more_vertAcute viral bronchiolitis is associated with lower respiratory tract infections in infants. Although generally self-limiting and managed in the community, acute viral bronchiolitis is the most common cause of hospital admission in infants younger than 12 months of age, and is associated with substantial morbidity and health-care costs. Admissions of infants to hospital for bronchiolitis have increased in the past 20 years for reasons that might be multifactorial, although the use of pulse oximeters and insufficient evidence and clarity about levels of tolerable hypoxaemia are thought to be associated with increased admission rates.
Preference: Respiratory Medicine
1039
[Seminar] Middle East respiratory syndrome
Middle East respiratory syndrome (MERS) is a highly lethal respiratory disease caused by a novel single-stranded, positive-sense RNA betacoronavirus (MERS-CoV). Dromedary camels, hosts for MERS-CoV, are implicated in direct or indirect transmission to human beings, although the exact mode of transmission is unknown. The virus was first isolated from a patient who died from a severe respiratory illness in June, 2012, in Jeddah, Saudi Arabia. As of May 31, 2015, 1180 laboratory-confirmed cases (483 deaths; 40% mortality) have been reported to WHO.
AMA updates stance on Climate and Health
Following an extensive engagement process with members, the AMA updated its Position Statement on Climate Change and Human Health (Revised 2015), which was last revised in 2008.
The updated Position Statement takes account of the most recent scientific evidence.
AMA President Professor Brian Owler said the AMA Position Statement focuses on the health impacts of climate change, and the need for Australia to plan for the major impacts, which includes reducing greenhouse gas emissions.
“It is the AMA’s view that climate change is a significant worldwide threat to human health that requires urgent action, and that human activity has contributed to climate change,” Professor Owler said.
“The evidence is clear – we cannot sit back and do nothing.
“There are already significant health and social effects of climate change and extreme weather events, and these effects will worsen over time if we do not take action now.
“The AMA believes that the Australian government must show leadership on addressing climate change.
“We are urging the Government to go to the United Nations Climate Change Conference in December in Paris with emission reduction targets that represent Australia’s fair share of global greenhouse gas emissions.
“There is considerable evidence to convince governments around the world to start planning for the major impacts of climate change immediately.
“The world is facing a higher incidence of extreme weather events, the spread of diseases, disrupted supplies of food and water, and threats to livelihoods and security.
“The health effects of climate change include increased heat-related illness and deaths, increased food and water borne diseases, and changing patterns of diseases.
“The incidence of conditions such as malaria, diarrhea, and cardio-respiratory problems is likely to rise.
“Vulnerable people will suffer the most because climate change will have its greatest effect on those who have contributed least to its cause and who have the least resources to cope with it.
“The Lancet has warned that climate change will worsen global health inequity through negative effects on the social determinants of health, and may undermine the last half-century of gains in development and global health,” Professor Owler said.
The AMA Position Statement on Climate Change and Human Health (Revised 2015) states that:
· Australia should adopt mitigation targets within an Australian carbon budget that represents Australia’s fair share of global greenhouse gas emissions, under the principle of common but differential responsibilities.
· Renewable energy presents relative benefits compared to fossil fuels with regard to air pollution and health. Therefore, active transition from fossil fuels to renewable energy sources should be considered.
· Decarbonisation of the economy can potentially result in unemployment and subsequent adverse health impacts. The transition of workers displaced from carbon intensive industries must be effectively managed.
· Regional and national collaboration across all sectors, including a comprehensive and broad-reaching adaptation plan is necessary to reduce the health impacts of climate change. This requires a National Strategy for Health and Climate Change.
· There should be greater education and awareness of the health impacts of climate change, and the public health benefits of mitigation and adaptation.
· Climate policies can have public health benefits beyond their intended impact on the climate. These health benefits should be promoted as a public health opportunity, with significant potential to offset some costs associated with addressing climate change.
The AMA Federal Council last month passed a policy resolution acknowledging the need for the healthcare sector to reduce its carbon footprint through improved energy efficiency, green building design, alternative energy generation, alternative transport methods, sustainable food sourcing, sustainable waste management, and water conservation.
The AMA Position Statement on Climate Change and Human Health (Revised 2015) is available at position-statement/ama-position-statement-climate-change-and-human-health-2004-revised-2015
John Flannery
Ciclesonide-induced bronchospasm: an important but preventable side effect
Despite recent advances in its management, asthma remains a significant ongoing cause of morbidity1 and mortality2 in Australia. Ciclesonide, a newer inhaled corticosteroid, offers exciting potential to improve both asthma control and longer-term outcomes. This is because of its improved safety profile relative to other asthma medications, and the potential for improved adherence to treatment, given its proven efficacy as a once-daily medication.3 It is administered as a prodrug, activated within the lungs, and has lower oral bioavailability and extensive first-pass metabolism which reduces its systemic side effect profile.4 In Australia, ciclesonide is now available on the Pharmaceutical Benefits Scheme for use in children from the age of 6 years. Despite increasing use of this drug, side effects are infrequently reported.
We highlight an important potential side effect of ciclesonide treatment, which occurred in three adolescent patients with asthma, who recently attended our tertiary paediatric hospital-based clinic with persistent asthma (ranging in severity from mild to moderately severe based on recommended classifications5). Ciclesonide therapy had been commenced in each patient in an attempt to improve both asthma control as well as compliance. All three patients experienced ciclesonide-induced bronchospasm after using ciclesonide, which was confirmed on formal challenge testing (with ciclesonide at the same dose that was being administered for asthma) in a specialised respiratory function laboratory. The bronchospasm was reversed by use of an inhaled bronchodilator (Box), and then prevented during ongoing treatment by use of a bronchodilator before dosing with ciclesonide. Ciclesonide treatment was subsequently shown to improve overall asthma control to within acceptable limits in two of the three patients. In the third, failure to achieve this reflected the severity of the underlying persistent asthma as shown by this patient’s need for daily oral corticosteroid therapy to achieve symptom control. The adverse reactions to ciclesonide in these patients were reported to the manufacturers of ciclesonide (Takeda Pharmaceuticals Australia), and ciclesonide-induced bronchoconstriction is now listed as a recognised side effect in the product information for this drug.
Ciclesonide is an attractive preventer medication for persistent asthma in children aged 6 years and over for several reasons. However, health professionals should be aware of this important potential side effect, which we speculate is currently underrecognised, but easily identified with careful questioning about wheeze and/or chest tightness after ciclesonide dosing. If suspected, we recommend that patients be referred for formal ciclesonide airway challenge testing (at the same ciclesonide dose being administered for treatment) in a specialised respiratory function laboratory. If the patient’s bronchoconstriction can be reversed by administering a bronchodilator, a subsequent trial of pretreatment with a bronchodilator before ciclesonide dosing should be performed before finally evaluating the role of ciclesonide therapy on asthma control.
1
Ciclesonide-induced bronchospasm during ciclesonide-based airway challenge testing
The green line indicates the reference data for a child of the same age, sex and height. Baseline and post-ciclesonide challenge flow-volume loops are shown by the purple and red lines, respectively. The fall in (forced expiratory volume in one second; FEV1) from 106% to 86% predicted represented a 19% fall in FEV1 with ciclesonide administration.
[Clinical Picture] Chocolate-coloured serum in methaemoglobinaemia
A 53-year-old man presented to the emergency department of our hospital in January, 2014, after a syncopal episode. He was a regular smoker and recreational drug user, and had taken heroin, cannabis, and benzodiazepine during that week. He had a history of glucose-6-phosphate dehydrogenase (G6PD) deficiency. On examination he had grey pallor and was dyspnoeic at rest (respiratory rate 23 breaths per minute). His oxygen saturation was 70% on 100% inspired oxygen and his blood sample, which showed anaemia (haemoglobin 54 g/L; normal 130–180 g/L), was chocolate brown (figure).
[Correspondence] Parenteral antibiotics are not enough to prevent pneumonia in stroke – Authors’ reply
The susceptibility of patients with stroke to pneumonia has been well recognised,1 and its cause is multifactorial.2 Luciano Silvestri and colleagues rightly point out pathophysiological differences between early pneumonia after stroke, defined as within the first week after stroke onset, and late pneumonia, defined as after the first week. The Pneumonia In Stroke ConsEnsuS (PISCES) group has recently recommended reserving the term stroke-associated pneumonia for the spectrum of lower respiratory tract infections within the first 7 days after stroke onset.
Appropriate use of oxygen in acute medicine
Oxygen use in acute medicine requires regular monitoring to maintain saturation levels within the prescribed range
It may seem intuitive that oxygen is “good”, so, for the ill or even just distressed, more must be better! However, the evidence for this common clinical approach is at best anecdotal and mainly cultural.1 In fact, both (very) low and high oxygen levels are bad and, indeed, inappropriate use of oxygen in acute medical treatment may be harmful.2–4 Hyperoxia leads to vasoconstriction, and oxygen uptake actually falls.5 Overly vigorous prehospital use of oxygen may well be a significant contributor to death in common acute medical conditions.6
When is a human truly hypoxaemic?
Technically, hypoxaemia occurs when tissues begin to produce lactic acid because of anaerobic metabolism. In the 1960s, a study showed that heart muscle in healthy people did not produce lactic acid until the circulating blood oxygen saturation level was in the region of 50% (equivalent to a partial pressure of less than 30 mmHg), but in people with ischaemic heart disease, oxygen saturation levels were usually in the range of 70%–79%, occasionally as high as 85%, (around 55 mmHg) when cardiac lactate was produced.5 In practice, hypoxaemia has been arbitrarily and conservatively assumed at a saturation level of 88%–90%, although humans can cope quite well at lower levels than this, for example, during sleep, on mountains and when flying. This threshold for hypoxia is also above the point at which central cyanosis is likely (ie, less than 85%). Thus, in clinical situations the target of 88%–90% in arterial oxygen saturation should provide a very adequate buffer. Of course, supply of oxygen to the tissues also depends vitally on haemoglobin concentration and cardiac output, and elevating the central oxygen saturation will not compensate for tissue hypoxia if that is due to abnormalities in oxygen carrying capacity.
Thoracic Society of Australia and New Zealand guidelines
In an attempt to provide evidence-based interpretation in this currently confusing clinical area, the Thoracic Society of Australia and New Zealand (TSANZ) has developed new guidelines for oxygen use in the acute medical setting. These guidelines used the evidence base of the 2008 British Thoracic Society guidelines7 and the draft of an update to these guidelines due to be published in 2015. However, the TSANZ guidelines differ in some practical ways, aiming to avoid the worst “compromises” made to achieve professional consensus in the United Kingdom. The TSANZ guidelines will shortly be published in the journal, Respirology, but have already been endorsed by the Board of the TSANZ and a wide range of other professional medical, nursing and allied health bodies.
A core and firm principle of the TSANZ guidelines is to formalise the use of oxygen as a drug that is rationally and precisely prescribed — that is, with a specified mode of delivery (our practical preference is by nasal cannulae), flow rate (or FiO2) and rational target range of oxygen saturation. The latter would be 88%–92% in patients with chronic obstructive pulmonary disease or other chronic respiratory conditions in which carbon dioxide retention is a possibility, and 92%–96% for most other medical conditions requiring oxygen supplementation. For the reasons discussed, 92%–96% is probably unnecessarily high, but it is the Australian guidelines’ compromise so as not to cause controversy. This range does allow both deterioration and improvement in the patient’s condition to be detected easily and in a timely way, rather than being masked by overoxygenation. Regular and iterative monitoring is necessary to determine if saturation levels are remaining within the prescribed range. If the patient’s need for oxygen decreases, then oxygen flow rates are adjusted down to stay within the prescribed range of oxygen saturation. Conversely, if a patient’s oxygen needs increase and flow rates need to be increased to keep saturation levels within the prescribed range, then medical review is needed and the patient may need to be moved to a high dependency unit. The emphasis is on heeding changes in the levels of oxygen saturation, not for their own sake, but as a reflection of the underlying condition.
The TSANZ guidelines support initial arterial blood gas measurements to define the true oxygen and carbon dioxide status of the patient. They discuss the usefulness of currently overpopular venous blood gas assessments (which cannot assess oxygenation and have problems with assessing carbon dioxide levels)8 and underutilised arterialised capillary blood gas assessments.
The most practical way to monitor oxygenation is with a pulse oximeter. Most manufacturers of oximeters quote an accuracy of ± 2%, although older published data quote higher variability.9 A new study with modern equipment is urgently needed, but the TSANZ guidelines include sufficient safety margins to make the variability of oximeters relatively unimportant.
It needs to be stressed that oxygen is not indicated for breathlessness without hypoxia. Further, acute hypoxaemia is commonly caused by hypoventilation and carbon dioxide retention, which must be recognised (by measuring arterial blood gases), and may mean that the patient requires assisted ventilation in an appropriate setting.10
Signs not good for flu season
The nation’s top medical officer has issued an urgent call for people, particularly vulnerable groups including pregnant women, the elderly and those with chronic illnesses, to get vaccinated against the flu amid signs the nation is headed for its worst season on record.
Official figures show that so far this year more than 14,124 have caught the flu – double the long-term average for the period – and a third higher than for the same time last year.
In a worrying sign that the flu season is gathering momentum, figures compiled through the National Notifiable Diseases Surveillance System show that in in just one month, from 5 June to 6 July, an extra 4911 laboratory-confirmed cases were reported, including almost 2000 in the first week of July.
Underlining the seriousness of the illness, the Health Department said it had so far been notified of 36 deaths associated with influenza since the beginning of the year, with the likelihood that number will rise sharply as the rate of infection accelerates.
Commonwealth Chief Medical Officer Professor Chris Baggoley specifically urged people considered to be at risk, including those aged 65 years and older, Indigenous Australians, pregnant women, and those with cardiac disease and chronic respiratory conditions and illnesses, to take advantage of the free vaccine provided by the Government.
“Flu is highly contagious and spreads easily from person to person, through the air, and on the hands,” Professor Baggoley said. “We need to get higher uptake [of the vaccine] among these groups.”
The Chief Medical Officer emphasised the importance of doctors and other health professionals in helping ensure people were vaccinated against the disease.
“Immunisation is still the best form of protection from influenza, and health care professionals play an essential role in ensuring high uptake,” he said.
The National Seasonal Influenza Immunisation Program began late this year because of a rare double strain change in the vaccine to cover two new strains of the virus – one of which caused havoc in the northern hemisphere.
In the US alone, around 100 children were reported to have died from the flu during the northern flu season, and there was also widespread illness among the elderly.
For the first time under the national immunisation program, Australians have access to single-dose vaccines covering the four most common flu viruses, including three quadrivalent formulations.
The World Health Organisation and the Australian Influenza Vaccine Committee have recommended that vaccines this year cover one existing and two new strains – the California H1N1-like virus that has been in circulation since 2010, the Switzerland H3N2-like virus and the Phuket 2013-like virus.
There have been claims that the delay to the vaccination program has contributed to the strong start to the flu season by leaving a large number of people unprotected, and Professor Robert Booy of the Influenza Specialist Group told the Herald Sun fewer people had been vaccinated that “we would have liked”.
But Health Minister Sussan Ley said the Government was ahead of where it was last year in acquiring vaccine doses.
Ms Ley said that so far in 2015 4.5 million doses had been bought under the National Immunisation Program, 200,000 more than were distributed in 2014.
She did not say how many of these doses had been administered.
Ms Ley said the flu season usually peaked in August and September which, given that it usually takes around three weeks following vaccination to develop immunity, meant people needed to get themselves vaccinated as soon as possible.
Promisingly, early figures suggest vaccinations are helping to reduce the number and severity of infections.
The pilot Flu Tracking surveillance system, a joint University of Newcastle, Hunter New England Area Health Service and Hunter Medical Research initiative that collects data from a weekly online survey, has so far identified only low levels of influenza infection.
But it found that 3.4 per cent of those not vaccinated against the flu suffered fevers and coughs, and 2.1 per cent had to take time off work, while among those vaccinated, 2.7 per cent had coughs and fevers and 1.6 per cent reported having to take sick leave.
The results underline calls from AMA Vice President Dr Stephen Parnis for people, particularly elderly and vulnerable patients and health professionals, to make sure they are vaccinated against the flu.
Dr Parnis said it was important for doctors, nurses and other health workers to get the flu vaccine, for the sake of their own health as well as that of their patients.
Adrian Rollins
Australian clinical trial activity and burden of disease: an analysis of registered trials in National Health Priority Areas
To improve Australia’s health, clinical research programs should devote substantial activity to advancing practice in areas of high clinical need. Clinical trials are designed to provide high-quality evidence of the effectiveness of new interventions to establish best clinical practice. However, few studies have examined the extent to which Australian clinical trials address priority areas of clinical need.
The Australian Institute of Health and Welfare (AIHW) National Health Priority Areas (NHPAs) were introduced to encourage appropriate targeting of health services and clinical research to improve health. Currently, there are nine NHPAs: cancer control, cardiovascular health, mental health, injury prevention and control, diabetes mellitus, obesity, arthritis and musculoskeletal conditions, dementia and asthma. These NHPAs account for approximately three-quarters of the total estimated burden of disease in Australia (1 915 600 of 2 632 800 disability-adjusted life-years [DALYs]).1
Previous studies have reported a disparity between the level of National Health and Medical Research Council (NHMRC) grant funding for studies investigating NHPA conditions relative to their disease burden.2,3 The founding of clinical trial registries, including the Australian New Zealand Clinical Trial Registry (ANZCTR) in 2005, provides the first opportunity to examine how well clinical trial activity in Australia is targeted to NHPAs.
Methods
We conducted a retrospective analysis using ANZCTR and ClinicalTrials.gov (CT.gov) data to report on Australian trial activity and characteristics for NHPAs; and to compare the level of trial activity to the relative burden of disease for each NHPA.
Ethics approval was not required for this analysis of publicly available trial data.
Data sources
Trial registration is voluntary in Australia.4
The ANZCTR is an online public registry of clinical trials maintained by the NHMRC Clinical Trials Centre, the University of Sydney. It collects information about trial interventions, investigated health conditions, planned recruitment, outcomes, funding and sponsorship using the World Health Organization-defined 20-item minimum dataset.5 Health conditions are coded using the United Kingdom Clinical Research Collaboration Health Research Classification System (http://www.hrcsonline.net). Additional data are collected about trial design, including randomisation and blinding. The ANZCTR 2011 Data Quality and Completeness Audit reported that, on average, at least 93 of 94 data fields for 148 trials were complete.6
CT.gov is an online public registry of clinical trials maintained by the United States National Library of Medicine (https://clinicaltrials.gov). It records similar data items to the ANZCTR.
Trial sample and characteristics
The trial sample included all trials of health-related interventions registered on the ANZCTR or CT.gov between 1 January 2008 and 31 December 2012 that included Australia as a country of recruitment. To avoid entering duplicate trial data, trials that listed a CT.gov or ANZCTR registration number as a secondary identifier were only included in the ANZCTR trial list.
Condition categories and codes were used to classify individual trials as addressing one or more NHPA conditions, or other, non-NHPA conditions. For each trial, we extracted information for: purpose of intervention (treatment, prevention, diagnosis, education/counselling/training, other/missing); allocation of intervention (randomised, non-randomised); trial phase (I–IV, not applicable, missing), blinding (blinded, open, other/missing), planned recruitment (reported as target sample size, and classified as < 100, 100–1000, > 1000 participants); participant age range (< 18 years, 18–69 years, ≥ 70 years); and countries of recruitment (Australia only, Australia and overseas).
Analysis
To measure trial activity, we recorded the total number and planned recruitment of registered trials investigating NHPA conditions. To assess whether trial activity reflected the burden of disease for each NHPA, we compared the relative trial activity targeted to each NHPA, measured as a proportion of the total trial activity, with the “expected” distribution of trial activity estimated from the relative burden of disease for that NHPA. Burden of disease was estimated from published estimates of DALYs for each NHPA expressed as a percentage of the total burden of disease and injury in Australia (%DALY).1
To describe disparities in relative trial activity by NHPA, we identified NHPAs where the observed trial activity was less than 50% or more than 200% of expected values. The χ2 goodness-of-fit test was also used to test for statistically significant differences between observed and expected trial activity for each NHPA. For these analyses, a two-sided P < 0.006 was regarded as statistically significant using the Bonferroni adjustment for multiple comparisons (nine comparisons).
For assessment of trial recruitment across NHPA, we also conducted a sensitivity analysis to examine trial recruitment to NHPA from Australian sites, where Australian recruitment was estimated from the planned recruitment from all ANZCTR trials plus 10% of the planned recruitment from CT.gov trials that included at least one Australian site. The figure of 10% was estimated from a randomly selected sample of 100 CT.gov registered trials that included at least one Australian site and represents the number of Australian sites as a proportion of all sites for each trial.
We also calculated the frequency distribution of trial characteristics for each NHPA. SAS, version 9.3 (SAS Institute) was used for data analyses.
Results
There were 5143 intervention trials registered during 2008–2012 that planned to recruit in Australia (ANZCTR, 3379; CT.gov, 1764). Of these, 3032 (59%) related to NHPA conditions (ANZCTR, 1908; CT.gov, 1124). Total planned recruitment for the trial sample was 2 404 609 participants, including 1 532 064 (64%) for NHPA trials (ANZCTR, 670 832; CT.gov, 861 232).
Trial activity in NHPA
The three disease areas that contribute the largest %DALY — cancer, cardiovascular diseases and mental disorders — also attracted the largest number of trial registrations and the largest planned recruitment (Box 1; Box 2).
The proportions of registered trials that investigated dementia or injury interventions were less than half those expected from their %DALYs (65/185 [35%] and 137/360 [38%], respectively; Box 1). The proportions of obesity and asthma trials were also lower than expected (195/386 [51%] and 68/123 [55%], respectively). In contrast, the proportion of registered arthritis and musculoskeletal diseases trials was about twice as high as expected on the basis of the %DALY (Box 1).
The proportions of planned recruitment to trials investigating obesity and dementia were also substantially lower than expected from their %DALYs (33 948/180 346 [19%] and 24 248/86 566 [28%], respectively), and was also low for asthma (29 468/57 711 [51%]) (Box 1).
When this analysis was repeated using estimated recruitment from Australian sites only, a similar pattern was observed, with the exception of recruitment to diabetes trials. For diabetes trials, total trial planned recruitment was relatively high (185 929/132 253 [141%]) compared with Australian sites (44 201/66 607 [66%]).
Trial characteristics
Overall, 2335 of 3032 (77%) NHPA trials used a randomised design and 1509 (50%) planned recruitment of ≤ 100 participants (Box 3). Of the 2931 NHPA trials that reported information about blinding, 1504 (51%) reported using it (Box 3).
About three-quarters of NHPA intervention trials investigated treatments (2321 [76%]) and 397 (13%) investigated prevention interventions (Box 3). The ratio of treatment to prevention trials ranged from less than 2 : 1 for obesity trials to 14 : 1 for cancer trials.
Most NHPA trials excluded children, whereas 2252 (75%) specified a maximum participant age of ≥ 70 years, or did not specify a maximum age (Box 3). International recruitment sites were reported in 1081 (36%) of NHPA trials (169 ANZCTR trials, 912 CT.gov trials) and varied by condition (Box 3).
Discussion
This study provides the first overview of clinical trial activity in Australia. We found that more than half of Australian registered intervention trials and planned trial recruitment are targeted to NHPA conditions.
Trial activity for cancer, cardiovascular diseases and mental disorders was high relative to other NHPA conditions, consistent with their position as the three major contributors to disability and premature death in Australia. In contrast, trial activity for obesity and dementia interventions was substantially less than the level expected from their contribution to the total DALY.
To interpret these results, the number of trials can be considered to provide a proxy measure for the number of active research questions being investigated to identify more effective interventions in each area. Planned trial recruitment provides a measure of the number of patients actively participating in research to determine best practice in each area.
These findings suggest there is a need to further examine research activity for obesity, dementia and asthma to determine if and how clinical trials research in these areas should be increased. However, this study does not allow us to define the optimum level of trial activity for each condition. Clearly, not all important research questions for NHPAs are amenable to investigation through clinical trials. For conditions where trial activity is already high relative to other disease areas, further increases may still represent good value for money by improving health care. For example, if promising new interventions are available; or practice variations or controversies exist with gaps in evidence to guide best practice. Conversely, for some conditions where trial activity is currently low, research priorities may warrant other study designs, such as those used in translational research or behavioural science, to develop new interventions.
This study also provides the first opportunity to assess the extent to which Australian trials are designed to provide robust, high-quality evidence for guiding practice. The use of randomisation and blinding provides a measure of trial quality; trial size provides an indicator of study power. Trials enrolling more than 100 participants are generally required to assess clinically meaningful health outcomes and to weigh up the benefits and harms of the new strategy, whereas smaller trials are generally designed to assess surrogate outcomes. About three-quarters of Australian trials used a randomised design; however, only around half reported blinding, or planned recruitment of more than 100 participants. These findings are slightly more favourable than those of a recent analysis of 79 413 intervention trials registered on CT.gov between 2000 and 2010, which reported that 70% used a randomised design, 44% used a blinded design and 38% enrolled 100 or more participants.7
One commonly raised concern about clinical trials research is the applicability of trial data to routine clinical practice populations and settings. Our finding that more than two-thirds of trials in NHPA areas did not exclude participants aged 70 years or older is encouraging.
The main strength of our study is that it provides a unique, timely overview of Australian clinical trials to inform current debate on the achievements, limitations and future directions for clinical trials research in Australia. Clinical researchers can use the same methods to further explore gaps for conditions within specific disease areas, as has been performed for cancer trials.8
There are two main limitations to our study that could affect our estimates of trial activity in different directions. First, we relied on trial registrations to estimate trial activity. As trial registration is not compulsory in Australia, we may have underestimated trial activity. Additionally, we only included international trials registered on the ANZCTR or CT.gov. A search using the WHO International Clinical Trials Registry Platform Search Portal (http://www.who.int/ictrp/search/en) showed that 11 096 of 11 412 (97%) trials with Australian sites are registered on these two registries. The total number of registered trials may therefore be 3% higher than our study estimate.
Second, our estimates of trial participation may overestimate the number of Australians participating in clinical trials, because 1622 of 5143 trials (32%) included sites outside Australia. Nevertheless, by including Australian sites, these trial recruitment figures capture participation in trials that can be expected to provide evidence relevant to Australian practice.
Despite these limitations, we believe our findings are valuable in informing initiatives to increase clinical trial activity.9,10 It is well documented that trial research is often not available to guide many routine clinical decisions about selecting interventions.11 To guide practice, large trials with adequate long-term follow-up are needed to identify small incremental improvements in health outcomes and/or adverse events. Our findings on trial size suggest that further efforts are needed to promote and support the conduct of large trials, or support the conduct of small high-quality trials that can later contribute data to meta-analyses.
Overall, we demonstrate the feasibility and value of using publicly available trial registry data to examine the profile of trials research for particular conditions and identify gaps in trial activity to inform trial initiatives. The ANZCTR provides a valuable resource for researchers to ensure new studies build on, or contribute to, existing trials.
1 Number of registered Australian intervention trials and total planned recruitment in National Health Priority Areas, as a percentage of total trial activity, and comparison to the expected number based on %DALY, Australian New Zealand Clinical Trials Registry and ClinicalTrials.gov, 2008–2012
|
DALY |
Trials |
Planned recruitment |
|||||||||||||
|
National Health Priority Area |
Rank |
% |
Rank |
Observed |
Expected no. |
Observed/ |
P* |
Rank |
Observed no. (%) |
Expected no. |
Observed/ |
P* |
|||
|
|
|||||||||||||||
|
Cancer control |
1 |
19.0% |
1 |
871 (16.9%) |
977 |
89% |
0.007 |
2 |
427 188 (17.8%) |
456 876 |
94% |
< 0.001 |
|||
|
Cardiovascular health |
2 |
18.0% |
3 |
646 (12.6%) |
926 |
70% |
< 0.001 |
1 |
577 178 (24.0%) |
432 830 |
133% |
< 0.001 |
|||
|
Mental health |
3 |
13.3% |
2 |
693 (13.5%) |
684 |
101% |
0.82 |
3 |
196 826 (8.2%) |
319 813 |
62% |
< 0.001 |
|||
|
Obesity |
4 |
7.5% |
6 |
195 (3.8%) |
386 |
51% |
< 0.001 |
7 |
33 948 (1.4%) |
180 346 |
19% |
< 0.001 |
|||
|
Injury prevention and control |
5 |
7.0% |
7 |
137 (2.7%) |
360 |
38% |
< 0.001 |
5 |
125 256 (5.2%) |
168 323 |
74% |
< 0.001 |
|||
|
Diabetes mellitus |
6 |
5.5% |
5 |
282 (5.5%) |
283 |
100% |
1.00 |
4 |
185 929 (7.7%) |
132 253 |
141% |
< 0.001 |
|||
|
Arthritis and musculoskeletal conditions |
7 |
4.0% |
4 |
410 (8.0%) |
206 |
199% |
< 0.001 |
6 |
109 107 (4.5%) |
96 184 |
113% |
< 0.001 |
|||
|
Dementia |
8 |
3.6% |
9 |
65 (1.3%) |
185 |
35% |
< 0.001 |
9 |
24 248 (1.0%) |
86 566 |
28% |
< 0.001 |
|||
|
Asthma |
9 |
2.4% |
8 |
68 (1.3%) |
123 |
55% |
< 0.001 |
8 |
29 468 (1.2%) |
57 711 |
51% |
< 0.001 |
|||
DALY = disability-adjusted life-years. %DALY = DALYs expressed as a proportion of the total burden of disease in Australia.1 Observed number of trials is expressed as a percentage of total 5143 registered intervention trials. Observed planned recruitment is expressed as a % of total 2 404 609 planned recruitment. Expected number of trials is calculated by applying %DALY to total 5143 registered intervention trials. Expected planned recruitment is calculated by applying %DALY to total 2 404 609 planned recruitment. * χ2 goodness-of-fit test for comparison of observed versus expected values.
2 Relationship between trial characteristics and %DALY for each NHPA, Australian New Zealand Clinical Trials Registry and ClinicalTrials.gov, 2008–2012
The diagonal line represents the line of equality where %DALY is equal to trial number as a percentage of total registered trials (A) or planned trial participation as % of total planned trial participation (B). Dots below the line show NHPAs where the variable falls below the %DALY. The size of dots corresponds to the size of planned trial participation (A) or number of trials (B) for the NHPA.
%DALY = disability-adjusted life-years expressed as a proportion of the total burden of disease in Australia.1 NHPA = National Health Priority Area.
3 Australian intervention trial characteristics, overall and by National Health Priority Area (NHPA),* Australian New Zealand Clinical Trials Registry and ClinicalTrials.gov, 2008–2012
|
Characteristic |
All trials |
NHPA |
Cancer |
Cardio- |
Mental |
Obesity |
Injury |
Diabetes |
Arthritis/ |
Dementia |
Asthma |
||||
|
|
|||||||||||||||
|
Total |
5143 |
3032 |
871 |
646 |
693 |
195 |
137 |
282 |
410 |
65 |
68 |
||||
|
Randomisation |
|||||||||||||||
|
Yes |
3990 (78%) |
2335 (77%) |
564 (65%) |
494 (77%) |
579 (84%) |
163 (84%) |
125 (91%) |
253 (90%) |
321 (78%) |
53 (82%) |
59 (87%) |
||||
|
No |
1137 (22%) |
691 (23%) |
304 (35%) |
150 (23%) |
113 (16%) |
31 (16%) |
12 (9%) |
28 (10%) |
89 (22%) |
12 (18%) |
9 (13%) |
||||
|
Missing |
16 |
6 |
3 |
2 |
1 |
1 |
1 |
||||||||
|
Intervention type |
|||||||||||||||
|
Treatment |
3834 (75%) |
2321 (76%) |
732 (84%) |
444 (69%) |
494 (71%) |
108 (55%) |
103 (75%) |
210 (75%) |
357 (87%) |
50 (77%) |
46 (68%) |
||||
|
Prevention |
781 (15%) |
397 (13%) |
52 (6%) |
131 (20%) |
98 (14%) |
67 (34%) |
25 (18%) |
46 (16%) |
34 (8%) |
5 (8%) |
10 (15%) |
||||
|
Diagnosis |
152 (3%) |
78 (3%) |
29 (3%) |
26 (4%) |
11 (2%) |
3 (2%) |
2 (2%) |
8 (3%) |
4 (1%) |
4 (6%) |
0 |
||||
|
Educational/ |
263 (5%) |
171 (6%) |
39 (5%) |
26 (4%) |
73 (11%) |
10 (5%) |
4 (3%) |
15 (5%) |
9 (2%) |
5 (8%) |
7 (10%) |
||||
|
Other/missing |
113 (2%) |
65 (2%) |
19 (2%) |
19 (3%) |
17 (2%) |
7 (4%) |
3 (2%) |
3 (1%) |
6 (2%) |
1 (2%) |
5 (7%) |
||||
|
Age group (years) |
|||||||||||||||
|
Minimum age < 18† |
987 (19%) |
490 (16%) |
122 (14%) |
60 (9%) |
156 (23%) |
29 (15%) |
42 (31%) |
28 (10%) |
57 (14%) |
7(11%) |
26 (38%) |
||||
|
Missing |
5 |
2 |
1 |
1 |
|||||||||||
|
Maximum age ≥ 70† |
3652 (71%) |
2252 (75%) |
774 (89%) |
558 (87%) |
397 (57%) |
69 (36%) |
98 (72%) |
199 (71%) |
316 (77%) |
59 (94%) |
41 (60%) |
||||
|
Missing |
18 |
10 |
2 |
2 |
1 |
2 |
2 |
||||||||
|
Blinding |
|||||||||||||||
|
Blinded |
2639 (53%) |
1504 (51%) |
270 (31%) |
347 (55%) |
405 (61%) |
93 (51%) |
89 (67%) |
141 (52%) |
249 (64%) |
47 (72%) |
48 (72%) |
||||
|
Open |
2322 (47%) |
1427 (49%) |
589 (69%) |
281 (45%) |
260 (39%) |
91 (49%) |
43 (33%) |
129 (48%) |
139 (36%) |
18 (28%) |
19 (28%) |
||||
|
Missing |
182 |
101 |
12 |
18 |
28 |
11 |
5 |
12 |
22 |
0 |
1 |
||||
|
Planned recruitment |
|||||||||||||||
|
1–100 |
2689 (52%) |
1509 (50%) |
361 (41%) |
325 (50%) |
361 (52%) |
132 (68%) |
66 (48%) |
133 (47%) |
228 (56%) |
22 (35%) |
33 (49%) |
||||
|
101–1000 |
2066 (40%) |
1274 (42%) |
427 (49%) |
244 (38%) |
300 (43%) |
58 (30%) |
61 (45%) |
119 (42%) |
161 (39%) |
35 (55%) |
31 (46%) |
||||
|
> 1000 |
383 (7%) |
246 (8%) |
83 (10%) |
77 (12%) |
30 (4%) |
5 (2%) |
10 (7%) |
30 (11%) |
21 (5%) |
6 (10%) |
3 (5%) |
||||
|
Missing |
5 |
3 |
1 |
2 |
2 |
1 |
|||||||||
|
Country of recruitment |
|||||||||||||||
|
Australia only |
3521 (68%) |
1951 (64%) |
349 (40%) |
401 (62%) |
578 (83%) |
184 (94%) |
113 (82%) |
192 (68%) |
286 (70%) |
37 (57%) |
47 (69%) |
||||
|
Australia and overseas |
1622 (32%) |
1081 (36%) |
522 (60%) |
245 (38%) |
115 (17%) |
11 (6%) |
24 (18%) |
90 (32%) |
124 (30%) |
28 (43%) |
21 (31%) |
||||
Data are no. (%) unless otherwise specified. * Trials may be classified under more than one NHPA (eg, obesity and diabetes). † Includes trials that did not specify age limits.
[World Report] Too many unknowns stymie response to MERS
The spread of the Middle East respiratory syndrome to Asia has put the public health community on trial for a lack of adequate preparedness in preventing such infections. John Maurice reports.