clarify the Association's position, if any, on prospective registration of trials.
It was also suggested that it would be important and useful to have input from patients and other users of evidence, for example, clinicians. Specifically, Richard Tiner (ABPI) suggested that the Longterm Medical Conditions Alliance might be able to provide contacts for potentially interested individuals.
It was also suggested that editors/publishers could contribute by routinely asking investigators submitting protocols or reports of a completed trial for publication to submit basic information about their trials for inclusion in the register (irrespective of whether the document went on to publication).
Widening the discussion
To provide a forum for the wider discussion that would be needed, Richard Smith (British Medical Journal) offered to host a conference in 1999 to present the prospective registration initiative, and to involve participants from other countries who were pursuing similar objectives. He also offered to consider publishing a theme issue of the British Medical Journal on prospective registration of trials.
Iain Chalmers (UK Cochrane Centre), Desmond Julian (Cardiovascular Clinical Trials Forum) and Richard Tiner (ABPI) offered to work with him on this. Hopefully it would be possible to have a flyer announcing the meeting in time for distribution at the British Medical Journal meeting 'Randomised Controlled Trials: 50 Years of Clinical Trials: Past Present and Future' on 29/30 October 1998. Iain Chalmers (UK Cochrane Centre) would ensure that he addressed prospective registration in the paper he is preparing for that meeting.
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