Registries and Registration of Clinical Trials
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《新英格兰医药杂志》
The arguments in favor of the registration of clinical trials are now familiar.1,2,3,4 Chief among these addresses the practice of selective reporting, whereby negative or detrimental studies are not brought into the public domain, which experts on the subject of clinical trials consider an important form of scientific misconduct.5 This practice, as illustrated in a number of high-profile examples, have increased the demand for the mandatory public registration of clinical trials. Registration of trials should improve the completeness, reliability, and quality of the interpretation of clinical research.
This need for registration prompts the question of where trials should be registered. It seems obvious that, to avoid conflicts of interest and to increase the public trust, the entities that establish and manage registries should meet certain requirements. One set of such requirements, as established by the International Committee of Medical Journal Editors (ICMJE),6 requires that registries be owned and operated by not-for-profit entities, that they contain a minimal, clinically directive data set,7 and that they be electronically searchable, without charge, by any interested party. Originally, only ClinicalTrials.gov, a public registry that was set up to fulfill the legislative requirement mandating the registration of U.S. clinical trials involving patients with serious and life-threatening diseases, met these requirements. At first, this database was limited to clinical trials sanctioned by a U.S. entity, but as of the fall of 2004, it began including clinical trials from anywhere in the world. Even so, many European researchers were reluctant to use ClinicalTrials.gov as a locus for trial registration; an article by Zarin et al. in this issue of the Journal8 provides a report card on this registry.
Many investigators already register their trials in national or European databases, but unfortunately, no pan-European agreement has been struck with regard to how to move forward with public registration of clinical trials.9 Through the European Clinical Trials Directive (Directive 2001/20/EC), the European Union introduced legislation requiring the registration of "clinical trials on medicinal products for human use" in a European database. Since May 2004, all clinical trials conducted in member states of the European Union had to be registered in the EudraCT database, supervised by the European Medicines Agency. This registry is confidential and open only to regulatory agencies and organizations that provide funding for research.
A private company, Current Controlled Trials, which is based in the United Kingdom, developed the International Standard Randomised Controlled Trial Number (ISRCTN) scheme. It was launched on a pilot basis in 2000 and formally began operations in May 2003. The goal of this system is to simplify the identification of trials and provide a unique number that can be used to track all publications and reports resulting from each trial. This registry charges a minimal fee to registrants but is free to all who search its contents. This past September, ownership of the database was transferred to a not-for-profit entity, and it now meets all the ICMJE registration requirements.
In addition to EudraCT and ISRCTN, publicly accessible national registries of clinical trials have been established in several European countries, Japan, and Australia. There has also been a proliferation of registries based on trials involving specific diseases. In addition to public registration, the confidential registration of most clinical trials already exists in France, Italy, Spain, and the Netherlands. If these databases were open to the public, a wealth of information would be unearthed.
Although the desire for regional and specialized registries may be understandable, it is important for all such registries to contain uniform data elements and to be linked electronically — and even better, to share data — so that a search for trials that meet certain criteria would automatically cover all trial registries. The United Kingdom–based Current Controlled Trials' meta-register is an example of a registry that may compile the data from smaller registries. The World Health Organization (WHO) is working together with the ISRCTN and ClinicalTrials.gov to develop a common scheme to reduce duplicate registrations and publications and to establish the unambiguous identification of trials with the use of a unique numbering system.10 This is an important standard that must be met if registries are to be maximally effective.
But the WHO does not have the last word on this subject. For example, the Ottawa statement11 on trial registration goes much further than the WHO minimal data set. Its principles are to disclose the protocol details up front, to disclose amendments along the way, and to post the results at the end. The principles underlying this statement have been endorsed by more than 100 persons and organizations on all five continents, but not by a single pharmaceutical company.
This strategy is more than wishful thinking. The ultimate goal should be to make trial protocols publicly available in their entirety, including any financial arrangements and agreements with regard to publication, so that patients can be sure that the results will become available. At the same time, it is the responsibility of those who set the rules and establish the registries to make them practical to use and understandable for all kinds of research groups, both small and large. Only then will the use of registries become sufficiently comprehensive. The widespread use of trial registries will not prevent negative trial results or unwelcome outcomes from remaining unpublished. The current demand for the public registration of all clinical trials at their inception must therefore be followed by a demand for the addition of all results after each trial is complete and a certain amount of time has elapsed, to allow the researchers to publish in a journal.
No potential conflict of interest relevant to this article was reported.
Source Information
From the Journal of the Norwegian Medical Association, Oslo (C.H.); the Nordic Cochrane Centre, Copenhagen (P.C.G.); and the Journal of the Danish Medical Association, Copenhagen (T.V.S.).
References
Simes RJ. Publication bias: the case for an international registry of clinical trials. J Clin Oncol 1986;4:1529-1541.
Whittington CJ, Kendall T, Fonagy P, Cottrell D, Cotgrove A, Boddington E. Selective serotonin reuptake inhibitors in childhood depression: systematic review of published versus unpublished data. Lancet 2004;363:1341-1345.
Dickersin K, Rennie D. Registering clinical trials. JAMA 2003;290:516-523.
Chan A-W, Hróbjartsson A, Haahr MT, G?tzsche PC, Altman DG. Empirical evidence for selective reporting of outcomes in randomized trials: comparison of protocols to published articles. JAMA 2004;291:2457-2465.
Al-Marzouki S, Roberts I, Marshall T, Evans S. The effect of scientific misconduct on the results of clinical trials: a Delphi survey. Contemp Clin Trials 2005;26:331-337.
De Angelis C, Drazen JM, Frizelle FA, et al. Clinical trial registration: a statement from the International Committee of Medical Journal Editors. N Engl J Med 2004;351:1250-1251.
De Angelis C, Drazen JM, Frizelle FA, et al. Is this clinical trial fully registered? -- a statement from the International Committee of Medical Journal Editors. N Engl J Med 2005;352:2436-2438.
Zarin DA, Tse T, Ide NC. Trial registration at ClinicalTrials.gov between May and October 2005. N Engl J Med 2005;353:2779-2787.
Tonks A. A clinical trials register for Europe. BMJ 2002;325:1314-1315.
Gulmezoglu AM, Pang T, Horton R, Dickersin K. WHO facilitates international collaboration in setting standards for clinical trial registration. Lancet 2005;365:1829-1831.
Krleza-Jeric K, Chan AW, Dickersin K, Sim I, Grimshaw J, Gluud C. Principles for international registration of protocol information and results from human trials of health related interventions: Ottawa statement (part 1). BMJ 2005;330:956-958.(Charlotte Haug, M.D., Pet)
This need for registration prompts the question of where trials should be registered. It seems obvious that, to avoid conflicts of interest and to increase the public trust, the entities that establish and manage registries should meet certain requirements. One set of such requirements, as established by the International Committee of Medical Journal Editors (ICMJE),6 requires that registries be owned and operated by not-for-profit entities, that they contain a minimal, clinically directive data set,7 and that they be electronically searchable, without charge, by any interested party. Originally, only ClinicalTrials.gov, a public registry that was set up to fulfill the legislative requirement mandating the registration of U.S. clinical trials involving patients with serious and life-threatening diseases, met these requirements. At first, this database was limited to clinical trials sanctioned by a U.S. entity, but as of the fall of 2004, it began including clinical trials from anywhere in the world. Even so, many European researchers were reluctant to use ClinicalTrials.gov as a locus for trial registration; an article by Zarin et al. in this issue of the Journal8 provides a report card on this registry.
Many investigators already register their trials in national or European databases, but unfortunately, no pan-European agreement has been struck with regard to how to move forward with public registration of clinical trials.9 Through the European Clinical Trials Directive (Directive 2001/20/EC), the European Union introduced legislation requiring the registration of "clinical trials on medicinal products for human use" in a European database. Since May 2004, all clinical trials conducted in member states of the European Union had to be registered in the EudraCT database, supervised by the European Medicines Agency. This registry is confidential and open only to regulatory agencies and organizations that provide funding for research.
A private company, Current Controlled Trials, which is based in the United Kingdom, developed the International Standard Randomised Controlled Trial Number (ISRCTN) scheme. It was launched on a pilot basis in 2000 and formally began operations in May 2003. The goal of this system is to simplify the identification of trials and provide a unique number that can be used to track all publications and reports resulting from each trial. This registry charges a minimal fee to registrants but is free to all who search its contents. This past September, ownership of the database was transferred to a not-for-profit entity, and it now meets all the ICMJE registration requirements.
In addition to EudraCT and ISRCTN, publicly accessible national registries of clinical trials have been established in several European countries, Japan, and Australia. There has also been a proliferation of registries based on trials involving specific diseases. In addition to public registration, the confidential registration of most clinical trials already exists in France, Italy, Spain, and the Netherlands. If these databases were open to the public, a wealth of information would be unearthed.
Although the desire for regional and specialized registries may be understandable, it is important for all such registries to contain uniform data elements and to be linked electronically — and even better, to share data — so that a search for trials that meet certain criteria would automatically cover all trial registries. The United Kingdom–based Current Controlled Trials' meta-register is an example of a registry that may compile the data from smaller registries. The World Health Organization (WHO) is working together with the ISRCTN and ClinicalTrials.gov to develop a common scheme to reduce duplicate registrations and publications and to establish the unambiguous identification of trials with the use of a unique numbering system.10 This is an important standard that must be met if registries are to be maximally effective.
But the WHO does not have the last word on this subject. For example, the Ottawa statement11 on trial registration goes much further than the WHO minimal data set. Its principles are to disclose the protocol details up front, to disclose amendments along the way, and to post the results at the end. The principles underlying this statement have been endorsed by more than 100 persons and organizations on all five continents, but not by a single pharmaceutical company.
This strategy is more than wishful thinking. The ultimate goal should be to make trial protocols publicly available in their entirety, including any financial arrangements and agreements with regard to publication, so that patients can be sure that the results will become available. At the same time, it is the responsibility of those who set the rules and establish the registries to make them practical to use and understandable for all kinds of research groups, both small and large. Only then will the use of registries become sufficiently comprehensive. The widespread use of trial registries will not prevent negative trial results or unwelcome outcomes from remaining unpublished. The current demand for the public registration of all clinical trials at their inception must therefore be followed by a demand for the addition of all results after each trial is complete and a certain amount of time has elapsed, to allow the researchers to publish in a journal.
No potential conflict of interest relevant to this article was reported.
Source Information
From the Journal of the Norwegian Medical Association, Oslo (C.H.); the Nordic Cochrane Centre, Copenhagen (P.C.G.); and the Journal of the Danish Medical Association, Copenhagen (T.V.S.).
References
Simes RJ. Publication bias: the case for an international registry of clinical trials. J Clin Oncol 1986;4:1529-1541.
Whittington CJ, Kendall T, Fonagy P, Cottrell D, Cotgrove A, Boddington E. Selective serotonin reuptake inhibitors in childhood depression: systematic review of published versus unpublished data. Lancet 2004;363:1341-1345.
Dickersin K, Rennie D. Registering clinical trials. JAMA 2003;290:516-523.
Chan A-W, Hróbjartsson A, Haahr MT, G?tzsche PC, Altman DG. Empirical evidence for selective reporting of outcomes in randomized trials: comparison of protocols to published articles. JAMA 2004;291:2457-2465.
Al-Marzouki S, Roberts I, Marshall T, Evans S. The effect of scientific misconduct on the results of clinical trials: a Delphi survey. Contemp Clin Trials 2005;26:331-337.
De Angelis C, Drazen JM, Frizelle FA, et al. Clinical trial registration: a statement from the International Committee of Medical Journal Editors. N Engl J Med 2004;351:1250-1251.
De Angelis C, Drazen JM, Frizelle FA, et al. Is this clinical trial fully registered? -- a statement from the International Committee of Medical Journal Editors. N Engl J Med 2005;352:2436-2438.
Zarin DA, Tse T, Ide NC. Trial registration at ClinicalTrials.gov between May and October 2005. N Engl J Med 2005;353:2779-2787.
Tonks A. A clinical trials register for Europe. BMJ 2002;325:1314-1315.
Gulmezoglu AM, Pang T, Horton R, Dickersin K. WHO facilitates international collaboration in setting standards for clinical trial registration. Lancet 2005;365:1829-1831.
Krleza-Jeric K, Chan AW, Dickersin K, Sim I, Grimshaw J, Gluud C. Principles for international registration of protocol information and results from human trials of health related interventions: Ottawa statement (part 1). BMJ 2005;330:956-958.(Charlotte Haug, M.D., Pet)