EDITORIALS |
Clinical trial registration
1Ipswich Hospital NHS Trust, Ipswich, 2School of Medicine, Health Policy and Practice, University of East Anglia, Norwich and 3British Society for Rheumatology, London, UK
Correspondence to: R. Watts, British Society for Rheumatology, Bride House, 18-20 Bride Lane, London EC4Y 8EE, UK. E-mail: editorial{at}rheumatology.org.uk
Randomized clinical trials are a fundamental part of the process by which new medical knowledge is acquired and translated into clinical practice. Patients volunteer to participate in clinical trials in good faith that the results will be made available as quickly and as openly as possible to the medical community and that their participation will contribute to improved health for others. Unfortunately, in practice this does not always happen. One of the major reasons is failure to publish the complete data set, in particular when the trial has produced results suggesting that the treatment under investigation is less effective or only marginally more effective than the comparator treatment. This is particularly a problem with industry sponsored studies. The problem is compounded by researchers and journal editors usually being more interested in publishing trial outcomes that either show a large effect for a new treatment (positive trials) or equivalence of two methods of treatment (non-inferiority trials). Journal editors and researchers are less keen to publish results that show that a new treatment was inferior to standard treatment (negative trials) and even less keen to publish the results of trials that are inconclusive since these trials will not change clinical practice.
The benefits of trial registration are substantial: reduction of the potential for patient harm, reduction in the duplication of trials, better planning of further studies and the reduction in negative reporting bias. Evidence-based medicine requires easy access to trial data especially when this is negative, otherwise the results of meta-analysis will overestimate any positive effects. If all clinical trials were registered in public registers at their inception as part of the public record, then all stakeholders in clinical research would be able to benefit by being able to explore the full range of clinical evidence.
In September 2004, the International Committee of Medical Journal Editors (ICMJE) proposed registration of a clinical trial as a pre-requisite for publication and initiated a policy for ICMJE journals in 2005 [1, 2]. The policy states that trials must be registered in a public trials registry before beginning the recruitment of patients. A number of registers exist and some are now quite large. The US NIH hosts the register ClinicalTrials.gov that contains details of 60 667 trials with locations in 157 countries in August 2008, whilst the UK-based International Standard Randomised Controlled Trial Number Register (ISRCTN) contains 7069 [3].
The World Health Organization (WHO) has developed a single worldwide standard for the information that trial authors must disclose (Table 1). It is important that the requested information is registered for each trial. Trial registration with missing or uninformative fields for the minimum data elements listed in Table 1 is inadequate even if the registration is in an acceptable registry. The WHO has also co-ordinated an initiative to link the available registers in a global network called the International Clinical Trials Registry Platform (ICTRP) to provide a single point of entry [4]. The WHO registry network is composed of: WHO Primary Registries and Partner Registries. WHO Primary Registries must meet certain criteria to ensure that the data collected meet the standards of the ICTRP. These criteria are categorized into six main areas: content; quality and validity; accessibility; unique identification; technical capacity; and administration and governance. Registries that currently meet these criteria are: Australian New Zealand Clinical Trials Registry (ANZCTR), Chinese Clinical Trials registry (ChiCTR), Clinical Trails Registry—India (CTRI), ISRCTN.org, The Netherlands National Trial Register (NTR) and Sri Lanka Clinical Trials Registry (SLCTR). Partner registries meet the same criteria as Primary Registries except that they do not need to: have a national or regional remit or the support of government; be managed by a not-for-profit agency; be open to all prospective registrants (they may be limited to trials in a particular condition or intervention). However, they must be also affiliated with either a WHO Primary Registry or an ICMJE approved registry. Current partner registries are: Physician Data Query Affiliated Registry, ClinicalTrials.gov; European Leukemia Trial Registry Affiliated Registry, DKTR. ICMJE approved registries: www.actr.prg.au; www.clinicaltrials.gov; www.ISRCTN.org; www.umin.ac.jp/ctr/index/htm; and www.trialregister.nl.
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Concerns have been raised that trial registration is just another bureaucratic hurdle for the hapless researcher to undertake before beginning a study; however, registration is quite speedy and now in many countries is a requirement for ethical committee approval.
The requirements for clinical registration and definitions of clinical trials have developed and been re-evaluated since the first registration policy was initiated by the ICMJE in 2005.
Rheumatology is adopting the WHO definition for clinical trials and the ICMJE criteria for health outcomes. For the purposes of registration, a clinical trial is ‘any research study that prospectively assigns human participants or groups of humans to one or more health-related interventions to evaluate the effects on health outcomes. Interventions include but are not restricted to drugs, cells and other biological products, surgical procedures, radiologic procedures, devices, behavioural treatments, process-of-care changes, preventative care, etc.’ [5]. The ICMJE criteria for health outcomes include any biomedical or health-related measures obtained in patients or participants, including pharmacokinetic measures and adverse events [6]. Purely observational studies (those in which the assignment of the medical intervention is not at the discretion of the investigator) will not require registration [6]. Those who are uncertain whether their trial meets the above definitions should err on the side of registration.
An increasing number of biomedical journals are adopting this policy, and we believe that Rheumatology should introduce a similar policy. Rheumatology will therefore require the registration of all clinical trials in line with the ICMJE and WHO declarations. We will require that from 1 January 2009 all prospective, interventional studies whether begun before or after that date must be registered with either with a WHO Primary Registry or an approved ICMJE registry. Trials beginning after 1 January 2009 must be registered before recruitment of the first patient. Rheumatology will accept ‘retrospective registration’ of trials that began before 1 January 2009 (retrospective meaning registration occurs after patient enrolment begins). When submitting a paper on a clinical trial, the trial registration number should be stated at the end of the abstract in the following format: Trial registration: [name of the trial registry, the registry URL and the trial registration number]. We hope that this policy will encourage the more open and honest reporting of the results from clinical trials benefiting the medical community.
Disclosure statement: The authors have declared no conflicts of interest.
References
- DeAngelis CD, Drazen JM, Frizelle FA, et al. Clinical trial registration: a statement from the Committee of Medical Editors. Lancet (2004) 364:911–2.[CrossRef][Web of Science][Medline]
- Clinical trial registration: a statement from the Committee of Medical Editors. 22 August 2008, date last accessed. http://www.icmje.org/clin_trial.pdf.
- Bulletin of the World Health Organization. (2006) 84:10–11.
- International Standard Randomised Controlled Trial Number Register. 22 August 2008, date last accessed. http://www.controlled-trials.com/.
- World Health Organization. What is a clinical trial? (22 August 2008, date last accessed). http://www.who.int/ictrp/en/.
- Laine CD, Horton R, DeAngelis C, et al. Clinical trial registration: looking back and moving ahead. (2007) 22 August 2008, date last accessed. http://www.icmje.org/clin_trial07.pdf.
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