- Email: [email protected]
Registering clinical trials: an essential role for WHO
COMMENTARY
Perhaps the most compelling clinical evidence to date for an anti-arrhythmic mechanism of action of the longchain n-3 polyunsaturated fatty acids comes from the largest randomised trial, the GISSI-Prevenzione Trial.11 Over 11 000 patients surviving a recent myocardial infarction were assigned at random, in an unblinded fashion, to fish oil and/or vitamin E in a two-by-two factorial design. The patients assigned to fish oil had a significant reduction in the primary endpoint (death, non-fatal myocardial infarction, and non-fatal stroke) due to a statistically significant reduction in total mortality (20%). Again, as in DART, there was no benefit on non-fatal cardiovascular events. When investigated further, much of the benefit on mortality was attributable to a 53% reduction in sudden cardiac death that emerged at 4 months of follow-up.12 In this issue of The Lancet, Rainer Schrepf and colleagues report an important addition to the evidence about the anti-arrhythmic properties of the long-chain n-3 fatty acids. These investigators present the first, albeit preliminary, data on the acute anti-arrhythmic effects of long-chain n-3 fatty acids in human beings. Patients with implantable cardioverter defibrillators, who had ventricular tachycardia at preimplant electrophysiological testing and repeated episodes of ventricular tachycardia, underwent subsequent non-invasive electrophysiological testing. Nine of the ten patients were men, had underlying coronary heart disease, and a history of sustained ventricular tachycardia and/or fibrillation. Of the ten patients who underwent testing, seven had monomorphic sustained ventricular tachycardia induced. Of these, five patients were rendered non-inducible after an intravenous infusion of 3·8 g n-3 polyunsaturated fatty acids. In addition, like many anti-arrhythmic drugs, the fish-oil infusion prolonged the ventricular effective refractoryperiod, a measure of myocardial excitability. As recognised by Schrepf and colleagues, the possibility that variability in the results of electrophysiological testing, rather than a true anti-arrhythmic effect of the n-3 fattyacid infusion, cannot be excluded and could provide an alternative explanation for the results. However, the immediate reproducibility of monomorphic ventricular tachycardia induced during invasive electrophysiological testing is high, ranging from 77 to 98%,13 which argues against this alternative as the sole explanation. Without a placebo group and a blinded randomised comparison, it is also impossible to exclude the possibility that chance accounts for the results in this small sample. Regardless, these preliminary data do not seem to demonstrate a proarrhythmic effect and support a possible anti-arrhythmic effect of these fatty acids. What are the implications of these findings? As has been shown with traditional anti-arrhythmic drugs, suppression of ventricular tachycardia during electrophysiological testing does not directly translate into a survival benefit when the same drugs are administered chronically.14 Therefore the implications of these data on their own are limited. However, Schrerf and colleagues’ findings, in conjunction with previous experimental data, provide a possible mechanism to explain the preferential benefit seen with dietary intake of n-3 fatty acids on sudden cardiac death in the earlier observational studies and randomised trials. These preliminary data need to be confirmed in randomised trials with hard arrhythmic endpoints in combination with mortality. Currently, three such randomised trials of the effect of fish-oil supplementation on recurrent episodes of ventricular tachycardia and/or fibrillation in patients with implantable cardioverter defibrillators are in progress or have been completed. If these and other trials confirm the anti-arrhythmic pro-
perties of these n-3 acids, fish oil might become a less toxic and more appetising alternative to traditional antiarrhythmic drugs. I have no conflict of interest to declare.
Christine Albert Division of Preventive Medicine, Brigham and Women's Hospital, and Cardiology Division, Massachusetts General Hospital, Boston, MA 02215, USA (e-mail: [email protected]) 1
2
3
4
5
6
7
8 9 10
11
12
13
14
Kris-Ethertom PM, Harris WS, Appel LJ, for the Nutrition Committee. AHA scientific statement: fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Circulation 2002: 106: 2747–27. McLennan PL, Abeywardena MY, Charnock JS. Dietary fish oil prevents ventricular fibrillation following coronary artery occlusion and reperfusion. Am Heart J 1988; 116: 709–17. Billman GE, Kang JX, Leaf A. Prevention of ischemia-induced cardiac sudden death by pure n-3 polyunsaturated fatty acids. Circulation 1999; 99: 2452–57. Leaf A, Kang JX, Xiao Y-F, Billman GE. Clinical prevention of sudden cardiac death by n-3 polyunsaturated fatty acids and mechanism of prevention of arrhythmias by n-3 fish oils. Circulation 2003; 107: 2646–52. Christensen JH, Korup E, Aaroe J, et al. Fish consumption, n-3 fatty acids in cell membranes, and heart rate variability in survivors of myocardial infarction with left ventricular dysfunction. Am J Cardiol 1997; 79: 1670–73. Burr ML, Fehily AM, Gilbert JF, et al. Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: diet and Reinfarction Trial (DART). Lancet 1989; 2: 757–61. Siscovick DS, Raghunathan TE, King I, et al. Dietary intake and cell membrane levels of long-chain n-3 polyunsaturated fatty acids and the risk of primary cardiac arrest. JAMA 1995; 274: 1363–67. Albert CM, Hennekens CH, O’Donnell CJ, et al. Fish consumption and decreased risk of sudden cardiac death. JAMA 1998; 279: 23–28. Albert CM, Campos H, Stampfer MJ, et al. Blood long-chain n-3 fatty acids and risk of sudden death. N Engl J Med 2002; 346: 1113–18. Guallar E, Hennekens CH, Sacks FM, Willett WC, Stampfer MJ. A prospective study of plasma fish oil levels and incidence of myocardial infarction in U.S. male physicians. J Am Coll Cardiol 1995; 25: 387–94. GISSI-Prevenzione Investigators. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Lancet 1999; 354: 447–55. Marchioli R, Barzi F, Bomba E, et al. Early protection against sudden death by n-3 polyunsaturated fatty acids after myocardial infarction: time-course analysis of the results of the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI)-Prevenzione. Circulation 2002; 105: 1897–903. Rosenbaum MS, Wilber DJ, Finkelstein D, Ruskin JN, Garan H. Immediate reproducibility of electrically induced sustained monomorphic ventricular tachycardia before and during antiarrhythmic therapy. J Am Coll Cardiol 1991; 17: 133–38. Buxton AE, Lee KL, Fisher JD, for the Multicenter Unsustained Tachycardia Trial Investigators. A randomized study of the prevention of sudden death in patients with coronary artery disease. N Engl J Med 1999; 341: 1882–90.
Registering clinical trials: an essential role for WHO Ideally, the results of relevant research should inform all health-care decisions. In fact, securing improvements in the health of the poor and achieving the health-related Millennium Development Goals (MDGs) depends on effective uptake and use of scientific knowledge.1 However, informing decisions and optimising health outcomes requires efficient and equitable access to the results of relevant research. Accessing the results of relevant research would be challenge enough if it only concerned access to published reports of research; but some important studies are never published, and are difficult or impossible to locate. This issue is important because the results of unpublished
THE LANCET • Vol 363 • May 1, 2004 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet.
1413
COMMENTARY
studies differ systematically from those that are published.2 Studies in which no statistically significant differences have been found are less likely to be published and, even when they are, they take longer to appear in print.3 About half the studies presented at scientific meetings never get published.4 A further problem is that researchers in developing countries whose first language is not English may experience difficulty publishing in internationally indexed journals. This would not be a serious problem if local journals published in other languages were easily accessible. But many such journals are not indexed in international databases such as MEDLINE or the Web of Science, even though they may contain research of importance to many low-income and middle-income countries. It is important to reduce this waste of information and resources. For some time, researchers, the scientific community, and journal publishers have been calling for prospective registration of a category of research that is particularly relevant to health-care decisions—randomised controlled trials.2,5 Carefully conducted trials are the fastest and safest way to find effective treatments for improving health. If universal registration led to access to basic information about all ongoing publicly and privately funded clinical trials, this would help those who try to use research results for the benefit of patients. Even if a trial had not been published, knowledge that it existed would help others to consider the likelihood that its findings might influence decision-making. The idea of clinical trial registers is not new. The Cochrane Collaboration has assembled a register containing more than 400 000 records, mainly of published reports of controlled trials in developed countries.6 There are several other registers of ongoing trials, including an internet site allowing cross-register searching, with links to other registers.7 National registers also exist in several developed countries but there is no registry that has comprehensive international coverage. There is a need for coordinated international collaboration to either build a single register or to link together all that exist. An encouraging start has been made with the establishment of an internationally unique trial numbering scheme—the ISRCTN (International Standard Randomised Controlled Trial Number).8 However, there is no systematic process for finding (published or unpublished) controlled trials done and reported in many of the poorer countries of the world. Consistent with its commitment to increasing knowledgesharing, access, and use in low-income and middleincome countries, WHO has decided to obtain unique trial-identification numbers for trials approved by its ethics review board. In addition, ISRCTN numbers have been assigned9 to all trials included in the HRP controlled trials register (UNDP/UNFPA/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction).10 These efforts should be seen within the context of a new emphasis on the need to increase international access to and use of health-related knowledge. Access to both published and ongoing research is necessary for informed decision-making, not just by those working in and using the health services, but also by organisations and individuals funding and doing research. Properly used trial registers would inform research ethics boards and research-funding agencies, making sure that it is ethical to conduct proposed trials and in prioritising the research they fund (by ensuring that a similar trial is not in progress or already done). Information about sponsors of trials 1414
would be of value in understanding the flows of resources to support clinical research and help in formulation of research policy related to the setting of priorities. Information about the location of trials might help to catalyse complimentary capacity, strengthening efforts as evidenced by the new initiative of the European Union to strengthen clinical trials capacity in Africa.11 In addition to their uses by researchers, reviewers, and policy makers, the trial registers are already used by patients on the internet to participate in trials.12 The public-good nature of such a register to this diversity of groups is likely to induce significant and perhaps overwhelming demands. Operationally, therefore, it would be important at least initially to keep the register simple—ie, ensure a minimum set of information on trials (such as title, what is being tested, the disease area, who are the participants, inclusion/exclusion criteria, what are the outcomes, the sponsors, contact name and address), to encourage registration and to reduce costs, logistic problems, and the need for maintenance and management. At a meeting in London convened by WHO, the UK’s Medical Research Council, and the Wellcome Trust on April 27–28, funding agencies, researchers, and publishers discussed how global registration of trials and other ways of improving access to knowledge could contribute to more informed decision making. By promoting the development of a global controlled-trials register, WHO will help to promote the idea that such trials are a global public-good and help not only those who produce health information but also enable others to use and produce knowledge for health improvement.13 MG coordinates the HRP controlled trials register, does Cochrane systematic reviews, and is an editor in two Cochrane review groups.
Timothy Evans, *Metin Gülmezoglu, Tikki Pang Evidence and Information for Policy (TE); Department of Reproductive Health & Research (MG); and Department of Research Policy & Cooperation (TP), World Health Organization, Geneva, CH-1211, Switzerland (email: [email protected])
1 2 3
4
5 6
7 8
9
10
11 12 13
Lee JW. Science and the health of the poor. Bull World Health Organ 2003; 81: 473. Dickersin K, Rennie D. Registering clinical trials. JAMA 2003; 290: 516–23. Hopewell S, Clarke M, Stewart L, Tierney J. Time to publication for results of clinical trials (Cochrane Methodology Review). In: The Cochrane Library, Issue 1, 2004. Chichester, UK: John Wiley & Sons, Ltd. Scherer RW, Langenberg P. Full publication of results initially presented in abstracts (Cochrane Methodology Review). In: The Cochrane Library, Issue 4, 2003. Chichester, UK: John Wiley & Sons, Ltd. Horton R, Smith R. Time to register randomised trials. Lancet 1999; 354: 1138–39. CENTRAL—Cochrane central register of controlled trials. In: The Cochrane Library, Issue 1, 2004. Chichester, UK: John Wiley & Sons, Ltd. Current Controlled Trials. metaRegister of controlled trials (mRCT). http://www.controlled-trials.com/mrct (accessed Feb 17, 2004). Current Controlled Trials. International standard randomised controlled trial register. http://www.controlled-trials.com/isrctn (accessed Feb 17, 2004). WHO. WHO leads drive for international coordination of clinical research. http://www.who.int/mediacentre/releases/2004/pr23/en/ print.html (accessed April 19, 2004). WHO programme to map best reproductive health practices. Human reproduction programme controlled trials register. http://www.who.int/ reproductive-health/rhl/trials.html (accessed Feb 17, 2004). EDCTP—European & developing countries clinical trials partnership. http://www.edctp.org (accessed March 30, 2004). TrialsCentral. http://www.trialscentral.org (accessed March 1, 2004). Bailey C. Using knowledge management to make health systems work. Bull World Health Organ 2003; 81: 777.
THE LANCET • Vol 363 • May 1, 2004 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet.
Perhaps the most compelling clinical evidence to date for an anti-arrhythmic mechanism of action of the longchain n-3 polyunsaturated fatty acids comes from the largest randomised trial, the GISSI-Prevenzione Trial.11 Over 11 000 patients surviving a recent myocardial infarction were assigned at random, in an unblinded fashion, to fish oil and/or vitamin E in a two-by-two factorial design. The patients assigned to fish oil had a significant reduction in the primary endpoint (death, non-fatal myocardial infarction, and non-fatal stroke) due to a statistically significant reduction in total mortality (20%). Again, as in DART, there was no benefit on non-fatal cardiovascular events. When investigated further, much of the benefit on mortality was attributable to a 53% reduction in sudden cardiac death that emerged at 4 months of follow-up.12 In this issue of The Lancet, Rainer Schrepf and colleagues report an important addition to the evidence about the anti-arrhythmic properties of the long-chain n-3 fatty acids. These investigators present the first, albeit preliminary, data on the acute anti-arrhythmic effects of long-chain n-3 fatty acids in human beings. Patients with implantable cardioverter defibrillators, who had ventricular tachycardia at preimplant electrophysiological testing and repeated episodes of ventricular tachycardia, underwent subsequent non-invasive electrophysiological testing. Nine of the ten patients were men, had underlying coronary heart disease, and a history of sustained ventricular tachycardia and/or fibrillation. Of the ten patients who underwent testing, seven had monomorphic sustained ventricular tachycardia induced. Of these, five patients were rendered non-inducible after an intravenous infusion of 3·8 g n-3 polyunsaturated fatty acids. In addition, like many anti-arrhythmic drugs, the fish-oil infusion prolonged the ventricular effective refractoryperiod, a measure of myocardial excitability. As recognised by Schrepf and colleagues, the possibility that variability in the results of electrophysiological testing, rather than a true anti-arrhythmic effect of the n-3 fattyacid infusion, cannot be excluded and could provide an alternative explanation for the results. However, the immediate reproducibility of monomorphic ventricular tachycardia induced during invasive electrophysiological testing is high, ranging from 77 to 98%,13 which argues against this alternative as the sole explanation. Without a placebo group and a blinded randomised comparison, it is also impossible to exclude the possibility that chance accounts for the results in this small sample. Regardless, these preliminary data do not seem to demonstrate a proarrhythmic effect and support a possible anti-arrhythmic effect of these fatty acids. What are the implications of these findings? As has been shown with traditional anti-arrhythmic drugs, suppression of ventricular tachycardia during electrophysiological testing does not directly translate into a survival benefit when the same drugs are administered chronically.14 Therefore the implications of these data on their own are limited. However, Schrerf and colleagues’ findings, in conjunction with previous experimental data, provide a possible mechanism to explain the preferential benefit seen with dietary intake of n-3 fatty acids on sudden cardiac death in the earlier observational studies and randomised trials. These preliminary data need to be confirmed in randomised trials with hard arrhythmic endpoints in combination with mortality. Currently, three such randomised trials of the effect of fish-oil supplementation on recurrent episodes of ventricular tachycardia and/or fibrillation in patients with implantable cardioverter defibrillators are in progress or have been completed. If these and other trials confirm the anti-arrhythmic pro-
perties of these n-3 acids, fish oil might become a less toxic and more appetising alternative to traditional antiarrhythmic drugs. I have no conflict of interest to declare.
Christine Albert Division of Preventive Medicine, Brigham and Women's Hospital, and Cardiology Division, Massachusetts General Hospital, Boston, MA 02215, USA (e-mail: [email protected]) 1
2
3
4
5
6
7
8 9 10
11
12
13
14
Kris-Ethertom PM, Harris WS, Appel LJ, for the Nutrition Committee. AHA scientific statement: fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Circulation 2002: 106: 2747–27. McLennan PL, Abeywardena MY, Charnock JS. Dietary fish oil prevents ventricular fibrillation following coronary artery occlusion and reperfusion. Am Heart J 1988; 116: 709–17. Billman GE, Kang JX, Leaf A. Prevention of ischemia-induced cardiac sudden death by pure n-3 polyunsaturated fatty acids. Circulation 1999; 99: 2452–57. Leaf A, Kang JX, Xiao Y-F, Billman GE. Clinical prevention of sudden cardiac death by n-3 polyunsaturated fatty acids and mechanism of prevention of arrhythmias by n-3 fish oils. Circulation 2003; 107: 2646–52. Christensen JH, Korup E, Aaroe J, et al. Fish consumption, n-3 fatty acids in cell membranes, and heart rate variability in survivors of myocardial infarction with left ventricular dysfunction. Am J Cardiol 1997; 79: 1670–73. Burr ML, Fehily AM, Gilbert JF, et al. Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: diet and Reinfarction Trial (DART). Lancet 1989; 2: 757–61. Siscovick DS, Raghunathan TE, King I, et al. Dietary intake and cell membrane levels of long-chain n-3 polyunsaturated fatty acids and the risk of primary cardiac arrest. JAMA 1995; 274: 1363–67. Albert CM, Hennekens CH, O’Donnell CJ, et al. Fish consumption and decreased risk of sudden cardiac death. JAMA 1998; 279: 23–28. Albert CM, Campos H, Stampfer MJ, et al. Blood long-chain n-3 fatty acids and risk of sudden death. N Engl J Med 2002; 346: 1113–18. Guallar E, Hennekens CH, Sacks FM, Willett WC, Stampfer MJ. A prospective study of plasma fish oil levels and incidence of myocardial infarction in U.S. male physicians. J Am Coll Cardiol 1995; 25: 387–94. GISSI-Prevenzione Investigators. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Lancet 1999; 354: 447–55. Marchioli R, Barzi F, Bomba E, et al. Early protection against sudden death by n-3 polyunsaturated fatty acids after myocardial infarction: time-course analysis of the results of the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI)-Prevenzione. Circulation 2002; 105: 1897–903. Rosenbaum MS, Wilber DJ, Finkelstein D, Ruskin JN, Garan H. Immediate reproducibility of electrically induced sustained monomorphic ventricular tachycardia before and during antiarrhythmic therapy. J Am Coll Cardiol 1991; 17: 133–38. Buxton AE, Lee KL, Fisher JD, for the Multicenter Unsustained Tachycardia Trial Investigators. A randomized study of the prevention of sudden death in patients with coronary artery disease. N Engl J Med 1999; 341: 1882–90.
Registering clinical trials: an essential role for WHO Ideally, the results of relevant research should inform all health-care decisions. In fact, securing improvements in the health of the poor and achieving the health-related Millennium Development Goals (MDGs) depends on effective uptake and use of scientific knowledge.1 However, informing decisions and optimising health outcomes requires efficient and equitable access to the results of relevant research. Accessing the results of relevant research would be challenge enough if it only concerned access to published reports of research; but some important studies are never published, and are difficult or impossible to locate. This issue is important because the results of unpublished
THE LANCET • Vol 363 • May 1, 2004 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet.
1413
COMMENTARY
studies differ systematically from those that are published.2 Studies in which no statistically significant differences have been found are less likely to be published and, even when they are, they take longer to appear in print.3 About half the studies presented at scientific meetings never get published.4 A further problem is that researchers in developing countries whose first language is not English may experience difficulty publishing in internationally indexed journals. This would not be a serious problem if local journals published in other languages were easily accessible. But many such journals are not indexed in international databases such as MEDLINE or the Web of Science, even though they may contain research of importance to many low-income and middle-income countries. It is important to reduce this waste of information and resources. For some time, researchers, the scientific community, and journal publishers have been calling for prospective registration of a category of research that is particularly relevant to health-care decisions—randomised controlled trials.2,5 Carefully conducted trials are the fastest and safest way to find effective treatments for improving health. If universal registration led to access to basic information about all ongoing publicly and privately funded clinical trials, this would help those who try to use research results for the benefit of patients. Even if a trial had not been published, knowledge that it existed would help others to consider the likelihood that its findings might influence decision-making. The idea of clinical trial registers is not new. The Cochrane Collaboration has assembled a register containing more than 400 000 records, mainly of published reports of controlled trials in developed countries.6 There are several other registers of ongoing trials, including an internet site allowing cross-register searching, with links to other registers.7 National registers also exist in several developed countries but there is no registry that has comprehensive international coverage. There is a need for coordinated international collaboration to either build a single register or to link together all that exist. An encouraging start has been made with the establishment of an internationally unique trial numbering scheme—the ISRCTN (International Standard Randomised Controlled Trial Number).8 However, there is no systematic process for finding (published or unpublished) controlled trials done and reported in many of the poorer countries of the world. Consistent with its commitment to increasing knowledgesharing, access, and use in low-income and middleincome countries, WHO has decided to obtain unique trial-identification numbers for trials approved by its ethics review board. In addition, ISRCTN numbers have been assigned9 to all trials included in the HRP controlled trials register (UNDP/UNFPA/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction).10 These efforts should be seen within the context of a new emphasis on the need to increase international access to and use of health-related knowledge. Access to both published and ongoing research is necessary for informed decision-making, not just by those working in and using the health services, but also by organisations and individuals funding and doing research. Properly used trial registers would inform research ethics boards and research-funding agencies, making sure that it is ethical to conduct proposed trials and in prioritising the research they fund (by ensuring that a similar trial is not in progress or already done). Information about sponsors of trials 1414
would be of value in understanding the flows of resources to support clinical research and help in formulation of research policy related to the setting of priorities. Information about the location of trials might help to catalyse complimentary capacity, strengthening efforts as evidenced by the new initiative of the European Union to strengthen clinical trials capacity in Africa.11 In addition to their uses by researchers, reviewers, and policy makers, the trial registers are already used by patients on the internet to participate in trials.12 The public-good nature of such a register to this diversity of groups is likely to induce significant and perhaps overwhelming demands. Operationally, therefore, it would be important at least initially to keep the register simple—ie, ensure a minimum set of information on trials (such as title, what is being tested, the disease area, who are the participants, inclusion/exclusion criteria, what are the outcomes, the sponsors, contact name and address), to encourage registration and to reduce costs, logistic problems, and the need for maintenance and management. At a meeting in London convened by WHO, the UK’s Medical Research Council, and the Wellcome Trust on April 27–28, funding agencies, researchers, and publishers discussed how global registration of trials and other ways of improving access to knowledge could contribute to more informed decision making. By promoting the development of a global controlled-trials register, WHO will help to promote the idea that such trials are a global public-good and help not only those who produce health information but also enable others to use and produce knowledge for health improvement.13 MG coordinates the HRP controlled trials register, does Cochrane systematic reviews, and is an editor in two Cochrane review groups.
Timothy Evans, *Metin Gülmezoglu, Tikki Pang Evidence and Information for Policy (TE); Department of Reproductive Health & Research (MG); and Department of Research Policy & Cooperation (TP), World Health Organization, Geneva, CH-1211, Switzerland (email: [email protected])
1 2 3
4
5 6
7 8
9
10
11 12 13
Lee JW. Science and the health of the poor. Bull World Health Organ 2003; 81: 473. Dickersin K, Rennie D. Registering clinical trials. JAMA 2003; 290: 516–23. Hopewell S, Clarke M, Stewart L, Tierney J. Time to publication for results of clinical trials (Cochrane Methodology Review). In: The Cochrane Library, Issue 1, 2004. Chichester, UK: John Wiley & Sons, Ltd. Scherer RW, Langenberg P. Full publication of results initially presented in abstracts (Cochrane Methodology Review). In: The Cochrane Library, Issue 4, 2003. Chichester, UK: John Wiley & Sons, Ltd. Horton R, Smith R. Time to register randomised trials. Lancet 1999; 354: 1138–39. CENTRAL—Cochrane central register of controlled trials. In: The Cochrane Library, Issue 1, 2004. Chichester, UK: John Wiley & Sons, Ltd. Current Controlled Trials. metaRegister of controlled trials (mRCT). http://www.controlled-trials.com/mrct (accessed Feb 17, 2004). Current Controlled Trials. International standard randomised controlled trial register. http://www.controlled-trials.com/isrctn (accessed Feb 17, 2004). WHO. WHO leads drive for international coordination of clinical research. http://www.who.int/mediacentre/releases/2004/pr23/en/ print.html (accessed April 19, 2004). WHO programme to map best reproductive health practices. Human reproduction programme controlled trials register. http://www.who.int/ reproductive-health/rhl/trials.html (accessed Feb 17, 2004). EDCTP—European & developing countries clinical trials partnership. http://www.edctp.org (accessed March 30, 2004). TrialsCentral. http://www.trialscentral.org (accessed March 1, 2004). Bailey C. Using knowledge management to make health systems work. Bull World Health Organ 2003; 81: 777.
THE LANCET • Vol 363 • May 1, 2004 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet.