Trauma care research and the war on uncertainty
http://www.100md.com
《英国医生杂志》
Improving trauma care demands large trials—and large trials need funding and collaboration
For people aged 5-45 years trauma is second only to HIV/AIDS as a cause of death.1 2 Every day world wide over 300 000 people are severely injured, about 10 000 of whom die. Road traffic crashes and violence are the leading causes. The global number of road deaths is forecast to rise by 65% between 2000 and 2020 and the number of violent deaths has increased steadily, with the 20th century being the most violent on record. Despite the best preventive efforts, providing effective trauma care will remain a major challenge for healthcare professionals. There is considerable potential to improve trauma outcomes by using clinical audit to increase the implementation of evidence based interventions in trauma services.3 However, for many trauma care interventions, the balance of risks and benefits is uncertain and they must be assessed in randomised trials before being implemented.
Compared with the disease burden there is a dearth of clinical trials in trauma care and the existing trials are small, contributing to uncertainty about effectiveness (see table).4 For example, few if any of the pharmacological treatments for brain and spinal cord injury have ever been proved to be effective.5 To avoid random errors, trials must recruit sufficient numbers of patients, implying the need for large international collaborative trials. The CRASH trial, run by the UK's Medical Research Council, was designed to confirm or refute the modest but promising effects of corticosteroids on outcome after traumatic brain injury by recruiting 20 000 patients. The trial was stopped after 10 000 patients had been recruited from 239 hospitals in 49 countries. The effect of corticosteroids was a highly significant relative increase of 18% in all cause mortality.6 It has been estimated that 10 000 patients with head injuries may have died because of the inappropriate administration of corticosteroids over the past 30 years.7
Disease burden and evidence from controlled trials for main categories of human disease in sub-Saharan Africa
Large international trials, such as the CRASH trial, also have advantages when it comes to disseminating results. Small trials can remain unpublished, contributing to publication bias. This is less likely with large trials.8 In international trials collaborators around the world have an investment in the results and disseminate them locally. Press releases sent by the national coordinators ensured that the results of the CRASH trial were reported in newspapers in over 20 countries. Also, participating hospitals are more likely to implement the results.9
There are several obstacles to conducting large trauma trials, some relating to the subject—trauma—and some common to all large trials. Funding for trauma research is less than for almost any other cause of human suffering. A WHO study compared the level of research funding with current and projected (2020) disease burdens.10 The results showed clearly the relative underfunding of research on road traffic injuries.
Doctors in many countries would collaborate in international trauma trials but there are no well established ways for bringing clinical trials to their attention. Investigators try to get editorials about trials published and will present trial protocols at conferences, but some journals are reluctant to advertise trials or are unwilling to publish editorials when the authors have a stake in the trial they are writing about, which they necessarily do.
People conducting large trials must now negotiate a large number of regulatory, ethical, and logistic hurdles, not least the good clinical practice (GCP) requirements, which are geared towards the development of drugs.11 Without a secure evidence base for doing so, the demands of the good clinical practice procedures are being indiscriminately applied not just to the drug industry trials they were designed for but to clinical trials of all types of interventions and to independent investigator-led non-commercially funded studies as well.
For example, the GCP emphasis on the monitoring and auditing of trial data might not be the best use of the scarce resources for large trials, as well as generating thousands of miles of unnecessary travel, when statistical approaches to monitoring may be more effective and more appropriate. Trauma care trials also have special circumstances and few countries have legislation in place to handle them. These trials take place in emergency situations, require quick decisions for early interventions, and include patients who are unable to give informed consent (and who usually are not accompanied by anyone who can make decisions for them). Few countries have legislation in place for the special circumstances in such trauma trials, and, as a result, trauma patients are unfairly denied the benefits of medical research. Servicing the numerous ethics committees involved in a large multicentre trial also has huge resource implications and can involve long delays. The CRASH trial collaborators completed over 500 ethics application forms.
University promotion is often related to the number of publications on which the researcher is first author. This encourages competition rather than collaboration. Collaborative trials often cite the collaborative group rather than individuals. Some journals accept this model but problems still arise in indexing.12 Citing as authors only a writing group is not a fair way of apportioning responsibility or credit. Reward systems favour small trials with named authors even though this increases the risk of inappropriate inferences due to the play of chance and publication bias.
There is an urgent need to improve the evidence base for trauma care. Large trials can provide important answers, but to wage war on uncertainty we need large collaborations of equals rather than small groups of individualists. Doctors internationally can join these collaborations but we need ways to bring trials to their attention, to reduce the regulatory burden, and to reward collaboration. Most importantly, the mismatch between the funding for trauma research and the burden of injury must be addressed.
Ian Roberts, professor of epidemiology and public health
(ian.roberts@lshtm.ac.uk)
London School of Hygiene and Tropical Medicine, London WC1E 7HT
Haleema Shakur, trial manager, Phil Edwards, statistician
London School of Hygiene and Tropical Medicine, London WC1E 7HT
David Yates, professor of emergency medicine
University of Manchester, Manchester M6 8HD
Peter Sandercock, professor of neurology
University of Edinburgh, Edinburgh EH4 2XU
Competing interests: IR, HS, and PE work on the CRASH-2 trial, a large international trauma trial, and are seeking further funding for this trial.
References
Murray CJL, Lopez AD. Global health statistics: a compendium of incidence, prevalence and mortality estimates for over 200 conditions. Boston: Harvard University Press, 1996.
Murray CJL, Lopez AD. Alternative projections of mortality and disability by cause 1990-2020: global burden of disease study. Lancet 1997;349: 1498-1504.
Lecky F, Woodford M, Yates DW. Trends in trauma care in England and Wales 1989-97. UK Trauma Audit and Research Network. Lancet 2000;355: 1771-5.
Isaakidis P, Swingler GH, Pienaar E, Volmink J, Ioannidis J. Relation between burden of disease and randomised evidence in sub-Saharan Africa: survey of research. BMJ 2002;324: 702.
Roberts I, Schierhout G, Alderson P. Absence of evidence for the effectiveness of five interventions routinely used in the intensive care management of severe head injury: a systematic review. J Neurol Neurosurg Psychiatry 1998;65: 729-33.
The CRASH Trial Collaborators: Effect of intravenous corticosteroids on death within 14 days in 10 008 adults with clinically significant head injury (MRC CRASH Trial): a randomised placebo-controlled trial. Lancet 2004;364: 1321-8.
Sauerland S, Maegele M. A CRASH landing in severe head injury. Lancet 2004;364: 1291-2.
Dickersin K. How important is publication bias? A synthesis of available data. AIDS Educ Prev 1997;9(1Suppl): 15-21.
Ketley D, Woods K. Impact of clinical trials on clinical practice: example of thrombolysis for acute myocardial infarction. Lancet 1993;342: 891-4.
Ad Hoc Committee on Health Research Relating to Future Intervention Options. Investing in health research and development. Geneva: WHO, 1996.
Grimes DA, Hubacher D, Nanda K, Schulz KF, Moher D, Altman DG. The Good Clinical Practice guideline: a bronze standard for clinical research. Lancet 2005;366: 172-4.
Dickersin K, Scherer R, Suci ES, Gil-Montero M. Problems with indexing and citation of articles with group authorship. JAMA 2002;287: 2772-4.
For people aged 5-45 years trauma is second only to HIV/AIDS as a cause of death.1 2 Every day world wide over 300 000 people are severely injured, about 10 000 of whom die. Road traffic crashes and violence are the leading causes. The global number of road deaths is forecast to rise by 65% between 2000 and 2020 and the number of violent deaths has increased steadily, with the 20th century being the most violent on record. Despite the best preventive efforts, providing effective trauma care will remain a major challenge for healthcare professionals. There is considerable potential to improve trauma outcomes by using clinical audit to increase the implementation of evidence based interventions in trauma services.3 However, for many trauma care interventions, the balance of risks and benefits is uncertain and they must be assessed in randomised trials before being implemented.
Compared with the disease burden there is a dearth of clinical trials in trauma care and the existing trials are small, contributing to uncertainty about effectiveness (see table).4 For example, few if any of the pharmacological treatments for brain and spinal cord injury have ever been proved to be effective.5 To avoid random errors, trials must recruit sufficient numbers of patients, implying the need for large international collaborative trials. The CRASH trial, run by the UK's Medical Research Council, was designed to confirm or refute the modest but promising effects of corticosteroids on outcome after traumatic brain injury by recruiting 20 000 patients. The trial was stopped after 10 000 patients had been recruited from 239 hospitals in 49 countries. The effect of corticosteroids was a highly significant relative increase of 18% in all cause mortality.6 It has been estimated that 10 000 patients with head injuries may have died because of the inappropriate administration of corticosteroids over the past 30 years.7
Disease burden and evidence from controlled trials for main categories of human disease in sub-Saharan Africa
Large international trials, such as the CRASH trial, also have advantages when it comes to disseminating results. Small trials can remain unpublished, contributing to publication bias. This is less likely with large trials.8 In international trials collaborators around the world have an investment in the results and disseminate them locally. Press releases sent by the national coordinators ensured that the results of the CRASH trial were reported in newspapers in over 20 countries. Also, participating hospitals are more likely to implement the results.9
There are several obstacles to conducting large trauma trials, some relating to the subject—trauma—and some common to all large trials. Funding for trauma research is less than for almost any other cause of human suffering. A WHO study compared the level of research funding with current and projected (2020) disease burdens.10 The results showed clearly the relative underfunding of research on road traffic injuries.
Doctors in many countries would collaborate in international trauma trials but there are no well established ways for bringing clinical trials to their attention. Investigators try to get editorials about trials published and will present trial protocols at conferences, but some journals are reluctant to advertise trials or are unwilling to publish editorials when the authors have a stake in the trial they are writing about, which they necessarily do.
People conducting large trials must now negotiate a large number of regulatory, ethical, and logistic hurdles, not least the good clinical practice (GCP) requirements, which are geared towards the development of drugs.11 Without a secure evidence base for doing so, the demands of the good clinical practice procedures are being indiscriminately applied not just to the drug industry trials they were designed for but to clinical trials of all types of interventions and to independent investigator-led non-commercially funded studies as well.
For example, the GCP emphasis on the monitoring and auditing of trial data might not be the best use of the scarce resources for large trials, as well as generating thousands of miles of unnecessary travel, when statistical approaches to monitoring may be more effective and more appropriate. Trauma care trials also have special circumstances and few countries have legislation in place to handle them. These trials take place in emergency situations, require quick decisions for early interventions, and include patients who are unable to give informed consent (and who usually are not accompanied by anyone who can make decisions for them). Few countries have legislation in place for the special circumstances in such trauma trials, and, as a result, trauma patients are unfairly denied the benefits of medical research. Servicing the numerous ethics committees involved in a large multicentre trial also has huge resource implications and can involve long delays. The CRASH trial collaborators completed over 500 ethics application forms.
University promotion is often related to the number of publications on which the researcher is first author. This encourages competition rather than collaboration. Collaborative trials often cite the collaborative group rather than individuals. Some journals accept this model but problems still arise in indexing.12 Citing as authors only a writing group is not a fair way of apportioning responsibility or credit. Reward systems favour small trials with named authors even though this increases the risk of inappropriate inferences due to the play of chance and publication bias.
There is an urgent need to improve the evidence base for trauma care. Large trials can provide important answers, but to wage war on uncertainty we need large collaborations of equals rather than small groups of individualists. Doctors internationally can join these collaborations but we need ways to bring trials to their attention, to reduce the regulatory burden, and to reward collaboration. Most importantly, the mismatch between the funding for trauma research and the burden of injury must be addressed.
Ian Roberts, professor of epidemiology and public health
(ian.roberts@lshtm.ac.uk)
London School of Hygiene and Tropical Medicine, London WC1E 7HT
Haleema Shakur, trial manager, Phil Edwards, statistician
London School of Hygiene and Tropical Medicine, London WC1E 7HT
David Yates, professor of emergency medicine
University of Manchester, Manchester M6 8HD
Peter Sandercock, professor of neurology
University of Edinburgh, Edinburgh EH4 2XU
Competing interests: IR, HS, and PE work on the CRASH-2 trial, a large international trauma trial, and are seeking further funding for this trial.
References
Murray CJL, Lopez AD. Global health statistics: a compendium of incidence, prevalence and mortality estimates for over 200 conditions. Boston: Harvard University Press, 1996.
Murray CJL, Lopez AD. Alternative projections of mortality and disability by cause 1990-2020: global burden of disease study. Lancet 1997;349: 1498-1504.
Lecky F, Woodford M, Yates DW. Trends in trauma care in England and Wales 1989-97. UK Trauma Audit and Research Network. Lancet 2000;355: 1771-5.
Isaakidis P, Swingler GH, Pienaar E, Volmink J, Ioannidis J. Relation between burden of disease and randomised evidence in sub-Saharan Africa: survey of research. BMJ 2002;324: 702.
Roberts I, Schierhout G, Alderson P. Absence of evidence for the effectiveness of five interventions routinely used in the intensive care management of severe head injury: a systematic review. J Neurol Neurosurg Psychiatry 1998;65: 729-33.
The CRASH Trial Collaborators: Effect of intravenous corticosteroids on death within 14 days in 10 008 adults with clinically significant head injury (MRC CRASH Trial): a randomised placebo-controlled trial. Lancet 2004;364: 1321-8.
Sauerland S, Maegele M. A CRASH landing in severe head injury. Lancet 2004;364: 1291-2.
Dickersin K. How important is publication bias? A synthesis of available data. AIDS Educ Prev 1997;9(1Suppl): 15-21.
Ketley D, Woods K. Impact of clinical trials on clinical practice: example of thrombolysis for acute myocardial infarction. Lancet 1993;342: 891-4.
Ad Hoc Committee on Health Research Relating to Future Intervention Options. Investing in health research and development. Geneva: WHO, 1996.
Grimes DA, Hubacher D, Nanda K, Schulz KF, Moher D, Altman DG. The Good Clinical Practice guideline: a bronze standard for clinical research. Lancet 2005;366: 172-4.
Dickersin K, Scherer R, Suci ES, Gil-Montero M. Problems with indexing and citation of articles with group authorship. JAMA 2002;287: 2772-4.