Downloaded from adc.bmj.com on June 12, 2014 - Published by group.bmj.com
Original article
Randomised controlled trials in child health in developing countries: trends and lessons over 11 years Trevor Duke,1,2 David Fuller3,4 1
Centre for International Child Health, University of Melbourne, MCRI, Royal Children’s Hospital, Parkville, Victoria, Australia 2 School of Medicine and Health Sciences, University of Papua New Guinea 3 Children’s Services, Barwon Health, Geelong, Victoria, Australia 4 Geelong Clinical school, School of Medicine, Deakin University, Geelong, Australia Correspondence to Professor Trevor Duke, Centre for International Child Health, University of Melbourne, MRCI, Royal Children’s Hospital, Flemington Road, Parkville, VIC 3052, Australia; [email protected] Received 22 November 2013 Revised 3 February 2014 Accepted 5 February 2014 Published Online First 10 March 2014
ABSTRACT Using a uniform systematic approach annually, we reviewed 1553 publications from randomised controlled trials in child health in developing countries published between July 2002 and June 2013. There were annual increases in such publications, from 38 in the 12 months to July 2003 to over 200 in each of 2012 and 2013. These trials involved children in 76 developing countries. Studies of nutrition (366 publications, 23.6%) and malaria (336 publications, 21%) predominated. 79% of nutrition trials have been of micronutrients (288 publications), with comparatively few publications related to macronutrient interventions or complimentary feeding (48 publications) or measures to improve breast feeding (20 publications). Trials of malaria have involved a comprehensive range of treatment and preventive strategies and have heralded the implementation of new interventions as routine health strategies, and reductions in malaria in each affected country in the world in the last decade. There have been a relatively small number of trials of interventions for treatment or prevention of acute respiratory infection (98 publications, 6.3%), neonatal health (64 publications, 4.1%) and tuberculosis in children (26 publications, 1.7%). In the last 5 years there has been increasing focus on non-communicable diseases such as asthma and allergy, obesity, diabetes and cardiac disease, and behavioural-developmental disorders. Mental health conditions have received little attention (21 publications, 1.4% of publications). There is increasing research activity and capacity in child health in developing countries. Some areas have been the subject of a large amount of research, and have led to the design and implementation of effective public health interventions and reduced disease burdens, while in other areas comprehensive approaches and the systematic application of research findings have been lacking.
INTRODUCTION
▸ http://dx.doi.org/10.1136/ archdischild-2014-306163
To cite: Duke T, Fuller D. Arch Dis Child 2014;99:615–620.
Since the setting of the Millennium Development Goals in 2000, substantial progress has been made in reducing child deaths worldwide.1–3 Reductions in child mortality rates have occurred in every developing country, although progress has not been evenly distributed between regions and countries and within countries.4 Much of this progress has been based on the implementation of high priority and effective interventions and approaches that can be scaled up in resource-limited settings. The evidence base for these interventions developed at a pace in 2003 with the publication of the Lancet Child Survival Series,5 6 and there have been
Duke T, et al. Arch Dis Child 2014;99:615–620. doi:10.1136/archdischild-2013-305702
numerous reviews and estimates of intervention effectiveness in the last decade. Each year, since 2003, we have published and distributed a compendium of all randomised controlled trials (RCTs) involving children in developing countries for the previous year.7 These compendia contain abstracts of all trials, arranged into topic areas. The aim is to make information rapidly available to healthcare workers and policymakers in countries where up-to-date information is difficult to access. This information is hopefully useful for revising clinical guidelines and public health policies and priorities, and for teaching evidence-based healthcare. This paper analyses 11 years of controlled trials in child health in developing countries, reporting trends in research output, priorities and lessons that can be learned.
METHODS Search and dissemination strategy The same search strategy to identify trials was applied in each of 11 years. We used PubMed, a search engine that is freely available and widely used throughout the world (http://www.ncbi.nlm.nih.gov/sites/entrez). The search strategy is reproducible by anyone with access to the Internet, Pubmed search: ((Developing countries; Developing country; Countries, developing; Developed countries; Country, developing; Countries, developed; Developed country; Country, developed; Nations, developing; Developing nations OR India OR Africa OR Asia OR South America OR Papua New Guinea OR Asia-Pacific) and (Child*)) AND (randomized controlled trial[Publication Type] OR (randomized[Title/Abstract] AND controlled[Title/ Abstract] AND trial[Title/Abstract])). Each year in July the trials published in the previous 12 months were identified, sorted and compiled into a booklet.7 By the end of August we distributed this by email to over 2000 contacts, including the heads of all national paediatric associations, the International Paediatric Association, WHO and Unicef country offices, national nursing associations and individual paediatricians, scientists and other health workers in many developing countries. The booklet was also distributed through other email networks, including Child2015; highlighted in several peer reviewed journals; and available through the website http://www.ichrc.org. Recipients were invited to distribute the booklet freely to health workers colleagues and members of their organisations. This study evaluated the published trials between 2002 and 2013. For each publication the following were recorded: author details; year of publication; 615
Downloaded from adc.bmj.com on June 12, 2014 - Published by group.bmj.com
Original article country where the trial was conducted; condition or disease that was the focus of study, and the intervention. We used the components of the PICOT format: population, intervention, comparator, and outcome. These data were entered into a spreadsheet (Microsoft Excel) for descriptive analyses. When a publication studied more than one intervention or disease, each of these was recorded. As an example, a trial of micronutrient supplements given to mothers who were HIV positive, to examine the effect on maternal weight and the birth weight of their offspring, was recorded under nutrition (micronutrients), HIV (related conditions), maternal interventions and neonatal interventions. Data were analysed using Microsoft Excel formulae and graphs were produced using Excel.
RESULTS Trends in research output A total of 1553 publications were identified from the period July 2002–June 2013 (table 1). There were 1522 original studies and 31 systematic reviews. There was a steady increase in publications from controlled trials, from 38 in the 12 months to July 2003 to over 200 in each of 2012 and 2013. These 1553 studies took place in 76 countries, from all developing regions of the world. Figure 1 shows the number of trial publications from each country for two eras (2002–2008 and 2009–2013). One thousand four hundred and seventy-eight publications were from single-country studies; 44 were from multi-country studies: 12 involved two countries; 17 involved three countries; and 15 involved more than three countries. There has been a substantial increase in trials published in the last 5 years, compared with the first 6 years. In all years researchers from the African region published the largest number of trials (figure 2). Since 2008 the numbers of publications from South Asia have increased significantly. This has been predominantly because of a substantial increase in studies conducted in India: 78 publications in 2002– 2008 and 233 in 2009–2013 (figure 1). Most studies have been conducted by researchers based predominantly in that country. Over the last decade the number and proportion of studies with a corresponding author located in the same country as the study took place has increased, from 16 (53%) in 2002–2003 to 162 (71%) in 2011–2012.
Conditions and areas studied Sixty-three topics or diseases were studied in RCTs over the last decade, however a few themes predominate (table 1). The two most common were studies of nutrition (366 RCT publications, 23.6%) and malaria (336 publications; 21.6%). An analysis of subgroups of trials in nutrition shows that the majority of publications are studies of micronutrients (288 publications). There were comparatively few publications related to macronutrient interventions or complimentary feeding (48 publications) or measures to improve breast feeding (20 publications) (figure 3). Zinc and iron were the micronutrients most commonly studied in the first half of the decade, whereas other micronutrients, particularly multiple micronutrient mixtures became more commonly trialled in the second half of the decade. Publications of controlled trials in malaria increased from 4 in 2002–2003 to 52 in 2009–2010. In the first half of the decade malaria related intervention trials were predominantly on the treatment of malaria, particularly artemisinin-based combination therapy. There has been a steady increase in publications related to malaria prevention, and in 2011–2012, studies of malaria prevention outnumbered studies of malaria treatment. Publications regarding insecticide treated bed nets have occurred 616
at a relatively steady rate throughout the decade, whereas there was a marked increase in publications related to intermittent preventive treatment since the middle part of the decade until 2011–2012, but there were no intermittent preventive treatment-related publications in 2012–2013. Publications related to malaria vaccine trials increased from 2009 to 2012. One hundred and thirty-one (8.4%) trials focused on diarrhoeal disease. Seventy-one (60.3%) were trials of prevention and 52 (39.7%) trials of treatment. Vaccines against rotavirus, shigella and cholera (23 trials, 29.1% of preventive trials), water purification (18, 22.8%) and zinc supplementation (17, 21.5%) have been the most common preventive strategies studied, while zinc supplementation (21 trials, 40.4% of treatment trials) and probiotics (12, 23.1%) have been the most common treatment strategies studied (figure 4). In contrast to high level of controlled trial activity in malaria and micronutrients, there have been a relatively small number of trials of interventions for treatment or prevention of acute respiratory infection (98 publications, 6.3%). Forty-four of these have related to treatment and 52 to prevention (figure 5) (with a further 2 related to diagnosis). Of the 44 controlled treatment trials that focused on acute respiratory infections (ARIs), 28 (63.6%) related to WHO defined ‘non-severe’ pneumonia. These trials of treatment have been most commonly related to antibiotic treatment (22 trials), with zinc supplements being the next most common intervention (11 trials), and the most common type of ARI trial in the last 2 years. ARI prevention trials have been predominantly vaccine related (22 trials, 42.3% of ARI prevention trials) with zinc supplementation the next most common preventive strategy studied (12 trials, 23.1% of prevention). There were even fewer trials related to tuberculosis in children (26 publications, 1.7% of controlled trial publications). Sixty-four controlled trial publications (4.1%) related to neonatal health (figure 6). Of these, 19 (29.7%) examined community or maternal interventions, 17 (26.6%) examined nutritional issues (most commonly micronutrient supplementation given in the antenatal or postnatal period) and 9 (14.1%) trials of acute postnatal care, including Kangaroo care. Follow-up of long-term complications of conditions encountered in the neonatal period accounted for 10 publications (15.6%), with more of these in the second half of the decade studied (figure 6).
Trends based on economic transition The impact of economic transition is seen in the attention given to non-communicable diseases (NCDs), and in increases in trial output in several countries. In the last 5 years conditions such as asthma and allergy, other NCDs (obesity, diabetes and cardiac disease), behavioural-developmental and mental health conditions have received an increased focus (table 1). Studies evaluating interventions to improve child development have received some attention (70 publications, 4.5%), however mental health has received very little attention (21 publications, 1.4% of publications) (table 1).
DISCUSSION There has been over a sevenfold increase in the number of papers published from randomised trials on child health in developing countries over the last decade. Research is one marker of the priority given to health problems, and controlled trials are only one metric of research. The number of trials for each condition and each year is not a measure of quality or impact, but it does reflect global priorities. The marked increase in trial publications since 2003 reflects how health and Duke T, et al. Arch Dis Child 2014;99:615–620. doi:10.1136/archdischild-2013-305702
Downloaded from adc.bmj.com on June 12, 2014 - Published by group.bmj.com
Original article Table 1 Number of trials in different topic areas or health conditions per year
2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 Total
Total
Nutrition
Malaria
Vaccines
HIV
Diarrhoea
ARI
Parasitic infections
Neonates
Child development
NCD*
Health education
Adolesc
TB
Mental health
32 77 85 95 123 161 157 179 195 238 211 1553
15 22 17 31 40 30 29 32 39 46 65 366
4 18 22 31 33 40 29 51 42 44 22 336
2 7 6 8 10 15 18 23 24 32 26 171
1 7 7 12 13 13 11 13 21 26 20 144
6 8 2 11 10 11 10 14 20 21 18 131
3 5 5 4 7 9 11 8 12 16 18 98
4 10 4 3 8 4 11 8 11 8 14 85
0 3 2 2 2 9 5 7 8 11 15 64
1 5 3 3 6 3 10 7 8 9 15 70
0 1 1 2 2 8 6 6 7 12 4 49
0 1 4 4 5 4 1 7 3 10 9 48
0 1 0 3 1 2 0 7 7 3 8 32
1 3 1 3 1 1 0 2 4 7 3 26
0 0 0 0 0 2 2 6 6 1 4 21
Note: a trial could classified as being in more than one topic area or health condition. *NCD (non-communicable disease): allergy, asthma, diabetes, cardiovascular disease, obesity. Adolesc, trials relevant to adolescent health; ARI, acute respiratory infection; TB, tuberculosis.
development of children in developing countries has been an increasing focus for the global health community since the setting of the Millennium Development Goal (MDG) targets. There has been increased local research capacity, as evidenced by a steadily increasing proportion of controlled trials conducted from within developing countries, and a rise in systematic reviews being conducted by developing country researchers. Of the estimated 7.6 million deaths in children younger than 5 years in 2010, pneumonia (14.1%), diarrhoea (9.9%) and malaria (7.4%) were the most common causes. Forty per cent of deaths in children under 5 years occurred in neonates, of which
preterm birth complications (14.1%), intrapartum-related complications (9.4%), and sepsis or meningitis (5.2%) were the leading causes.2 Such global mortality burden estimates have some limitations;2 8 9 common comorbidities, particularly malnutrition, diseases that cause significant morbidity but are hard to identify (such as tuberculosis), injuries and diseases occurring in older children (such as rheumatic heart disease) are often under-represented. Previous studies have reported on gaps in disease burden information for children from many developing countries.10 Comparing the number of trials with proportional mortality or global disease burden estimates allows only tentative
Figure 1 Map showing the number of trial publications from each developing country in 2002–2008 (blue circles) and 2009–2013 (red circles). Duke T, et al. Arch Dis Child 2014;99:615–620. doi:10.1136/archdischild-2013-305702
617
Downloaded from adc.bmj.com on June 12, 2014 - Published by group.bmj.com
Original article Figure 2 Region of published trials.
conclusions, and raises many questions. However this review revealed some common disease burdens that have received a lot of research focus, while other areas have received very little. The impact of the large number of trials of malaria (21.6% of all RCT publications in the last decade) is seen in the uptake of new interventions and reductions in malaria in each affected country in the world.11 A comprehensive range of treatment and preventive strategies for malaria have been studied and then implemented as routine health strategies.12 The funding of programmes to implement the results for ‘Roll Back Malaria’ is an example of the optimum benefit of research, and the rapidity with which trial results can become policy and practice in the modern era. While malaria rates are falling in developing countries, the same rates of decline are not being seen for pneumonia (with a corresponding 6.3% of all publications related to acute respiratory infection), malnutrition (3.1% of publications) or neonatal illness (4.3% of trial publications, but representing 40% of the mortality burden).13 14 Childhood tuberculosis has been particularly neglected in the metric of controlled trials (1.7% of all trial publications). Similar comprehensive approaches to the research agenda and to research-driven public health interventions as seen in malaria are needed for these other areas. If this were to happen, further progress could be made towards the Millennium Development Goals for reduction in child mortality, and the ground would be laid for the post-2015 agenda.8
The large number of controlled trial publications of nutrition (23.6% of trial publications) is due predominantly to studies of micronutrient supplementation and their trialling in a wide variety of illnesses and nutritionally at-risk populations (78.6% of nutrition trial publications were micronutrient studies). There has been much less focus on other areas in nutrition, including effective ways to treat malnutrition, ways to increase breast feeding and improve complimentary feeding, and modifying environmental effects on childhood nutrition. Even the large numbers of studies of micronutrients has not necessarily translated into coordinated public health interventions. Despite over 60 randomised trials of zinc sulfate over the last decade, less than 1% of children with diarrhoea or malnutrition in developing countries have access to zinc.15 This emphasises the need for research to be part of a comprehensive approach to implementation of public health initiatives, including research on the implementation of research findings. Over the time of this review the impact of economic transition, Western morbidities and higher-technology research has become more evident, with clinical trials from developing countries related to NCD, including obesity, diabetes, congenital heart disease, allergy and modifying risk factors in childhood for adult cardiovascular disease becoming more common. It is notable that mental health is largely neglected in clinical trials, and this may be reflected in the limited focus on mental health in public health in many developing countries.
Figure 3 Trial publications in nutrition. 618
Duke T, et al. Arch Dis Child 2014;99:615–620. doi:10.1136/archdischild-2013-305702
Downloaded from adc.bmj.com on June 12, 2014 - Published by group.bmj.com
Original article
Figure 4 Trial publications in preventative and treatment strategies for diarrhoea. For some health interventions a randomised trial is not the appropriate method; because of unfeasibility, lack of equipoise, ethical issues, high cost or limited acceptability to a community. Rigorous analyses of public health and clinical interventions can use other methods. Thus the number of RCTs is just one perspective of the research that is done and the research that is needed. We have taken a liberal view of what constitutes a RCT over the years, and included in the annual compendia the publication output of controlled non-randomised trials when that information would be of value to the readers. The Pubmed filter for RCT: “AND (randomized controlled trial[Publication Type] OR (randomized[Title/Abstract] AND controlled[Title/Abstract] AND trial[Title/Abstract]” captures many non-randomised comparison trials. The search strategy we used for identifying studies may have missed some trials. The search strategy was chosen to capture as many studies as possible that were relevant to health workers and policy makers in developing countries, using a widely and freely available search engine (Pubmed). The same search strategy was used for each of the 11 years, so it is likely that changes in numbers of publications reflect real changes that have taken place, even if a small number of studies have been missed. It should be noted that the increase in publications is an indication of increased research activity over the 11 years, but does not entirely represent the number of controlled trials conducted over that time. Several papers reporting on different aspects of many trials have been counted. There has also been an increasing trend to publish study protocols and interim results for
some larger RCTs over the last decade, and a rise in the number of online journals in that time such that the threshold for publication may be reduced. The marked rise in publication of trials from India (figure 1) partly reflects increasing capacity in research. A fourfold rise in the proportion of Pubmed-cited publications from India in the 20 years to 2008 has been previously reported, and the alignment of this reported increase with public health priorities in India has been questioned.16 The relatively much smaller number of trial publications from China may reflect that many research results from that country are published in Chinese language journals which are not cited in Pubmed. Despite the African region having the highest child health trial output in the 11 years of this review, it is notable that some countries had no trial publications, including Libya, Chad, the Central African Republic and Somalia, each of which had bloody civil wars or conflict during this time.
CONCLUSIONS There is increasing research activity and capacity in child health in developing countries. Some areas have been the subject of a large amount of research, and led directly to the design and implementation of effective public health interventions and reduced disease burdens, while in other areas comprehensive approaches and the systematic application of research findings have been lacking. In some areas which represent major disease burdens, such as malnutrition, research has been focused on narrow interventions for which controlled trials are relatively easy to conduct, rather than comprehensive approaches to trials that also address underlying causes. There are a
Figure 5 Trial publications in preventative and treatment strategies for acute respiratory infections.
Duke T, et al. Arch Dis Child 2014;99:615–620. doi:10.1136/archdischild-2013-305702
619
Downloaded from adc.bmj.com on June 12, 2014 - Published by group.bmj.com
Original article
Figure 6 Trial publications involving neonatal outcomes.
number of other conditions, such as neonatal care, pneumonia, tuberculosis and mental health, where research attention has been very low relative to burden of disease. There is a risk with the rise of transitional economy-driven research that conditions primarily affecting the children in the poorest regions of the world will be neglected. Comprehensive approaches, based on controlled trials, implementation effectiveness trials and building research capacity in these areas would have major public health benefits, and should be part of the post-2015 agenda. Contributors Each year TD compiled the annual summary of controlled trials. TD and DF designed the project, DF analysed the 11-year data, and created the graphs, and both authors wrote the paper. The authors are very grateful to Igor Balgavi (Sombor, Serbia) for preparing figure 1. Funding The Centre for International Child Health received funding through AusAID as part of the Knowledge Hubs for Health Initiative, and is a WHO Collaborating Centre for Research and Training in Child and Neonatal Health. The authors are grateful to the RE Ross Trust (Victoria) for funding support. Competing interests None.
4 5 6
7
8 9
10
11 12
Provenance and peer review Not commissioned; externally peer reviewed.
13
REFERENCES
14
1
2
3
620
Lozano R, Wang H, Foreman KJ, et al. Progress towards Millennium Development Goals 4 and 5 on maternal child mortality: an updated systematic analysis. Lancet 2011;378:1139–65. Liu L, Johnson HL, Cousens S, et al. Global, regional, and national causes of child mortality: an updated systematic review for 2010 with time trends since 2000. Lancet 2012;379(June 9):2151–61. UNICEF. Committing to child survival: a promise renewed. New York: United Nations Children’s Fund, 2012. Ref Type: Report.
15
16
You D, Wardlaw T, Salama P, et al. Levels and trends in under-5 mortality. Lancet 2010;375:100–3. Black RE, Moris SS, Bryce J. Where and why are 10 million children dying every year? Lancet 2003;361:2226–34. Jones G, Steketee RW, Black RE, et al.; The Bellagio Child Survival Study Group. How many child deaths can we prevent this year? Lancet 2003; 362:65–71. Duke T. ed Randomised trials in child health in developing countries. Editions 1–11: 2002–2013. Melbourne: International Child Health Review Collaboration, 2013. http://www.ichrc.org/evidence-0. Ref Type: Online Source. Bryce J, Boschi-Pinto C, Shibuya K, et al. WHO estimates of the causes of death in children. Lancet Infect Dis 2005;365:1152. Black RE, Cousens S, Johnson HL, et al. Global, regional, and national causes of child mortality in 2008: a systematic analysis. Lancet 2010; 375:1969–87. Rudan I, Lawn J, Cousens S, et al. Gaps in policy-relevant information on burdens of disease in children: a systematic review. Lancet 2005; 365:2031–40. World Health Organization. World Malaria Report 2012. Geneva, 2012. Ref Type: Report. Akachi Y, Atun R. Effect of investment in malaria control on child mortality in sub-Saharan Africa in 2002–2008. PLoS ONE 2013;6:e21309. Oestergaard MZ, Inoue M, Yoshida S, et al. Neonatal mortality levels for 193 countries in 2009 with trends since 1990: a systematic analysis of progress, projections, and priorities. PLoS Med 2011;8:e1001080. Fischer Walker CL, Rudan I, Liu L, et al. Global burden of childhood pneumonia and diarrhoea. Lancet 2013;381:1405–16. http://dx.doi.org/10.1016/S0140-6736 (13)60222-6(April12) Gill CJ, Young M, Schroder K, et al. Bottlenecks, barriers, and solutions: results from multicountry consultations focused on reduction of childhood pneumonia and diarrhoea deaths . Lancet 2013;381:1487–98. On-line April 12. http://dx.doi.org/ 10.1016/S0140-6736(13)60314-1 Dandona L, Katock VM, Dandona R. Research to achieve health care for all in India. Lancet 2011;377:1055–7.
Duke T, et al. Arch Dis Child 2014;99:615–620. doi:10.1136/archdischild-2013-305702
Downloaded from adc.bmj.com on June 12, 2014 - Published by group.bmj.com
Randomised controlled trials in child health in developing countries: trends and lessons over 11 years Trevor Duke and David Fuller Arch Dis Child 2014 99: 615-620 originally published online March 10, 2014
doi: 10.1136/archdischild-2013-305702
Updated information and services can be found at: http://adc.bmj.com/content/99/7/615.full.html
These include:
References
This article cites 13 articles http://adc.bmj.com/content/99/7/615.full.html#ref-list-1
Email alerting service
Receive free email alerts when new articles cite this article. Sign up in the box at the top right corner of the online article.
To request permissions go to: http://group.bmj.com/group/rights-licensing/permissions
To order reprints go to: http://journals.bmj.com/cgi/reprintform
To subscribe to BMJ go to: http://group.bmj.com/subscribe/
Downloaded from adc.bmj.com on June 12, 2014 - Published by group.bmj.com
Topic Collections
Articles on similar topics can be found in the following collections ADC Global child health (23 articles) Childhood nutrition (456 articles) Childhood nutrition (paediatrics) (245 articles) Child health (2494 articles) Child and adolescent psychiatry (paedatrics) (468 articles) Travel medicine (68 articles) Tropical medicine (infectious diseases) (83 articles) Clinical trials (epidemiology) (372 articles) Infant nutrition (including breastfeeding) (250 articles) Asthma (296 articles) Health education (384 articles) Health promotion (427 articles) Immunology (including allergy) (1377 articles) Obesity (nutrition) (218 articles) Obesity (public health) (218 articles) Reproductive medicine (586 articles) TB and other respiratory infections (435 articles)
Notes
To request permissions go to: http://group.bmj.com/group/rights-licensing/permissions
To order reprints go to: http://journals.bmj.com/cgi/reprintform
To subscribe to BMJ go to: http://group.bmj.com/subscribe/
Original article
Randomised controlled trials in child health in developing countries: trends and lessons over 11 years Trevor Duke,1,2 David Fuller3,4 1
Centre for International Child Health, University of Melbourne, MCRI, Royal Children’s Hospital, Parkville, Victoria, Australia 2 School of Medicine and Health Sciences, University of Papua New Guinea 3 Children’s Services, Barwon Health, Geelong, Victoria, Australia 4 Geelong Clinical school, School of Medicine, Deakin University, Geelong, Australia Correspondence to Professor Trevor Duke, Centre for International Child Health, University of Melbourne, MRCI, Royal Children’s Hospital, Flemington Road, Parkville, VIC 3052, Australia; [email protected] Received 22 November 2013 Revised 3 February 2014 Accepted 5 February 2014 Published Online First 10 March 2014
ABSTRACT Using a uniform systematic approach annually, we reviewed 1553 publications from randomised controlled trials in child health in developing countries published between July 2002 and June 2013. There were annual increases in such publications, from 38 in the 12 months to July 2003 to over 200 in each of 2012 and 2013. These trials involved children in 76 developing countries. Studies of nutrition (366 publications, 23.6%) and malaria (336 publications, 21%) predominated. 79% of nutrition trials have been of micronutrients (288 publications), with comparatively few publications related to macronutrient interventions or complimentary feeding (48 publications) or measures to improve breast feeding (20 publications). Trials of malaria have involved a comprehensive range of treatment and preventive strategies and have heralded the implementation of new interventions as routine health strategies, and reductions in malaria in each affected country in the world in the last decade. There have been a relatively small number of trials of interventions for treatment or prevention of acute respiratory infection (98 publications, 6.3%), neonatal health (64 publications, 4.1%) and tuberculosis in children (26 publications, 1.7%). In the last 5 years there has been increasing focus on non-communicable diseases such as asthma and allergy, obesity, diabetes and cardiac disease, and behavioural-developmental disorders. Mental health conditions have received little attention (21 publications, 1.4% of publications). There is increasing research activity and capacity in child health in developing countries. Some areas have been the subject of a large amount of research, and have led to the design and implementation of effective public health interventions and reduced disease burdens, while in other areas comprehensive approaches and the systematic application of research findings have been lacking.
INTRODUCTION
▸ http://dx.doi.org/10.1136/ archdischild-2014-306163
To cite: Duke T, Fuller D. Arch Dis Child 2014;99:615–620.
Since the setting of the Millennium Development Goals in 2000, substantial progress has been made in reducing child deaths worldwide.1–3 Reductions in child mortality rates have occurred in every developing country, although progress has not been evenly distributed between regions and countries and within countries.4 Much of this progress has been based on the implementation of high priority and effective interventions and approaches that can be scaled up in resource-limited settings. The evidence base for these interventions developed at a pace in 2003 with the publication of the Lancet Child Survival Series,5 6 and there have been
Duke T, et al. Arch Dis Child 2014;99:615–620. doi:10.1136/archdischild-2013-305702
numerous reviews and estimates of intervention effectiveness in the last decade. Each year, since 2003, we have published and distributed a compendium of all randomised controlled trials (RCTs) involving children in developing countries for the previous year.7 These compendia contain abstracts of all trials, arranged into topic areas. The aim is to make information rapidly available to healthcare workers and policymakers in countries where up-to-date information is difficult to access. This information is hopefully useful for revising clinical guidelines and public health policies and priorities, and for teaching evidence-based healthcare. This paper analyses 11 years of controlled trials in child health in developing countries, reporting trends in research output, priorities and lessons that can be learned.
METHODS Search and dissemination strategy The same search strategy to identify trials was applied in each of 11 years. We used PubMed, a search engine that is freely available and widely used throughout the world (http://www.ncbi.nlm.nih.gov/sites/entrez). The search strategy is reproducible by anyone with access to the Internet, Pubmed search: ((Developing countries; Developing country; Countries, developing; Developed countries; Country, developing; Countries, developed; Developed country; Country, developed; Nations, developing; Developing nations OR India OR Africa OR Asia OR South America OR Papua New Guinea OR Asia-Pacific) and (Child*)) AND (randomized controlled trial[Publication Type] OR (randomized[Title/Abstract] AND controlled[Title/ Abstract] AND trial[Title/Abstract])). Each year in July the trials published in the previous 12 months were identified, sorted and compiled into a booklet.7 By the end of August we distributed this by email to over 2000 contacts, including the heads of all national paediatric associations, the International Paediatric Association, WHO and Unicef country offices, national nursing associations and individual paediatricians, scientists and other health workers in many developing countries. The booklet was also distributed through other email networks, including Child2015; highlighted in several peer reviewed journals; and available through the website http://www.ichrc.org. Recipients were invited to distribute the booklet freely to health workers colleagues and members of their organisations. This study evaluated the published trials between 2002 and 2013. For each publication the following were recorded: author details; year of publication; 615
Downloaded from adc.bmj.com on June 12, 2014 - Published by group.bmj.com
Original article country where the trial was conducted; condition or disease that was the focus of study, and the intervention. We used the components of the PICOT format: population, intervention, comparator, and outcome. These data were entered into a spreadsheet (Microsoft Excel) for descriptive analyses. When a publication studied more than one intervention or disease, each of these was recorded. As an example, a trial of micronutrient supplements given to mothers who were HIV positive, to examine the effect on maternal weight and the birth weight of their offspring, was recorded under nutrition (micronutrients), HIV (related conditions), maternal interventions and neonatal interventions. Data were analysed using Microsoft Excel formulae and graphs were produced using Excel.
RESULTS Trends in research output A total of 1553 publications were identified from the period July 2002–June 2013 (table 1). There were 1522 original studies and 31 systematic reviews. There was a steady increase in publications from controlled trials, from 38 in the 12 months to July 2003 to over 200 in each of 2012 and 2013. These 1553 studies took place in 76 countries, from all developing regions of the world. Figure 1 shows the number of trial publications from each country for two eras (2002–2008 and 2009–2013). One thousand four hundred and seventy-eight publications were from single-country studies; 44 were from multi-country studies: 12 involved two countries; 17 involved three countries; and 15 involved more than three countries. There has been a substantial increase in trials published in the last 5 years, compared with the first 6 years. In all years researchers from the African region published the largest number of trials (figure 2). Since 2008 the numbers of publications from South Asia have increased significantly. This has been predominantly because of a substantial increase in studies conducted in India: 78 publications in 2002– 2008 and 233 in 2009–2013 (figure 1). Most studies have been conducted by researchers based predominantly in that country. Over the last decade the number and proportion of studies with a corresponding author located in the same country as the study took place has increased, from 16 (53%) in 2002–2003 to 162 (71%) in 2011–2012.
Conditions and areas studied Sixty-three topics or diseases were studied in RCTs over the last decade, however a few themes predominate (table 1). The two most common were studies of nutrition (366 RCT publications, 23.6%) and malaria (336 publications; 21.6%). An analysis of subgroups of trials in nutrition shows that the majority of publications are studies of micronutrients (288 publications). There were comparatively few publications related to macronutrient interventions or complimentary feeding (48 publications) or measures to improve breast feeding (20 publications) (figure 3). Zinc and iron were the micronutrients most commonly studied in the first half of the decade, whereas other micronutrients, particularly multiple micronutrient mixtures became more commonly trialled in the second half of the decade. Publications of controlled trials in malaria increased from 4 in 2002–2003 to 52 in 2009–2010. In the first half of the decade malaria related intervention trials were predominantly on the treatment of malaria, particularly artemisinin-based combination therapy. There has been a steady increase in publications related to malaria prevention, and in 2011–2012, studies of malaria prevention outnumbered studies of malaria treatment. Publications regarding insecticide treated bed nets have occurred 616
at a relatively steady rate throughout the decade, whereas there was a marked increase in publications related to intermittent preventive treatment since the middle part of the decade until 2011–2012, but there were no intermittent preventive treatment-related publications in 2012–2013. Publications related to malaria vaccine trials increased from 2009 to 2012. One hundred and thirty-one (8.4%) trials focused on diarrhoeal disease. Seventy-one (60.3%) were trials of prevention and 52 (39.7%) trials of treatment. Vaccines against rotavirus, shigella and cholera (23 trials, 29.1% of preventive trials), water purification (18, 22.8%) and zinc supplementation (17, 21.5%) have been the most common preventive strategies studied, while zinc supplementation (21 trials, 40.4% of treatment trials) and probiotics (12, 23.1%) have been the most common treatment strategies studied (figure 4). In contrast to high level of controlled trial activity in malaria and micronutrients, there have been a relatively small number of trials of interventions for treatment or prevention of acute respiratory infection (98 publications, 6.3%). Forty-four of these have related to treatment and 52 to prevention (figure 5) (with a further 2 related to diagnosis). Of the 44 controlled treatment trials that focused on acute respiratory infections (ARIs), 28 (63.6%) related to WHO defined ‘non-severe’ pneumonia. These trials of treatment have been most commonly related to antibiotic treatment (22 trials), with zinc supplements being the next most common intervention (11 trials), and the most common type of ARI trial in the last 2 years. ARI prevention trials have been predominantly vaccine related (22 trials, 42.3% of ARI prevention trials) with zinc supplementation the next most common preventive strategy studied (12 trials, 23.1% of prevention). There were even fewer trials related to tuberculosis in children (26 publications, 1.7% of controlled trial publications). Sixty-four controlled trial publications (4.1%) related to neonatal health (figure 6). Of these, 19 (29.7%) examined community or maternal interventions, 17 (26.6%) examined nutritional issues (most commonly micronutrient supplementation given in the antenatal or postnatal period) and 9 (14.1%) trials of acute postnatal care, including Kangaroo care. Follow-up of long-term complications of conditions encountered in the neonatal period accounted for 10 publications (15.6%), with more of these in the second half of the decade studied (figure 6).
Trends based on economic transition The impact of economic transition is seen in the attention given to non-communicable diseases (NCDs), and in increases in trial output in several countries. In the last 5 years conditions such as asthma and allergy, other NCDs (obesity, diabetes and cardiac disease), behavioural-developmental and mental health conditions have received an increased focus (table 1). Studies evaluating interventions to improve child development have received some attention (70 publications, 4.5%), however mental health has received very little attention (21 publications, 1.4% of publications) (table 1).
DISCUSSION There has been over a sevenfold increase in the number of papers published from randomised trials on child health in developing countries over the last decade. Research is one marker of the priority given to health problems, and controlled trials are only one metric of research. The number of trials for each condition and each year is not a measure of quality or impact, but it does reflect global priorities. The marked increase in trial publications since 2003 reflects how health and Duke T, et al. Arch Dis Child 2014;99:615–620. doi:10.1136/archdischild-2013-305702
Downloaded from adc.bmj.com on June 12, 2014 - Published by group.bmj.com
Original article Table 1 Number of trials in different topic areas or health conditions per year
2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 Total
Total
Nutrition
Malaria
Vaccines
HIV
Diarrhoea
ARI
Parasitic infections
Neonates
Child development
NCD*
Health education
Adolesc
TB
Mental health
32 77 85 95 123 161 157 179 195 238 211 1553
15 22 17 31 40 30 29 32 39 46 65 366
4 18 22 31 33 40 29 51 42 44 22 336
2 7 6 8 10 15 18 23 24 32 26 171
1 7 7 12 13 13 11 13 21 26 20 144
6 8 2 11 10 11 10 14 20 21 18 131
3 5 5 4 7 9 11 8 12 16 18 98
4 10 4 3 8 4 11 8 11 8 14 85
0 3 2 2 2 9 5 7 8 11 15 64
1 5 3 3 6 3 10 7 8 9 15 70
0 1 1 2 2 8 6 6 7 12 4 49
0 1 4 4 5 4 1 7 3 10 9 48
0 1 0 3 1 2 0 7 7 3 8 32
1 3 1 3 1 1 0 2 4 7 3 26
0 0 0 0 0 2 2 6 6 1 4 21
Note: a trial could classified as being in more than one topic area or health condition. *NCD (non-communicable disease): allergy, asthma, diabetes, cardiovascular disease, obesity. Adolesc, trials relevant to adolescent health; ARI, acute respiratory infection; TB, tuberculosis.
development of children in developing countries has been an increasing focus for the global health community since the setting of the Millennium Development Goal (MDG) targets. There has been increased local research capacity, as evidenced by a steadily increasing proportion of controlled trials conducted from within developing countries, and a rise in systematic reviews being conducted by developing country researchers. Of the estimated 7.6 million deaths in children younger than 5 years in 2010, pneumonia (14.1%), diarrhoea (9.9%) and malaria (7.4%) were the most common causes. Forty per cent of deaths in children under 5 years occurred in neonates, of which
preterm birth complications (14.1%), intrapartum-related complications (9.4%), and sepsis or meningitis (5.2%) were the leading causes.2 Such global mortality burden estimates have some limitations;2 8 9 common comorbidities, particularly malnutrition, diseases that cause significant morbidity but are hard to identify (such as tuberculosis), injuries and diseases occurring in older children (such as rheumatic heart disease) are often under-represented. Previous studies have reported on gaps in disease burden information for children from many developing countries.10 Comparing the number of trials with proportional mortality or global disease burden estimates allows only tentative
Figure 1 Map showing the number of trial publications from each developing country in 2002–2008 (blue circles) and 2009–2013 (red circles). Duke T, et al. Arch Dis Child 2014;99:615–620. doi:10.1136/archdischild-2013-305702
617
Downloaded from adc.bmj.com on June 12, 2014 - Published by group.bmj.com
Original article Figure 2 Region of published trials.
conclusions, and raises many questions. However this review revealed some common disease burdens that have received a lot of research focus, while other areas have received very little. The impact of the large number of trials of malaria (21.6% of all RCT publications in the last decade) is seen in the uptake of new interventions and reductions in malaria in each affected country in the world.11 A comprehensive range of treatment and preventive strategies for malaria have been studied and then implemented as routine health strategies.12 The funding of programmes to implement the results for ‘Roll Back Malaria’ is an example of the optimum benefit of research, and the rapidity with which trial results can become policy and practice in the modern era. While malaria rates are falling in developing countries, the same rates of decline are not being seen for pneumonia (with a corresponding 6.3% of all publications related to acute respiratory infection), malnutrition (3.1% of publications) or neonatal illness (4.3% of trial publications, but representing 40% of the mortality burden).13 14 Childhood tuberculosis has been particularly neglected in the metric of controlled trials (1.7% of all trial publications). Similar comprehensive approaches to the research agenda and to research-driven public health interventions as seen in malaria are needed for these other areas. If this were to happen, further progress could be made towards the Millennium Development Goals for reduction in child mortality, and the ground would be laid for the post-2015 agenda.8
The large number of controlled trial publications of nutrition (23.6% of trial publications) is due predominantly to studies of micronutrient supplementation and their trialling in a wide variety of illnesses and nutritionally at-risk populations (78.6% of nutrition trial publications were micronutrient studies). There has been much less focus on other areas in nutrition, including effective ways to treat malnutrition, ways to increase breast feeding and improve complimentary feeding, and modifying environmental effects on childhood nutrition. Even the large numbers of studies of micronutrients has not necessarily translated into coordinated public health interventions. Despite over 60 randomised trials of zinc sulfate over the last decade, less than 1% of children with diarrhoea or malnutrition in developing countries have access to zinc.15 This emphasises the need for research to be part of a comprehensive approach to implementation of public health initiatives, including research on the implementation of research findings. Over the time of this review the impact of economic transition, Western morbidities and higher-technology research has become more evident, with clinical trials from developing countries related to NCD, including obesity, diabetes, congenital heart disease, allergy and modifying risk factors in childhood for adult cardiovascular disease becoming more common. It is notable that mental health is largely neglected in clinical trials, and this may be reflected in the limited focus on mental health in public health in many developing countries.
Figure 3 Trial publications in nutrition. 618
Duke T, et al. Arch Dis Child 2014;99:615–620. doi:10.1136/archdischild-2013-305702
Downloaded from adc.bmj.com on June 12, 2014 - Published by group.bmj.com
Original article
Figure 4 Trial publications in preventative and treatment strategies for diarrhoea. For some health interventions a randomised trial is not the appropriate method; because of unfeasibility, lack of equipoise, ethical issues, high cost or limited acceptability to a community. Rigorous analyses of public health and clinical interventions can use other methods. Thus the number of RCTs is just one perspective of the research that is done and the research that is needed. We have taken a liberal view of what constitutes a RCT over the years, and included in the annual compendia the publication output of controlled non-randomised trials when that information would be of value to the readers. The Pubmed filter for RCT: “AND (randomized controlled trial[Publication Type] OR (randomized[Title/Abstract] AND controlled[Title/Abstract] AND trial[Title/Abstract]” captures many non-randomised comparison trials. The search strategy we used for identifying studies may have missed some trials. The search strategy was chosen to capture as many studies as possible that were relevant to health workers and policy makers in developing countries, using a widely and freely available search engine (Pubmed). The same search strategy was used for each of the 11 years, so it is likely that changes in numbers of publications reflect real changes that have taken place, even if a small number of studies have been missed. It should be noted that the increase in publications is an indication of increased research activity over the 11 years, but does not entirely represent the number of controlled trials conducted over that time. Several papers reporting on different aspects of many trials have been counted. There has also been an increasing trend to publish study protocols and interim results for
some larger RCTs over the last decade, and a rise in the number of online journals in that time such that the threshold for publication may be reduced. The marked rise in publication of trials from India (figure 1) partly reflects increasing capacity in research. A fourfold rise in the proportion of Pubmed-cited publications from India in the 20 years to 2008 has been previously reported, and the alignment of this reported increase with public health priorities in India has been questioned.16 The relatively much smaller number of trial publications from China may reflect that many research results from that country are published in Chinese language journals which are not cited in Pubmed. Despite the African region having the highest child health trial output in the 11 years of this review, it is notable that some countries had no trial publications, including Libya, Chad, the Central African Republic and Somalia, each of which had bloody civil wars or conflict during this time.
CONCLUSIONS There is increasing research activity and capacity in child health in developing countries. Some areas have been the subject of a large amount of research, and led directly to the design and implementation of effective public health interventions and reduced disease burdens, while in other areas comprehensive approaches and the systematic application of research findings have been lacking. In some areas which represent major disease burdens, such as malnutrition, research has been focused on narrow interventions for which controlled trials are relatively easy to conduct, rather than comprehensive approaches to trials that also address underlying causes. There are a
Figure 5 Trial publications in preventative and treatment strategies for acute respiratory infections.
Duke T, et al. Arch Dis Child 2014;99:615–620. doi:10.1136/archdischild-2013-305702
619
Downloaded from adc.bmj.com on June 12, 2014 - Published by group.bmj.com
Original article
Figure 6 Trial publications involving neonatal outcomes.
number of other conditions, such as neonatal care, pneumonia, tuberculosis and mental health, where research attention has been very low relative to burden of disease. There is a risk with the rise of transitional economy-driven research that conditions primarily affecting the children in the poorest regions of the world will be neglected. Comprehensive approaches, based on controlled trials, implementation effectiveness trials and building research capacity in these areas would have major public health benefits, and should be part of the post-2015 agenda. Contributors Each year TD compiled the annual summary of controlled trials. TD and DF designed the project, DF analysed the 11-year data, and created the graphs, and both authors wrote the paper. The authors are very grateful to Igor Balgavi (Sombor, Serbia) for preparing figure 1. Funding The Centre for International Child Health received funding through AusAID as part of the Knowledge Hubs for Health Initiative, and is a WHO Collaborating Centre for Research and Training in Child and Neonatal Health. The authors are grateful to the RE Ross Trust (Victoria) for funding support. Competing interests None.
4 5 6
7
8 9
10
11 12
Provenance and peer review Not commissioned; externally peer reviewed.
13
REFERENCES
14
1
2
3
620
Lozano R, Wang H, Foreman KJ, et al. Progress towards Millennium Development Goals 4 and 5 on maternal child mortality: an updated systematic analysis. Lancet 2011;378:1139–65. Liu L, Johnson HL, Cousens S, et al. Global, regional, and national causes of child mortality: an updated systematic review for 2010 with time trends since 2000. Lancet 2012;379(June 9):2151–61. UNICEF. Committing to child survival: a promise renewed. New York: United Nations Children’s Fund, 2012. Ref Type: Report.
15
16
You D, Wardlaw T, Salama P, et al. Levels and trends in under-5 mortality. Lancet 2010;375:100–3. Black RE, Moris SS, Bryce J. Where and why are 10 million children dying every year? Lancet 2003;361:2226–34. Jones G, Steketee RW, Black RE, et al.; The Bellagio Child Survival Study Group. How many child deaths can we prevent this year? Lancet 2003; 362:65–71. Duke T. ed Randomised trials in child health in developing countries. Editions 1–11: 2002–2013. Melbourne: International Child Health Review Collaboration, 2013. http://www.ichrc.org/evidence-0. Ref Type: Online Source. Bryce J, Boschi-Pinto C, Shibuya K, et al. WHO estimates of the causes of death in children. Lancet Infect Dis 2005;365:1152. Black RE, Cousens S, Johnson HL, et al. Global, regional, and national causes of child mortality in 2008: a systematic analysis. Lancet 2010; 375:1969–87. Rudan I, Lawn J, Cousens S, et al. Gaps in policy-relevant information on burdens of disease in children: a systematic review. Lancet 2005; 365:2031–40. World Health Organization. World Malaria Report 2012. Geneva, 2012. Ref Type: Report. Akachi Y, Atun R. Effect of investment in malaria control on child mortality in sub-Saharan Africa in 2002–2008. PLoS ONE 2013;6:e21309. Oestergaard MZ, Inoue M, Yoshida S, et al. Neonatal mortality levels for 193 countries in 2009 with trends since 1990: a systematic analysis of progress, projections, and priorities. PLoS Med 2011;8:e1001080. Fischer Walker CL, Rudan I, Liu L, et al. Global burden of childhood pneumonia and diarrhoea. Lancet 2013;381:1405–16. http://dx.doi.org/10.1016/S0140-6736 (13)60222-6(April12) Gill CJ, Young M, Schroder K, et al. Bottlenecks, barriers, and solutions: results from multicountry consultations focused on reduction of childhood pneumonia and diarrhoea deaths . Lancet 2013;381:1487–98. On-line April 12. http://dx.doi.org/ 10.1016/S0140-6736(13)60314-1 Dandona L, Katock VM, Dandona R. Research to achieve health care for all in India. Lancet 2011;377:1055–7.
Duke T, et al. Arch Dis Child 2014;99:615–620. doi:10.1136/archdischild-2013-305702
Downloaded from adc.bmj.com on June 12, 2014 - Published by group.bmj.com
Randomised controlled trials in child health in developing countries: trends and lessons over 11 years Trevor Duke and David Fuller Arch Dis Child 2014 99: 615-620 originally published online March 10, 2014
doi: 10.1136/archdischild-2013-305702
Updated information and services can be found at: http://adc.bmj.com/content/99/7/615.full.html
These include:
References
This article cites 13 articles http://adc.bmj.com/content/99/7/615.full.html#ref-list-1
Email alerting service
Receive free email alerts when new articles cite this article. Sign up in the box at the top right corner of the online article.
To request permissions go to: http://group.bmj.com/group/rights-licensing/permissions
To order reprints go to: http://journals.bmj.com/cgi/reprintform
To subscribe to BMJ go to: http://group.bmj.com/subscribe/
Downloaded from adc.bmj.com on June 12, 2014 - Published by group.bmj.com
Topic Collections
Articles on similar topics can be found in the following collections ADC Global child health (23 articles) Childhood nutrition (456 articles) Childhood nutrition (paediatrics) (245 articles) Child health (2494 articles) Child and adolescent psychiatry (paedatrics) (468 articles) Travel medicine (68 articles) Tropical medicine (infectious diseases) (83 articles) Clinical trials (epidemiology) (372 articles) Infant nutrition (including breastfeeding) (250 articles) Asthma (296 articles) Health education (384 articles) Health promotion (427 articles) Immunology (including allergy) (1377 articles) Obesity (nutrition) (218 articles) Obesity (public health) (218 articles) Reproductive medicine (586 articles) TB and other respiratory infections (435 articles)
Notes
To request permissions go to: http://group.bmj.com/group/rights-licensing/permissions
To order reprints go to: http://journals.bmj.com/cgi/reprintform
To subscribe to BMJ go to: http://group.bmj.com/subscribe/
