- Email: [email protected]
Review Clinical Trials
INTERNATIONAL CONNECTIONS
Review Clinical Trials Margo A. Pritchard, RM, ANN, BA, PhD and Carole Kenner, PhD, RNC-NIC, FAAN
Our world is shrinking owing to computerized linkages and the mobility of society. Information is shared rapidly around the world. Issues surrounding newborn and infant nursing are global. In efforts to acknowledge the international community, each Newborn and Infant Nursing Review issue will feature a column that highlights care-related issues from a featured country or region of the world. This article focuses on Australia. Keywords: Clinical trials; Neonates; Preterm; Systematic review
Newborn and infant health issues are global ones. To review issues occurring in different areas of the world, a different area of the globe will be featured that addresses Newborn and Infant Nursing Review's theme-oriented topic. This month, Australia will be featured. Our guest author is Dr Margo A Pritchard, RN, RM, ANN, BA, PhD, a Principal Maternal and Perinatal Clinical Trialist at the Perinatal Research Centre, Women's and Newborn Services, Royal Brisbane Women's Hospital and The University of Queensland Centre for Clinical Research. 1 This month's article focuses on Clinical Trials in Neonates: An Evolving Methodology.
Clinical Trials in Neonates: An Evolving Methodology Of the US $5.3 trillion allocated annually to health systems, 20% to 40% is currently wasted through health care inefficiency, including inefficient use of treatment interventions. 1 Poorly researched 2 and used health care interventions are costly 1 and implicated in the estimates of avoidable neonatal deaths (70% of the 4 million), 3 stillbirths (40% of the 3 million), 4 disability (5.9% of the worlds Disability Life Adjusted Life Years), 5 and poor development in low- and middle- (N200 From the Perinatal Research Centre, Women's and Newborn Services, Royal Brisbane Women's Hospital, The University of Queensland Centre for Clinical Research, Level 6, Ned Hanlon Building, Butterfield Street, Herston, 4029 Australia; Bouvé College of Health Sciences, Northeastern University, 94 Lyall Terrace, West Roxbury, MA 02132; and Council of International Neonatal Nurses, Inc., 94 Lyall Terrace, West Roxbury, MA 02132. Address correspondence to Margo A. Pritchard, Perinatal Research Centre, Women's and Newborn Services, Royal Brisbane Women's Hospital, The University of Queensland Centre for Clinical Research, Level 6, Ned Hanlon Building, Butterfield St, Herston, 4029 Australia. Tel.: +61 7 3636 2121/0438 660 494(Mobile). E-mails: [email protected], [email protected]. URL: http://www.uqccr.uq.edu.au (M.A. Pritchard). Crown Copyright © 2012 Published by Elsevier Inc. All rights reserved. 1527-3369/1203-0471$36.00/0 http://dx.doi.org/10.1053/j.nainr.2012.06.006
million children) 6 and high-income countries. 7 Although most of this burden is carried by poorer countries, much of the research deals with neonatal care in high-income countries. Redressing this imbalance has been slow particularly in terms of the paucity of publicly funded research on disease burden 8 and treatment evaluation in general (b10% of global US $100 billion annual biomedical research budget). 2 Clearly, decisions in health care intervention are dependent on political, social, economic, and industry circumstances. Reliable scientific evidence is one important and fundamental component of this decision-making process. The scientific application of clinical trial methodology is well established in providing reliable information on effective health care intervention. Our responsibility is to ensure the scientific integrity and efficient application of clinical trials to a range of treatment interventions to improve neonatal outcomes. This column will focus on clinical trial registries, research networks, and systematic reviews as 3 important vehicles in meeting that responsibility in today's environment. 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 (World Health Organization [WHO] 9 /International Committee of Medical Journal Editors [ICMJE] clinical trial definition). 10
Demanding Evidence The primary goal of clinical trials is to provide evidence on health care interventions—in terms of its (1) efficacy, that is, proof of principle and (2) effectiveness, that is, does it work in a clinical setting—to answer questions and guide management. All trials need to be justified as ethical and requiring Human Research Ethics Committee approval, plausible in light of similar research, which is systematically reviewed, methodologically sound, and reported according to the Consolidated Standards of Reporting Trials (CONSORT) statement (http://
www.equator-network.organd) available to all health care users through peer-reviewed publication. Trials should be conducted in accordance with legislative and good clinical practice guidelines and be registered. Failing to meet the demands of these requirements will threaten the scientific integrity and usefulness of a clinical trial. Registering clinical trials has been a major step in addressing this challenge. Clinical trials…should be registered, including early phase uncontrolled trials (phase I) in patients or healthy volunteers (WHO recommendation 9/ICMJE policy). 10
Clinical Trials Registries Our reliance on clinical trials as an essential source of evidence for health interventions is too often undermined by poor scientific integrity and accessibility. 11-13 Recent reports suggest that design and publication bias exists in up to 85% of clinical trials. 2 Openaccess prospective registration of clinical trials has been a significant move toward improving trial integrity and quantification of trial research. A standardised data set of information is now required for trial registration and is publicly available on a global level through the WHO International Clinical Trial Registry Platform (http://apps.who.int/trialsearch/). Currently, 14 international clinical trial registries contribute 147806 trials to the WHO Platform. The WHO-endorsed trial registration is now mandatory for publication in ICMJE (http://www.icmje.org/member) journals and a requirement for government research funding in Australia (http://www.nhmrc.gov.au/) and Canada (http://www. cihr-irsc.gc.ca/). More recently, the revised Declaration of Helsinki in 2008 and revised CONSORT in 2010 14 now endorse prospective trial registration. Although the WHO Platform is gaining momentum and providing a greater level of trial transparency, its impact on all aspects of trial integrity have yet to be fully realized and evaluated. 2,11 Registry information is proving useful in assessing clinical trial research activity in various areas of neonatal health care. Recent registry data on drug therapy trials have been used to assess current national and international strategies to improve drug research in off-label and new drug development in neonates. Recent legislation in Europe (http://www.ema.europa.eu/) and America (http://www.fda.gov/has) broadened the capacity for assessment of drug safety and efficacy in neonates. Registry data monitoring in America and Europe has shown a consistently slow research response in drug therapy trials in neonates to these strategies in terms of quantity (in America by 2009 only 6% of 6788 pediatric drugs studied involved neonates) 15 and priorities (in Europe only 4 of 25 European Medicines Agency priority list for studies in off-label paediatric drugs were being studied). 16,17 Monitoring the pace of these strategies in the broader context of drug development and neonatal health priorities are an important step in driving efficiencies in research and therapy intervention resources worldwide. Registry data information to assess the research situation in nondrug or device interventions has received less attention. 18 More than 20 years ago, Jack Sinclair identified several areas including attachment-behaviour as “under researched” in neonates. 19 In light
NEWBORN
of this, we searched the 26631 registered trials in the WHO Clinical Trials in Children portal to estimate a broad breakdown of trials in neonates. We used the search term “neonat,” which revealed 633 trials of which 185 are “recruiting” and 57 of these were “registered” in 2011. Of the 57 trials, we categorized 32 as other-medicalsurgical, 23 as drug, and 2 as behavioural-attachment–based interventions. Evaluating behaviour-based interventions are challenging; however, many nondrug therapies (eg, developmental care, psychodynamic) have a well-documented disease impact and should qualify for clinical trials research in neonates broadening intervention options for a range of neonatal disease. What we know about effective and efficient intervention management in neonates is largely derived from collaborative clinical trial research.
Clinical Trial Research Networks There is little doubt of the value attached to the human and material resource efficiencies and integrity that large research collaborations have brought to neonatal clinical trial research. The research that they conduct is generally reported to CONSORT standards and translated into clinical practice in developed 20–22 and developing countries (http://www.seaorchid.org). Continuing the example above, of drug therapy strategies, large research networks are thought to be best positioned to impact cost (drugs account for 30%–40% of global health spending) 1 and off-label or unlicensed drugs use in neonates (currently 90% of drug use). 23,24 The pharmacokinetic and effectiveness evidence required for market authorization of drugs in neonates is increasingly being provided by neonatal networks such as the Treat Infections in Neonates Network (www.tinn2-project.org), the Medicines for Children Research Network–Neonatal Network (www.nepeu.ox.ac.uk), and the Paediatric Pharmacological Research Unit Network (http://www.ppru.org). Drug therapy including the antibiotics, azithromycin, meropenem, and others on the WHO and national priority lists are targets for study. Network-driven drug studies are also important because they offer opportunity for comparisons with a greater range nondrug interventions and treatment options. Neonatal research networks have also been effective platforms for designing large nondrug neonatal trials particularly for interventions, which have small, but important, effect differences. The NeOProM collaboration offers an example of a pragmatic study in neonatal oxygenation. NeOProM uses a prospective meta-analysis (PMA) of individual patient data from five similar trials. Prospective meta-analysis enables the detection of a 4% difference in death or disability, with high precision across subgroups, in a sample of 5000 preterm neonates. 25 Prospective meta-analysis is important because we are unlikely to see the large survival (40%) advantage of earlier trials (eg, surfactant, thermoregulation), and these new methodologies will ensure that we can continue to answer more questions with small but important outcome effects. Those who say that systematic reviews and meta-analyses are not “proper research” are wrong.—Ian Chalmers, 2005. 26
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Systematic Reviews Systematic reviews are the most frequently cited form of clinical research. 2 An estimated 2500 systematic reviews, involving 33700 studies are indexed annually on Medline, with 20% of them originating in the Cochrane Database of Systematic Reviews (http://www.cochrane.org/). 18 Theoretically, it is well recognized that clinical trials of health care interventions should be designed and reported in the context of a systematic review of related studies. However, clinical trials have remained poorly correlated with published systematic reviews since 1997. 11 In addition, Cochrane reviews, compared with the large number of non-Cochrane reviews, are reported to be significantly less biased and of greater quality. 27 Although most searches on the Cochrane data base are for nondrug interventions, 2 the most common reviews are for pharmaceuticals, accounting for 63% of all trials, whereas educational, physical, and behavioral account individually for 2% to 3% of all reviews conducted. 18 This same trend is seen in the Cochrane Neonatal Group (http://neonatal.cochrane. org/). However, the trend is different in other well-used, evidencebased portals. Searching for reviews of effectiveness in neonates in The Joanna Briggs Institute (http://www.joannabriggs.edu.au/), a source of nursing based systematic reviews, reveals 22 entries of which only five are drug related, and a search in PEDro, the Physiotherapy Evidence Base data base, (http://www.pedro.org. au/) revealed 28 entries, most of which are Cochrane reviews. In a sense, systematic reviews have provided a “clearing house” function on past clinical trials to simplify and facilitate evidence-based decisions on treatment interventions. More recently, a trend for identifying global priorities for Cochrane systematic review 28 and the development of more sophisticated approaches such as PMA are poised to push integrity and the usefulness of interventions in neonatal care into better alignment in the future. “A diversity of methodological approaches… should influence decisions about health care interventions and policy”.—Sir Michael Rawlins, 2008. 29
Conclusion Sir Michael Rawlins' comment serves to remind us of the breadth and complexity of providing evidence-based health and the need to improve and evolve our methodologies if we are to impact health outcomes. As neonatal nurses, we contribute to all levels of care and are well placed to continue exploring neglected fields of neonatal health care that would be suitably assessed by clinical trials. Through greater collaborations, we can broaden the range of quality intervention options available in clinical practice.
References 1. The World Health Report: Health Systems Financing: the path to universal coverage Geneva, Switzerland WHO; 2010.
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2. Chalmers I, Glasziou P. Avoidable waste in the production and reporting of research evidence. Lancet. 2009:374. 3. Knippenberg R, Lawn JE, Darmstadt GL, et al. Systematic scaling up of neonatal care in countries. Lancet. 2005;365. 4. Pattinson R, Kerber K, Buchmann E, et al. Stillbirths: how can health systems deliver for mothers and babies? Lancet. 2011;377:1610. 5. Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray CJ. Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data. Lancet. 2006;367:1747–1757. 6. Grantham-McGregor S, Cheung YB, Cueto S, et al. Developmental potential in the first 5 years for children in developing countries. Lancet. 2007;369. 7. Keating DP, Hertzman C. Developmental Health and the Wealth of Nations: social, biological and educational dynamics. New York: The Guildford Press; 1999. 8. Perel P, Miranda JJ, Ortiz Z, Casas JP. Relation between the global burden of disease and randomized clinical trials conducted in Latin America published in the five leading medical journals. PLoS One. 2008;3. 9. World Health Organisation. International Clinical Trials Registry Platform (ICTRP) http://www.who.int/ictrp/en/ [Accessed 27 Janurary 2012]. 10. Clinical trial registration: a statement from the International Committee of Medical Journal Editors. http://www.icmje. org/clin_trial.pdf [Accessed 28 January 2012]. 11. Clarke M, Hopewell S, Chalmers I. Clinical trials should begin and end with systematic reviews of relevant evidence: 12 years and waiting. Lancet. 2010;376. 12. Glasziou P, Chalmers I, Altman DG. Taking healthcare interventions from trial to practice. BMJ. 2010;13. 13. Wood L, Egger M, Gluud LL, et al. Empirical evidence of bias in treatment effect estimates in controlled trials with different interventions and outcomes: meta-epidemiological studies. BMJ. 2008;336. 14. Schulz KF, Altman DG, Moher D. CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials. PLoS Med. 2010;7. 15. Ward RM, Kern SE. Clinical trials in neonates: a therapeutic imperative. Clin Pharmacol Ther. 2009;86. 16. Pandolfini C, Bonati M, Sammons HM. Registration of trials in children: update of current international initiatives. Arch Dis Child. 2009;94. 17. Conroy S, McIntyre J. The use of unlicensed and off-label medicines in the neonate. Semin Fetal Neonatal Med. 2005;10. 18. Davey J, Turner RM, Clarke MJ, Higgins JP. Characteristics of meta-analyses and their component studies in the Cochrane Database of Systematic Reviews: a cross-sectional, descriptive analysis. BMC Med Res Methodol. 2011;11. 19. Sinclair J, Bracken M. Effective care of the newborn infant. Oxford: Oxford University Press; 1992. 20. Horbar JD, Carpenter JH, Buzas J, et al. Collaborative quality improvement to promote evidence based surfactant for preterm infants: a cluster randomised trial. BMJ. 2004;329.
VOLUME 12, NUMBER 3, www.nainr.com
21. Lee SK, Aziz K, Singhal N, et al. Improving the quality of care for infants: a cluster randomized controlled trial. CMAJ. 2009;181:469. 22. A multicenter, randomized trial comparing synthetic surfactant with modified bovine surfactant extract in the treatment of neonatal respiratory distress syndrome. Vermont-Oxford Neonatal Network. Pediatrics. 1996;97. 23. O'Donnell CP, Stone RJ, Morley CJ. Unlicensed and offlabel drug use in an Australian neonatal intensive care unit. Pediatrics. 2002;110. 24. Conroy C. Association between licence status and medication errors. Arch Dis Child. 2011;96.
25. Askie LM, Brocklehurst P, Darlow BA, et al. NeOProM: neonatal oxygenation prospective meta-analysis collaboration study protocol. BMC Pediatr. 2011;11:6. 26. Chalmers I. Academia's failure to support systematic reviews. Lancet. 2005;365. 27. Moher D, Tetzlaff J, Tricco AC, Sampson M, Altman DG. Epidemiology and reporting characteristics of systematic reviews. PLoS Med. 2007;4:78. 28. Doyle J, Waters E, Yach D, et al. Global priority setting for Cochrane systematic reviews of health promotion and public health research. J Epidemiol Community Health. 2005;59. 29. Rawlins M. De testimonio: on the evidence for decisions about the use of therapeutic interventions. Lancet. 2008;372.
Erratum McGrath J, Cone S, Samra H. Neuroprotection in the Preterm Infant: Further Understanding of the Short- and Long-term Implications for Brain Development. Newborn & Infant Nursing Reviews [serial online]. September 2011;11(3):109–112. In the published version of this article, there was a failure to cite and properly attribute the following manuscript:
Pickler R, McGrath J, Reyna, B, McCain, N, Lewis, M, Cone, S, Wetzel, P, Best A, et al. A model of neurodevelopmental risk and protection for preterm infants. Journal Of Perinatal & Neonatal Nursing [serial online]. October 2010;24(4):356–365. A Model of Neurodevelopmental Risk and Protection for Preterm Infants The authors regret the error.
DOI of original article: http://dx.doi.org/10.1053/j.nainr.2011.07.002. © 2012 Elsevier Inc. All rights reserved. 1527-3369/00104-3$36.00/0 http://dx.doi.org/10.1053/j.nainr.2012.08.001
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Review Clinical Trials Margo A. Pritchard, RM, ANN, BA, PhD and Carole Kenner, PhD, RNC-NIC, FAAN
Our world is shrinking owing to computerized linkages and the mobility of society. Information is shared rapidly around the world. Issues surrounding newborn and infant nursing are global. In efforts to acknowledge the international community, each Newborn and Infant Nursing Review issue will feature a column that highlights care-related issues from a featured country or region of the world. This article focuses on Australia. Keywords: Clinical trials; Neonates; Preterm; Systematic review
Newborn and infant health issues are global ones. To review issues occurring in different areas of the world, a different area of the globe will be featured that addresses Newborn and Infant Nursing Review's theme-oriented topic. This month, Australia will be featured. Our guest author is Dr Margo A Pritchard, RN, RM, ANN, BA, PhD, a Principal Maternal and Perinatal Clinical Trialist at the Perinatal Research Centre, Women's and Newborn Services, Royal Brisbane Women's Hospital and The University of Queensland Centre for Clinical Research. 1 This month's article focuses on Clinical Trials in Neonates: An Evolving Methodology.
Clinical Trials in Neonates: An Evolving Methodology Of the US $5.3 trillion allocated annually to health systems, 20% to 40% is currently wasted through health care inefficiency, including inefficient use of treatment interventions. 1 Poorly researched 2 and used health care interventions are costly 1 and implicated in the estimates of avoidable neonatal deaths (70% of the 4 million), 3 stillbirths (40% of the 3 million), 4 disability (5.9% of the worlds Disability Life Adjusted Life Years), 5 and poor development in low- and middle- (N200 From the Perinatal Research Centre, Women's and Newborn Services, Royal Brisbane Women's Hospital, The University of Queensland Centre for Clinical Research, Level 6, Ned Hanlon Building, Butterfield Street, Herston, 4029 Australia; Bouvé College of Health Sciences, Northeastern University, 94 Lyall Terrace, West Roxbury, MA 02132; and Council of International Neonatal Nurses, Inc., 94 Lyall Terrace, West Roxbury, MA 02132. Address correspondence to Margo A. Pritchard, Perinatal Research Centre, Women's and Newborn Services, Royal Brisbane Women's Hospital, The University of Queensland Centre for Clinical Research, Level 6, Ned Hanlon Building, Butterfield St, Herston, 4029 Australia. Tel.: +61 7 3636 2121/0438 660 494(Mobile). E-mails: [email protected], [email protected]. URL: http://www.uqccr.uq.edu.au (M.A. Pritchard). Crown Copyright © 2012 Published by Elsevier Inc. All rights reserved. 1527-3369/1203-0471$36.00/0 http://dx.doi.org/10.1053/j.nainr.2012.06.006
million children) 6 and high-income countries. 7 Although most of this burden is carried by poorer countries, much of the research deals with neonatal care in high-income countries. Redressing this imbalance has been slow particularly in terms of the paucity of publicly funded research on disease burden 8 and treatment evaluation in general (b10% of global US $100 billion annual biomedical research budget). 2 Clearly, decisions in health care intervention are dependent on political, social, economic, and industry circumstances. Reliable scientific evidence is one important and fundamental component of this decision-making process. The scientific application of clinical trial methodology is well established in providing reliable information on effective health care intervention. Our responsibility is to ensure the scientific integrity and efficient application of clinical trials to a range of treatment interventions to improve neonatal outcomes. This column will focus on clinical trial registries, research networks, and systematic reviews as 3 important vehicles in meeting that responsibility in today's environment. 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 (World Health Organization [WHO] 9 /International Committee of Medical Journal Editors [ICMJE] clinical trial definition). 10
Demanding Evidence The primary goal of clinical trials is to provide evidence on health care interventions—in terms of its (1) efficacy, that is, proof of principle and (2) effectiveness, that is, does it work in a clinical setting—to answer questions and guide management. All trials need to be justified as ethical and requiring Human Research Ethics Committee approval, plausible in light of similar research, which is systematically reviewed, methodologically sound, and reported according to the Consolidated Standards of Reporting Trials (CONSORT) statement (http://
www.equator-network.organd) available to all health care users through peer-reviewed publication. Trials should be conducted in accordance with legislative and good clinical practice guidelines and be registered. Failing to meet the demands of these requirements will threaten the scientific integrity and usefulness of a clinical trial. Registering clinical trials has been a major step in addressing this challenge. Clinical trials…should be registered, including early phase uncontrolled trials (phase I) in patients or healthy volunteers (WHO recommendation 9/ICMJE policy). 10
Clinical Trials Registries Our reliance on clinical trials as an essential source of evidence for health interventions is too often undermined by poor scientific integrity and accessibility. 11-13 Recent reports suggest that design and publication bias exists in up to 85% of clinical trials. 2 Openaccess prospective registration of clinical trials has been a significant move toward improving trial integrity and quantification of trial research. A standardised data set of information is now required for trial registration and is publicly available on a global level through the WHO International Clinical Trial Registry Platform (http://apps.who.int/trialsearch/). Currently, 14 international clinical trial registries contribute 147806 trials to the WHO Platform. The WHO-endorsed trial registration is now mandatory for publication in ICMJE (http://www.icmje.org/member) journals and a requirement for government research funding in Australia (http://www.nhmrc.gov.au/) and Canada (http://www. cihr-irsc.gc.ca/). More recently, the revised Declaration of Helsinki in 2008 and revised CONSORT in 2010 14 now endorse prospective trial registration. Although the WHO Platform is gaining momentum and providing a greater level of trial transparency, its impact on all aspects of trial integrity have yet to be fully realized and evaluated. 2,11 Registry information is proving useful in assessing clinical trial research activity in various areas of neonatal health care. Recent registry data on drug therapy trials have been used to assess current national and international strategies to improve drug research in off-label and new drug development in neonates. Recent legislation in Europe (http://www.ema.europa.eu/) and America (http://www.fda.gov/has) broadened the capacity for assessment of drug safety and efficacy in neonates. Registry data monitoring in America and Europe has shown a consistently slow research response in drug therapy trials in neonates to these strategies in terms of quantity (in America by 2009 only 6% of 6788 pediatric drugs studied involved neonates) 15 and priorities (in Europe only 4 of 25 European Medicines Agency priority list for studies in off-label paediatric drugs were being studied). 16,17 Monitoring the pace of these strategies in the broader context of drug development and neonatal health priorities are an important step in driving efficiencies in research and therapy intervention resources worldwide. Registry data information to assess the research situation in nondrug or device interventions has received less attention. 18 More than 20 years ago, Jack Sinclair identified several areas including attachment-behaviour as “under researched” in neonates. 19 In light
NEWBORN
of this, we searched the 26631 registered trials in the WHO Clinical Trials in Children portal to estimate a broad breakdown of trials in neonates. We used the search term “neonat,” which revealed 633 trials of which 185 are “recruiting” and 57 of these were “registered” in 2011. Of the 57 trials, we categorized 32 as other-medicalsurgical, 23 as drug, and 2 as behavioural-attachment–based interventions. Evaluating behaviour-based interventions are challenging; however, many nondrug therapies (eg, developmental care, psychodynamic) have a well-documented disease impact and should qualify for clinical trials research in neonates broadening intervention options for a range of neonatal disease. What we know about effective and efficient intervention management in neonates is largely derived from collaborative clinical trial research.
Clinical Trial Research Networks There is little doubt of the value attached to the human and material resource efficiencies and integrity that large research collaborations have brought to neonatal clinical trial research. The research that they conduct is generally reported to CONSORT standards and translated into clinical practice in developed 20–22 and developing countries (http://www.seaorchid.org). Continuing the example above, of drug therapy strategies, large research networks are thought to be best positioned to impact cost (drugs account for 30%–40% of global health spending) 1 and off-label or unlicensed drugs use in neonates (currently 90% of drug use). 23,24 The pharmacokinetic and effectiveness evidence required for market authorization of drugs in neonates is increasingly being provided by neonatal networks such as the Treat Infections in Neonates Network (www.tinn2-project.org), the Medicines for Children Research Network–Neonatal Network (www.nepeu.ox.ac.uk), and the Paediatric Pharmacological Research Unit Network (http://www.ppru.org). Drug therapy including the antibiotics, azithromycin, meropenem, and others on the WHO and national priority lists are targets for study. Network-driven drug studies are also important because they offer opportunity for comparisons with a greater range nondrug interventions and treatment options. Neonatal research networks have also been effective platforms for designing large nondrug neonatal trials particularly for interventions, which have small, but important, effect differences. The NeOProM collaboration offers an example of a pragmatic study in neonatal oxygenation. NeOProM uses a prospective meta-analysis (PMA) of individual patient data from five similar trials. Prospective meta-analysis enables the detection of a 4% difference in death or disability, with high precision across subgroups, in a sample of 5000 preterm neonates. 25 Prospective meta-analysis is important because we are unlikely to see the large survival (40%) advantage of earlier trials (eg, surfactant, thermoregulation), and these new methodologies will ensure that we can continue to answer more questions with small but important outcome effects. Those who say that systematic reviews and meta-analyses are not “proper research” are wrong.—Ian Chalmers, 2005. 26
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Systematic Reviews Systematic reviews are the most frequently cited form of clinical research. 2 An estimated 2500 systematic reviews, involving 33700 studies are indexed annually on Medline, with 20% of them originating in the Cochrane Database of Systematic Reviews (http://www.cochrane.org/). 18 Theoretically, it is well recognized that clinical trials of health care interventions should be designed and reported in the context of a systematic review of related studies. However, clinical trials have remained poorly correlated with published systematic reviews since 1997. 11 In addition, Cochrane reviews, compared with the large number of non-Cochrane reviews, are reported to be significantly less biased and of greater quality. 27 Although most searches on the Cochrane data base are for nondrug interventions, 2 the most common reviews are for pharmaceuticals, accounting for 63% of all trials, whereas educational, physical, and behavioral account individually for 2% to 3% of all reviews conducted. 18 This same trend is seen in the Cochrane Neonatal Group (http://neonatal.cochrane. org/). However, the trend is different in other well-used, evidencebased portals. Searching for reviews of effectiveness in neonates in The Joanna Briggs Institute (http://www.joannabriggs.edu.au/), a source of nursing based systematic reviews, reveals 22 entries of which only five are drug related, and a search in PEDro, the Physiotherapy Evidence Base data base, (http://www.pedro.org. au/) revealed 28 entries, most of which are Cochrane reviews. In a sense, systematic reviews have provided a “clearing house” function on past clinical trials to simplify and facilitate evidence-based decisions on treatment interventions. More recently, a trend for identifying global priorities for Cochrane systematic review 28 and the development of more sophisticated approaches such as PMA are poised to push integrity and the usefulness of interventions in neonatal care into better alignment in the future. “A diversity of methodological approaches… should influence decisions about health care interventions and policy”.—Sir Michael Rawlins, 2008. 29
Conclusion Sir Michael Rawlins' comment serves to remind us of the breadth and complexity of providing evidence-based health and the need to improve and evolve our methodologies if we are to impact health outcomes. As neonatal nurses, we contribute to all levels of care and are well placed to continue exploring neglected fields of neonatal health care that would be suitably assessed by clinical trials. Through greater collaborations, we can broaden the range of quality intervention options available in clinical practice.
References 1. The World Health Report: Health Systems Financing: the path to universal coverage Geneva, Switzerland WHO; 2010.
122
2. Chalmers I, Glasziou P. Avoidable waste in the production and reporting of research evidence. Lancet. 2009:374. 3. Knippenberg R, Lawn JE, Darmstadt GL, et al. Systematic scaling up of neonatal care in countries. Lancet. 2005;365. 4. Pattinson R, Kerber K, Buchmann E, et al. Stillbirths: how can health systems deliver for mothers and babies? Lancet. 2011;377:1610. 5. Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray CJ. Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data. Lancet. 2006;367:1747–1757. 6. Grantham-McGregor S, Cheung YB, Cueto S, et al. Developmental potential in the first 5 years for children in developing countries. Lancet. 2007;369. 7. Keating DP, Hertzman C. Developmental Health and the Wealth of Nations: social, biological and educational dynamics. New York: The Guildford Press; 1999. 8. Perel P, Miranda JJ, Ortiz Z, Casas JP. Relation between the global burden of disease and randomized clinical trials conducted in Latin America published in the five leading medical journals. PLoS One. 2008;3. 9. World Health Organisation. International Clinical Trials Registry Platform (ICTRP) http://www.who.int/ictrp/en/ [Accessed 27 Janurary 2012]. 10. Clinical trial registration: a statement from the International Committee of Medical Journal Editors. http://www.icmje. org/clin_trial.pdf [Accessed 28 January 2012]. 11. Clarke M, Hopewell S, Chalmers I. Clinical trials should begin and end with systematic reviews of relevant evidence: 12 years and waiting. Lancet. 2010;376. 12. Glasziou P, Chalmers I, Altman DG. Taking healthcare interventions from trial to practice. BMJ. 2010;13. 13. Wood L, Egger M, Gluud LL, et al. Empirical evidence of bias in treatment effect estimates in controlled trials with different interventions and outcomes: meta-epidemiological studies. BMJ. 2008;336. 14. Schulz KF, Altman DG, Moher D. CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials. PLoS Med. 2010;7. 15. Ward RM, Kern SE. Clinical trials in neonates: a therapeutic imperative. Clin Pharmacol Ther. 2009;86. 16. Pandolfini C, Bonati M, Sammons HM. Registration of trials in children: update of current international initiatives. Arch Dis Child. 2009;94. 17. Conroy S, McIntyre J. The use of unlicensed and off-label medicines in the neonate. Semin Fetal Neonatal Med. 2005;10. 18. Davey J, Turner RM, Clarke MJ, Higgins JP. Characteristics of meta-analyses and their component studies in the Cochrane Database of Systematic Reviews: a cross-sectional, descriptive analysis. BMC Med Res Methodol. 2011;11. 19. Sinclair J, Bracken M. Effective care of the newborn infant. Oxford: Oxford University Press; 1992. 20. Horbar JD, Carpenter JH, Buzas J, et al. Collaborative quality improvement to promote evidence based surfactant for preterm infants: a cluster randomised trial. BMJ. 2004;329.
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21. Lee SK, Aziz K, Singhal N, et al. Improving the quality of care for infants: a cluster randomized controlled trial. CMAJ. 2009;181:469. 22. A multicenter, randomized trial comparing synthetic surfactant with modified bovine surfactant extract in the treatment of neonatal respiratory distress syndrome. Vermont-Oxford Neonatal Network. Pediatrics. 1996;97. 23. O'Donnell CP, Stone RJ, Morley CJ. Unlicensed and offlabel drug use in an Australian neonatal intensive care unit. Pediatrics. 2002;110. 24. Conroy C. Association between licence status and medication errors. Arch Dis Child. 2011;96.
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Erratum McGrath J, Cone S, Samra H. Neuroprotection in the Preterm Infant: Further Understanding of the Short- and Long-term Implications for Brain Development. Newborn & Infant Nursing Reviews [serial online]. September 2011;11(3):109–112. In the published version of this article, there was a failure to cite and properly attribute the following manuscript:
Pickler R, McGrath J, Reyna, B, McCain, N, Lewis, M, Cone, S, Wetzel, P, Best A, et al. A model of neurodevelopmental risk and protection for preterm infants. Journal Of Perinatal & Neonatal Nursing [serial online]. October 2010;24(4):356–365. A Model of Neurodevelopmental Risk and Protection for Preterm Infants The authors regret the error.
DOI of original article: http://dx.doi.org/10.1053/j.nainr.2011.07.002. © 2012 Elsevier Inc. All rights reserved. 1527-3369/00104-3$36.00/0 http://dx.doi.org/10.1053/j.nainr.2012.08.001
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