Editorials

Combining commercial interests and public good is a broad social, political and ethical challenge Health care, the practice of medicine, provision of medicines and medical information management are big business. There are deep, inherent tensions and potential for conflict between the needs and vulnerabilities of the sick, and the conduct of a large proportion of health care as a commercial activity. Every doctor in private practice spans this ethical tension each working day. Commercial organisations which provide essential health care and health goods, such as pharmaceutical companies, also tread this fine line. Industry is the largest funder of medical research and provides needed medicines and vaccines. The timelines, costs and risks of product development are substantial — around 80% of pharmaceutical and vaccine candidates which enter human clinical trials do not make it to registration, and the road to registration is formidable. An average of around a decade’s preclinical research, up to 9 years’ clinical development, and a highly variable but average cost of around US$500–800 million are involved in bringing on-stream a new product that is a new entity rather than a “me-too” product.1-3 Coupling these realities with the benefits of global reach to access the best knowledge, candidates and processes means that innovative drug and vaccine development needs big, responsive organisations with diverse skills. But marrying the private, commercial sector with equitable and sustainable development and provision of public goods is a much broader social, political and ethical challenge. The promotional dollars the pharmaceutical industry spends can have clear benefits, such as appropriate use of established and new therapies, encouraging best practice and contributing to policy development. However, the many billions of dollars spent each year in promotion dwarfs, by a factor of 2–3, its research and development expenditures4 — an issue not only for the industry but for all of us in terms of distorted priorities and large opportunity costs. Research in this issue of the Journal suggests that there are serious issues regarding the complex relationship between commercial health care organisations and the healing professions, and regulation of this relationship. Harvey and colleagues (page 75) demonstrate potential breaches of compliance with the Medicines Australia Code of Conduct in many pharmaceutical advertisements placed within the most widely used general practice prescribing software.5 This Code is the benchmark for the pharmaceutical industry’s marketing and promotional activities in Australia, including its interactions with health professionals, and adherence to it is solely the responsibility of pharmaceutical companies. Some of the criteria used in the study were subjective (eg, legibility, inadequate time for comprehension) or quite conservative (eg, reference to the Product Information considered present only if contained within the body of an advertisement, not adjacent to it), and analysis was not comprehensive (eg, accuracy of promotional claims was not systematically assessed). Although the proportion of all advertisements noncompliant by at least one criterion is not specified, this was a majority. The pharmaceutical industry’s Code of Conduct was first developed in 1960 and is currently in its 14th edition; newness or lack of familiarity should not apply. The Code contains a section (3.10) on “Advertising in electronic prescribing software packages”.6 However, compliance with the Code is the responsibility of the pharmaceutical companies, not the software developer. Software companies have the Medical Software Industry Association Code of Practice,7 which refers only to the Media Council of Australia Advertising Code of Ethics. The Media Council has been replaced by the Therapeutic Goods Advertising Code Council.8 The thematic analysis by Harvey et al of email postings by a self-selected group of general practitioners indicates that some GPs may be perturbed by pharmaceutical advertising appearing in their clinical software. Nevertheless, the software package referred to by Harvey et al as “the only Australian prescribing software containing pharmaceutical advertisements” continues its market dominance among GPs,9 although other prescribing software packages are available.10 It follows that many GPs, irrespective of their opinion on the promotional material it contains, continue to use the package and tolerate pharmaceutical advertising for a complex variety of reasons. These are likely to include ease of use, cost, lack of knowledge of competitive products, reluctance to change and lack of flexibility in learning new systems, absence of standards for electronic health records, and time limitation. Ultimately, the question posed by Harvey et al as to “whether pharmaceutical advertisements in clinical software should be banned” does not revolve solely around the opinions and behaviour of GPs, already subject to a range of forces. It also turns on the ethical principles and professional standards that guide the relationship between health care professionals and their patients, the genuine willingness of powerful health care organisations to affirm and facilitate the application of these principles, along with legal and other enforcement mechanisms. A number of recommendations flow from the findings of Harvey et al: All codes of conduct and other professional standards require regular review and updating, as well as implementation. As expressed by the Australian Competition and Consumer Commission in its November 2003 authorisation of the 14th edition, concern remains about the enforcement of the Code.11 Sanctions for breaches are generally modest, especially in comparison with the sales revenue of many widely prescribed pharmaceuticals. During 2003–04, 41 complaints were finalised by the Code of Conduct Committee. Fines totalling $205 000 were imposed in 12 cases (an average of $17 083).11 Corrective letters or advertisements were required in only seven cases. Sanctions could appropriately be increased, and perhaps linked to sales revenue for the product in question. Capping advertising expenditures across the industry, as occurs in the United Kingdom, deserves serious consideration.12 The closer to the doctor–patient interface, the less appropriate is the presence of advertising. The doctor–patient relationship should be free of intrusion or interference. Advertising at the doctor–patient interface is at a minimum intrusive, and may cause distraction and delay in the consultation. At worst, it may inappropriately influence prescribing and, as noted by Harvey et al, when visible on the doctor’s desk during a consultation, could function as prohibited direct-to-consumer advertising of prescription products. In our view, Harvey and colleagues’ recommendation that pharmaceutical promotion be eliminated from prescribing software is justified. Appropriate professional interactions with industry and standards for these should be part of undergraduate and postgraduate medical training programs, and Continuing Medical Education. All clinicians should have ready access to authoritative, independent, regularly updated, best-practice prescribing guidelines, such as Therapeutic guidelines,13 the Australian medicines handbook,14 Central Australian Rural Practitioners Association standard treatment manual15 and Australian adverse drug reactions bulletin.16 Such resources should be user-friendly and could appropriately be included in prescribing software. Doctors working in the pharmaceutical industry play a crucial role as ethical and scientific guardians and gatekeepers. They should be trained and supported in this role from inside and outside the companies, with companies unequivocally committed to developing and sustaining organisational cultures that have ethical and scientifically-based conduct and compliance with the Code at their core. All staff — especially sales and marketing staff — involved in the development, review and approval of promotional material should have compliance with the Code as individual objectives subject to performance appraisal, and should face personal sanction, such as forfeiture of bonus, for breaches of the Code for which they bear responsibility. Pharmaceutical companies should make scientific and ethical competence, and demonstrated familiarity with the Code, a condition of selecting agencies and individuals involved in developing promotional materials. Many of these recommendations are also relevant to medical software companies. Deficiencies described in medical software relate not only to advertising, but also to technical content, for example, in relation to quality of travel medicine information17 — more effective implementation of scientific and ethical standards, and regulation, are required. A step towards addressing these deficiencies is the evaluation and accreditation of GP clinical software packages. The work program of the General Practice Computing Group relating to the Review of Software Systems and the feasibility of a Software Supplier Accreditation Scheme18 is timely; the latter should incorporate the ethical standards, codes of practice and legal requirements for the industry.

Tilman A Ruff MB BS(Hons), FRACP · Hadia Haikal-Mukhtar MB BS, LLB(Hons), FRACGP

The Australian Primary Health Care Research Institute undertakes and commissions research with the aim of increasing the links between research and policy “Family, neighborhood, community are apple pie virtues, unassailable and unavoidable in political rhetoric.”1 In primary health care, we have our own rhetoric. The challenges facing the primary health care system are endlessly rehearsed: ageing of the population, management of chronic disease, equity, new technologies and workforce issues are but a few. These challenges are not unique to Australia — they drive reform of primary health care around the world. It is agreed that the goal of this reform is to improve health for individuals and communities, and that public policy on this reform should be in the public good, have clear objectives, be transparently communicated, and be assessable in terms of effectiveness, efficiency and achievements. It should also be informed by research evidence.2,3 Yet, sadly this is no more than comfortable rhetoric if there is no practical outcome. How can we move on? Moving beyond rhetoricBoth researchers and policy makers should move out of their “silos”.4 Research cannot be an isolated activity that never impacts on primary health care. Equally, policy formulation cannot be a secretive bureaucratic activity, viewing research as “naive, jargon-ridden and irresponsible in relationship to practical realities.”2 All players within the primary health care system must be engaged, including policy- and decision-makers in both the Commonwealth and the states and territories, researchers, and providers and users of primary health care services. Yet, lack of engagement is common. For example, the Asthma 3+ Visit Plan was tested as an intervention in a randomised controlled trial of structured asthma care in general practice.5 The design, conduct and reporting of this study were research-driven, and the results could not be disseminated until the peer-reviewed publication process was complete. However, just as the early results of the trial were becoming known to the research team, policy makers were fitting the Plan into Medicare through paid incentives for GPs to adopt and complete the Plan. The policy had to be implemented before the trial was formally published. There was no link between the researchers and the policy makers. Would the policy have been different if there was engagement between these parties across these activities? The players must be engaged at all stages of the policy research “cycle” — from priority setting and question formulation, through the development of research methods and conduct of research, to analysis and interpretation of results. Engagement must be real and may be uncomfortable. The role of research“Research” and “evidence” are value-laden words with different meanings for different players. The goal is valid and reliable knowledge that responds to the real needs of those using and providing health services, along with wisdom in applying this knowledge. If we are to achieve this, then all players must be willing to understand research and evidence from the viewpoints of the others. A range of research traditions will yield helpful insights.6 For example, policies for evidence-based clinical care of Aboriginal and Torres Strait Islander communities will be informed both by evidence-based medicine (EBM) and by a well developed understanding of Indigenous cultures derived from other research traditions, such as sociology. This is not a call for less rigour — it is a call for thinking beyond narrow methodological approaches. The role of research evidence in informing policy is broad.2 It should not be understood solely in terms of the findings of individual studies directly shaping particular policies. At times, the use of research evidence may be more symbolic — to add weight to a particular policy direction. At other times, research evidence may be used for enlightenment. For example, it may prompt participants to think in new ways about issues and potential solutions. The National Service Improvement Framework (NSIF) for Cancer is an example. This government initiative aims to drive improvements in health services through the development of a guide to “best practice”. Policy makers, the research community, clinicians, and other stakeholders have been actively engaged in the process through a consultative committee and a public consultation process. The resulting framework incorporates their different perspectives. Its usefulness is evidenced by its adoption as the model for the other NSIFs.7 Research needs to be undertaken within timeframes that are useful to policy makers. This does not rule out research programs longer than 3 years, but means that researchers should be aware of the timeframes that drive policy, such as 3-year election cycles, and should be willing to contribute to policy discussions despite their research being incomplete. In addition, concepts such as “track record” need to be rethought, as publications and grants received are not relevant measures of the success of policy makers and service providers. Methods need to be developed to appraise the relevance of research to policy making. Primary studies should be funded only when systematic reviews of existing evidence indicate they are required. For example, research to resolve the controversy about the role of nurses in Australian general practice should be built on what is already known from a systematic literature review, which is not yet available. If primary health care reform was easy, this editorial would be unnecessary. Research will not be perfect. Evidence will not be complete. Solutions will not be simple or universally acceptable. Reform will not happen overnight. Well intended innovations might deliver unintended harms. Patience, collaboration, good will and resilience are essential for the challenges to be met. The Australian Primary Health Care Research Institute (APHCRI) is a government initiative to increase the links between evidence and policy. Its brief includes prioritising research topics and questions relevant to national primary health care, and then commissioning and undertaking research to address these priorities. Announced as part of the federal government Primary Health Care Research and Evaluation Development Strategy,8 the Institute began operations in 2003. It is committed to a collaborative model that engages policy makers, researchers, providers and consumers in its activities. It adopts new approaches in setting its research priorities and funding research activities. It will go beyond rehearsing the challenges, and question some of our basic assumptions about how to achieve a more equitable, more efficient primary health care system delivering enhanced health outcomes for all Australians.

Nicholas J Glasgow MD, FRACGP · Beverly M Sibthorpe NZRN, BAHons, PhD · Robert Wells

Australia needs a coherent long-term strategy for implementing these systems Electronic Decision Support Systems (EDSS) have been defined as “access to knowledge stored electronically to aid patients, carers and service providers in making decisions on health care”.1 These systems provide relevant evidence-based information to both patients and health care providers at the time of making a decision about clinical management. More sophisticated systems provide a clinical decision based on information from a range of knowledge bases. EDSS are currently espoused as one of the keys to good quality and safe health care.2 With the current explosion of medical knowledge, most of which is stored electronically, both clinicians and consumers will increasingly require EDSS to assimilate and summarise information. Yet for most clinicians, there is a gulf between this ideal (see Box 1) and reality. Here, we look specifically at general practice, and we argue for the creation of a guiding body — a deus ex machina — to provide a comprehensive framework to remove all the constraints on achieving the full potential of EDSS. General practice cannot be considered in isolation, and EDSS will be used across the whole health care system. For this to happen, certain “clinical knowledge processes”, as identified by the National Electronic Decision Support Taskforce (NEDST), need to occur (Box 2).1 The NEDST was established under the ministerial National Health Information Management Advisory Council (NHIMAC) to address significant issues in the health sector’s information requirements for implementing electronic decision support . Australia has already done much to foster the uptake of EDSS (Box 3). In particular, the development of a vocabulary, data model and core data set for general practice within the Standards Work Plan by the General Practice Computing Group (Box 3) would allow seamless communication between different clinical software packages. These are important steps that should not be stalled because of political imperatives. While this progress has been important, significant developmental gaps still exist, and the entire “clinical knowledge process” must be embraced in a coordinated manner. Generating and integrating knowledgeDevelopment of computer-interpretable guidelines is not limited by clinical content, but by the clinical systems that exist today. To incorporate clinical concepts for use within an EDSS requires gathering specific clinical information and then incorporating it within the EDSS tool. The ideal EDSS knowledge base would seamlessly link these clinical concepts with standardised patient clinical records. Yet, it is unclear how this crucial linkage will be achieved when clinical computerised systems are presently imposed on general practice in an ad hoc and proprietary manner. Currently, there is no apparent active engagement between software developers, government, clinicians and funding bodies to establish a transparent and sustainable program of EDSS development in Australia. It is crucial that national bodies generate knowledge bases by developing clinical practice guidelines. Evidence points to the need for research on how guidelines may be implemented within EDSS to increase their acceptability in day-to-day practice.6 Each national body that develops guidelines should be working within a framework that explicitly states the eventual role of EDSS in their implementation. Clinical applicationWe currently lack a generic standards-based “middleware” that would sit outside all clinical desktop software systems and support the exchange of information with other clinical systems and clinical knowledge repositories. In Australia, no such standards exist, leaving EDSS development dependent on the whims of the software vendors. In the United Kingdom, although the National Health Service (NHS) has just agreed to allow greater choice among clinical desktop software packages, all clinical software must conform to minimum standards of interoperability within the NHS.7 Evaluation of efficacyA recent systematic review of 100 randomised and non-randomised trials of EDSS that aimed to improve clinical performance and patient outcomes found that, of the 97 studies that measured practitioner performance, 62 (64%) showed improvement — four in diagnosis; 16 in reminder systems; 23 in disease management systems, and 19 in prescribing.8 Of 51 studies examining patient outcomes, only 7 (13%) showed improvement (in blood pressure control, rates of urinary incontinence, outcomes with acute respiratory distress syndrome, asthma, anticoagulation management, and the care of people with acute myocardial infarction). The EDSS research agenda must begin to look more systematically at the influence of EDSS on patient outcomes and quality of care. One report argues that more multidisciplinary research is required to map and understand the “complex system” of day-to-day general practice, “in which technologies, people and organisational routines dynamically interact”.2 Other studies have identified similar concerns.9 Multidisciplinary research teams involving psychologists, fulltime GPs, practice staff and qualitative researchers must be adequately funded and supported over a number of years to realise this goal.10 NEDST has called for rigorous evaluation of EDSS programs, but only after programs were well established within a workplace.3 ConclusionThere is clearly much to be done and, at the moment, there is no obvious coherent long-term strategy in Australia to drive the EDSS agenda forward. The solution may be to establish a national EDSS coordinating centre with substantial funding and expertise. A multidisciplinary framework will be required, which includes appropriate long-term funding and meaningful intellectual property arrangements with software vendors to promote open standards. This would be an excellent first step to move this agenda forward in a balanced, integrated and evidence-based framework linked to appropriate policies, legislation and standards development. 1 Electronic decision support systems (EDSS) case study: the ideal A 44-year-old man presents to his general practitoner with newly diagnosed hypertension. The GP reviews his blood pressure and prepares to assess his cardiovascular risk using the EDSS. The EDSS directly integrates all his electronic medical record information (lipid levels, smoking status, family history, age, sex, and weight) to calculate his risk score. This provides a comprehensive profile that contains all relevant information which can be quickly updated on subsequent visits. The GP opens the software, selects the patient from the practice database and begins to work through the tool, entering the clinical information directly into the EDSS. As he goes, he shows the patient how he calculates his risk of cardiovascular disease and how the patient can alter the level of risk. This visual demonstration helps the patient realise that he must change his behaviours. They discuss the options available. To educate the patient on how to moderate his risk and adopt healthy behaviours, the doctor shows him the embedded resources and video on hypertension, exercise and salt intake. The GP chooses the best evidence-based management plan and prescribes new medication. The management plan is instantly updated in his notes. The EDSS automatically places the patient on the practice-based cardiovascular disease register. The patient feels reassured and informed. Details of his clinical management will now form part of the GP’s quality improvement audit. 2 The “clinical knowledge process”, from building the evidence to implementing a decision support “product” Identified by the National Electronic Decision Support Taskforce.1 3 Achievements in implementing Electronic Decision Support Systems (EDSS) in the Australian health sector to date Identification of six key areas for improvement by the National Electronic Decision Support Taskforce: (i) fostering research; (ii) development and best practice in the implementation of EDSS; (iii) enhancing the safety and quality of EDSS; (iv) establishing a national standards framework; (v) encouraging an evaluation culture; (vi) encouraging the use of EDSS and establishing a national governance model.1 Creation of an evaluation framework for EDSS by the Australian Health Information Council.3 Establishment of the National e-Health Transition Authority to accelerate the adoption of e-health by such measures as developing standards for the exchange of clinical information; enabling the unique identification of patients, providers, products and services; and integrating infrastructure.4 Initiation of the Standards Work Plan by the General Practice Computing Group to develop a vocabulary, data model and core data set for general practice.5

Justin J Beilby MD, MPH, FRACGP · Andre J Duszynski BSc · Anne Wilson PhD, BN, MN · Deborah A Turnbull MPsych(Clin), PhD

Treating the paradox of an important emerging public health problem The international perception of bronzed Australians inhabiting a “sunburnt country” is under threat. Most Australians, including children, now sensibly avoid excessive sun exposure to reduce the risk of skin cancer. However, other Australians, particularly those who are older, disabled or institutionalised often do not receive even modest levels of sunlight exposure. This has led to the paradox of vitamin D deficiency emerging as a public health issue in sunny Australia. . . . despite Australia being a “sunburnt country”, vitamin D deficiency is common. But why is it important? Besides older and institutionalised Australians, others particularly at risk of vitamin D deficiency are people with pigmented skin from Africa, India and Pakistan; women who practise veiling; those on certain medications (eg, anti-epileptic drugs); and those with malabsorption or a low vitamin D intake. Even young Australians, pregnant women and their infants are at risk of this emerging health problem.1 The prevalence of vitamin D deficiency among Indigenous Australians has not been determined, but is likely to be high. The problem was highlighted recently in the Journal in a position statement on vitamin D and bone health in adults.2 Vitamin D deficiency is usually classified as mild (25-hydroxyvitamin D [25OHD] level, 25–49 nmol/L), moderate (12.5–24 nmol/L) or severe (< 12.5 nmol/L). The Geelong Osteoporosis Study detected mild or moderate deficiency in more than one in three women surveyed in summer, which rose to one in two in winter.3 Even in south-east Queensland, Western Australia, New South Wales and Victoria, nearly a third of men and women have mild to moderate vitamin D deficiency.4 Almost half of nursing home patients, and almost all patients in aged care facilities surveyed have at least mild vitamin D deficiency. Thus, despite Australia being a “sunburnt country”, vitamin D deficiency is common. But why is it important? Severe vitamin D deficiency results in osteomalacia in adults and rickets in children. Milder vitamin D deficiency results in secondary hyperparathyroidism and increased bone turnover, predisposing to osteoporosis. Proximal myopathy and muscle pains may occur in moderate or severe vitamin D deficiency, and the incidence of falls is increased.5 Less well known is the impact of vitamin D deficiency on depression, immunity and autoimmunity, obesity, and the progression of type 2 diabetes mellitus. It is also important to correct vitamin D deficiency to optimise the effects of other anti-osteoporotic drugs. In a recent United States study of 1536 women receiving anti-osteoporotic therapy, 52% had vitamin D deficiency.6 Treatment with intravenous or (more rarely) oral bisphosphonates may also cause severe hypocalcaemia in people with severe vitamin D deficiency,7,8 so it is prudent to screen for vitamin D deficiencies before initiating bisphosphonate therapy. In the broad context of vitamin D deficiency as an emerging public health issue, the article by Diamond et al in this issue of the Journal (page 10)9 is timely. Their prospective open label study of 50 elderly women and men with vitamin D deficiency showed that a single intramuscular injection of 600 000 IU (or 15 mg) of cholecalciferol (vitamin D3) increased serum 25OHD concentrations to above 50 nmol/L in all patients. Over 12 months, serum 25OHD concentration rose, on average, by 128% to 73 nmol/L — a level most would consider to be optimal. Secondary hyperparathyroidism, present in about 50% of participants, was abolished in most. The complications of therapy were mild hypercalcaemia in two participants (4%) and fasting hypercalciuria in 10 participants (20%) tested at 12 months. The study by Diamond and colleagues represents a step forward in currently available treatment options for vitamin D deficiency. Currently, this is limited to doses of 200–1000 IU of either vitamin D2 (ergocalciferol) or vitamin D3 (cholecalciferol). The commonest form is 1000 IU of ergocalciferol (Ostelin; Boots Healthcare Australia). Loading doses of 3000–5000 IU per day are required to treat severe vitamin D deficiency and, as commercially available radioimmunoassays do not always measure vitamin D2 as well as vitamin D3, measuring treatment response is difficult. Daily dosing is also difficult or unrealistic for many community-dwelling older people in whom compliance would be expected to be poor. A single intramuscular “megadose” of cholecalciferol would overcome this compliance issue in a simple and cost-effective manner. The mild hypercalcaemia and fasting hypercalciuria are of concern, but further controlled trials are planned, which will include 24-hour urine calcium excretion measurements, to evaluate the safety of “megadose” cholecalciferol therapy. The effect of this treatment on fracture risk is not established. A recent British study of 9440 community-dwelling participants aged 75–100 years, randomly allocated to receive either an annual injection of 300 000 IU cholecalciferol or placebo, showed no reduction in fracture rate.10 Nevertheless, the greatest clinical utility of an annual megadose injection is likely to be in older institutionalised people, most of whom are vitamin D deficient. The most important outcome in osteoporosis prevention or treatment is a reduction in fracture risk. Some data suggest treating vitamin D deficiency may prevent low-trauma fractures. A large French study in institutionalised, ambulatory older women found that daily doses of 800 IU of cholecalciferol and 1.2 g of calcium significantly decreased the incidence of hip and non-vertebral fractures compared with placebo after 18 months.11 Daily vitamin D and calcium treatment also reduced non-vertebral fractures in community-dwelling older American men and women.12 A recent large trial in community-dwelling British men and women aged over 65 years showed that a large oral dose of cholecalciferol (100 000 IU) every 4 months reduced osteoporotic fractures by 33%.13 The RECORD trial attempted to determine the relative contribution of calcium versus vitamin D on fractures. Ambulatory patients (5292) who had sustained a low-trauma fracture were randomly allocated to receive calcium (1000 mg/day), vitamin D3 (800 IU/day), a combination of the two, or placebo. After at least 24 months, fracture rates did not differ between the four groups. However, compliance at 2 years was poor.14 Further large studies of vitamin D and its effects on fractures and falls are still needed, particularly in populations at risk of vitamin D deficiency; these studies need to use varying oral doses of vitamin D and to include men. The treatment described by Diamond et al is a good start to introducing new alternatives for treatment of vitamin D deficiency in targeted people. However, much more work is needed to identify successful public health approaches that can be more broadly applied to this emerging public health problem.

Peter R Ebeling MD, FRACP

Canteens are not the main source of food for Australian school kids, but their symbolism is big There is widespread awareness of the obesity epidemic in Australian children,1 and the focus has now, quite appropriately, turned to action. In the United Kingdom, celebrity chef Jamie Oliver is trying to transform a 100-year-old school lunch service from “soggy and fried” to “crisp and fresh”. In Australia, the question is whether school canteens should be a high priority for action, because of their accessibility and visibility, or a low priority, on the grounds that canteen foods contribute little to children’s energy intake. Negative ripples from canteensOver the period of a year, children aged 5–15 years obtain only about 16% of their total energy intake from food eaten at school, and probably less than 3% comes from canteens.2 But while the energy contribution is small, the symbolism is big. Canteen users consume significantly greater amounts of foods likely to promote unhealthy weight gain, such as fast foods, confectionery and packaged snacks.2 The types of foods and beverages that predominate in school canteens not only undermine the health and nutrition curriculum, but also create the impression that foods and drinks that are high in fat, sugar and salt belong on the plate as “everyday foods”, rather than on the side as “occasional foods”. Other common practices in schools that undermine healthy eating messages include rewarding children with sweets, having soft-drink and confectionery vending machines, holding sporting events with fast-food vouchers as prizes, and using chocolate drives for fundraising. All these practices create negative ripple effects on Australian family eating practices and beliefs.3 Children are developing the food preferences that they will carry with them into adulthood, so strengthening family and school environments for enjoying healthier food choices is critical. In a 2004 survey of 18 Victorian primary schools (unpublished data), we found that, of the 17 with a food service, all sold meat pies, but only five sold fruit on a regular basis. As a rule, canteen managers provided foods that sold well and had a long shelf life. They usually had no mandate or support to do otherwise. A reliance on profits from canteens, vending machines and “junk food fundraising” also makes it hard for schools, particularly high schools, to model healthy eating. In common with a survey of 500 New Zealand schools,4 we found that schools readily recognise the rather poor job they do of providing a healthy food environment. Most schools do not see food provision as part of their core business and lack the inclination or resources to take on this “added” responsibility. Private enterprise fills this vacuum, with the result that the health of profits increasingly dominates the health of pupils. An extreme example is the “cola war” in the United States, in which the weapons of choice have been contracts with schools to sell minimum volumes of Coca Cola or Pepsi.5 Creating a new epidemic?Perhaps we should consider the task ahead of us as the creation of a new epidemic of healthy eating rather than reducing an obesity epidemic. Using the principles in Gladwell’s recent bestseller The tipping point,6 the school canteen and students themselves could be the catalyst for healthier eating among children and adolescents — turning negative ripples into positive waves. Can a “tipping point” be created from a handful of champion schools that decide to embrace the whole-of-school policies and strategies needed to get their canteens right (healthy, enjoyable, profitable and supported), hoping that others will follow their lead? This is almost certainly too much to expect to happen in 9000 schools across Australia, which tend to function semi-autonomously on these matters. Lessons from successful public health programs, such as sun protection and injury prevention, show that tipping the balance in targeted behaviours from unhealthy to healthy requires a backbone of strong central policy, ongoing social marketing, and supported and coordinated implementation of programs. Some Australian modelsVarious government-supported models influence how school canteens operate in Australia. Probably the least effective include the Victorian model of simply disseminating canteen guidelines7 and the Australian Government model from the pre-election spending spree, wherein each school could apply for $1500 to reinvent the “healthy canteen” wheel. Neither has policy, social marketing or implementation support. A third model, which has some merit, is exemplified by the Western Australian (StarCAP8) and Tasmanian (Cool CAP9) school canteen accreditation programs. Both have well developed criteria and processes for schools to work through to achieve program accreditation. StarCAP is backed by the WA government, but is managed on a shoestring budget, without policy and social marketing support, and thus has a low accreditation rate (7% of schools) and declining reach.10 Cool CAP is newer, with a higher accreditation rate (42% of schools accredited or working towards it), and so far has been successful in securing legislative and monetary support. Ultimately, however, the impact of these types of programs will probably be modest as long as the impetus to change remains with each individual school. Because they are well supported and centrally driven, the most promising models come from New South Wales and South Australia. The NSW Healthy School Canteen Strategy (“Fresh Tastes @ School”)11 grew out of the NSW Government Childhood Obesity Summit in 2002. It is now mandatory for state schools to provide food and beverage choices consistent with the Australian guide to healthy eating.12 NSW Health has also boosted support for the NSW Canteen Association so that it, in turn, can support schools to operate economically viable, nutrition-oriented school canteens. Early positive waves include support from parents, canteen managers, some food companies and, increasingly, local health and education services. A similar model released in 2004 in South Australia brings SA government backing to a set of healthy eating guidelines.13 The guidelines encourage links between the canteen, the community and teaching about nutrition food skills. Both the NSW and SA government models would now benefit from social marketing explaining the rationale, processes and support for the program. It would make sense, for example, to link these strategies with the national “Go for 2&5” (2 serves of fruit and 5 serves of vegetables) campaign.14 If we are serious about the childhood obesity epidemic, school canteens are a good place to start, because they carry a symbolism that ripples into the Australian diet far beyond their contribution to energy intake. At the moment, the ripples are a negative and undermining force. However, full implementation of the NSW or SA models for school canteens throughout the country could just tip the balance towards an outbreak of healthier eating.

A Colin Bell BSc(Hons), MSc, PhD · Boyd A Swinburn MB ChB, MD, FRACP

Not so long ago, the International Committee of Medical Journal Editors (ICMJE) — represented by 11 general medical journals including The Medical Journal of Australia — took a fairly passive and advisory role in medical publishing. The major outcome of its efforts was the Uniform requirements for manuscripts submitted to biomedical journals, which is an internationally accepted reference for biomedical publishing. It gives recommendations for preparing manuscripts for submission, and includes statements on editorial roles and responsibilities, authorship, and ethical issues governing biomedical publication.1 Recently, the ICMJE has adopted a more aggressive, interventional role. This new function first surfaced with the ICMJE’s 2001 statement Sponsorship, authorship and accountability, which conveyed the requirements for publishing clinical trials conducted with corporate sponsorship.2 The statement’s bottom line was that publication of such trials depended on compliance with transparent processes regarding responsibility for the trial, access to and control of data, and control of publication by researchers. In short, transparency and independence were stressed. The next ICMJE foray came with its 2004 statement on Clinical trial registration,3 which, despite being cautiously welcomed by research and media commentators,4,5 has reverberated in the research community, and in particular in the pharmaceutical industry, ever since.6 This statement was a response to the pharmaceutical industry’s longstanding unethical practice of “silent” clinical trials. It decreed that ICMJE journals would only consider publishing reports of trials that had been registered before enrolling the first participant. This policy came into operation on or after 1 July 2005 for new trials, and any ongoing trials are to be registered before 13 September 2005. The need for prospective registration of clinical trials is not a new idea.7,8 Almost a decade ago, for example, the Australian Health Ethics Committee first acknowledged the need to establish a clinical trials register in Australia.9 Now, in one swoop, the ICMJE has provided the impetus to move trial registration from the realm of theoretical nicety to its rightful place on various ethical and political agendas. In a follow-up statement in May this year, Is this clinical trial fully registered?,10 the ICMJE reaffirmed its clinical trial registration policy and endorsed the World Health Organization’s minimal registration data set of 20 fields. It also reaffirmed its requirements for an acceptable clinical trial registry: it must be electronically searchable, with free access; it must be open to all registrants; the trial data must be validated; and it must be a not-for-profit concern. The clinical trial registry site currently endorsed by the ICMJE is sponsored by the United States National Library of Medicine (http://www.clinicaltrials.gov), but the committee acknowledges that further registries will come on stream. These are under development in Japan, India and South Africa.11 In May this year, the Australian Government announced a grant of $1.5 million for the establishment of The Australian Clinical Trial Registry at the National Health and Medical Research Council Clinical Trials Centre at Sydney University.12 The Australian Registry (http://www.actr.org.au) complies with ICMJE and WHO requirements and became available for registrations in late June 2005. It is highly likely that more national trial registries will emerge. The WHO is currently developing an approval process to assess compliance of registers with ICMJE and WHO requirements.11 The WHO also plans to provide a web-based portal to all registries. These developments make sense: a cluster of national and regional clinical trial registries linked by an international agency. The WHO is ideally suited to assume this role and it will free the ICMJE to do what it does best — formulate publication policy.

Martin B Van Der Weyden MD, FRACP, FRCPA · Davina Ghersi BAppSc, MPH

The problem of surgical waiting lists requires multifactorial solutions The provision of public hospital services inevitably involves managing the demand for these services. This is usually achieved by rationing. Elective surgery is the easiest service for health administrators to manipulate to meet budget imperatives and to manage demand pressures, through controlling surgical waiting lists. In short, the pestle of demand grinds against the mortar of budget restriction in the management of elective surgical lists. Although health planners are able to accurately predict demand for surgical services, administrators often plan not to meet that demand because of budgetary restrictions. With effective management, the only day-of-surgery cancellations should be occasional patients with an acute change in their medical condition. In this issue of the Journal, Schofield and colleagues report on one aspect of demand management: the cancellation of operations on the day of surgery.1 This is almost unheard of in the private health-care sector, where the supply of surgical services is virtually uncapped. Schofield et al also shed some light on the reasons for these cancellations. In the tertiary-care hospital that was the focus of their investigations, the rate of on-the-day cancellations of surgery (11.9% overall, and 13.2% for weekday elective surgery) is a cause for concern. The Australian Council on Health Care Standards guideline is that the day-of-surgery cancellation rate should be low,2 which, in New South Wales, is interpreted to mean not exceeding 1.5%. In my own hospital, Nepean (also a tertiary-care hospital), it is about 3%. A higher rate of cancellations can be expected in hospitals where patients, such as those undergoing major general and cardiac surgery, depend postoperatively on a dedicated intensive-care bed. For these patients, Schofield et al found cancellation rates of 31.2% and 28.5%, respectively; these are higher than would usually be expected. As intensive-care beds are assigned in NSW as part of a statewide coordination service, the management of this problem requires involvement of agencies at a higher level than hospital administration. However, it is not clear why surgical services in the survey by Schofield et al, such as ear, nose and throat or plastic surgery (which should be largely independent of intensive-care and inpatient beds), had such high cancellation rates. The reasons for elective surgery cancellations revealed by Schofield and colleagues fell into five nearly even groups — lack of theatre time, lack of postoperative beds, cancellation by patient or carer, patient clinical change, and procedural reasons. As elective surgery is one of the most predictable aspects of hospital medicine, the great bulk of these cancellations could be avoided with better management systems. With effective management, the only day-of-surgery cancellations should be occasional patients with an acute change in their medical condition. Managing elective surgery more efficiently requires a well thought out management system with quarantining of resources to ensure patient flow. Such a system has recently been described by Ryan and colleagues — the 23-hour ward model.3 In this model, it is expected that the episode of care can be delivered within an envelope of 23 hours, during which time patients require only pain relief and monitoring in a supervised setting until fit for discharge. This model is quarantined from the rest of the hospital or area bed-base, either in a designated ward or a smaller hospital in the area. Patient care is protocol driven, and patients are not admitted unless they are on a clinical pathway. The protocol includes compulsory pre-admission and pre-anaesthetic assessment, careful construction of lists matching patients to available beds and operating-room slots, and a guarantee that elective procedures will not be cancelled. Patient flows are predetermined, with a staged recovery process. This model does not lead to significant increases in readmission rates, nor does it significantly affect community services.3 It is suitable for about 80% of patients requiring elective surgery. The NSW Surgical Service task force has recently recommended the adoption of this model, and the NSW Department of Health has advised all area health services to institute it. Adopting this model’s approach may also help patients who require stays of over 23 hours. A management process that links the predictable demand for elective surgery to operating sessions and beds can avoid cancellations and enable effective and predictable access for all patients. Waiting times are multifactorial and vary between areas, between hospitals in areas and between individual surgeons within hospitals.4 In addition to better management practices based on operational research,5 other solutions to the problem of waiting lists are needed. In elective orthopaedic surgery, there is a need for more resources for prostheses and a better system of prosthetic purchasing. In ear, nose and throat surgery, there is a need for more creative schemes to better utilise the few available specialists. Other solutions may involve contracting specific groups of patients to the private sector (the subject of a pilot study in NSW6) and developing whole new approaches, especially in the apparently insoluble area of intensive-care bed provision (eg, the surgical acute-care unit7). Currently, 1% of the NSW population is on a surgical waiting list, with similar figures in other states and territories. We have clear evidence of the harm that excessive waiting times cause patients.8 All available means must be used to solve this problem. Above all, there is a need to avoid the distress caused to patients by day-of-surgery cancellations.

Patrick C Cregan FRACS

A common-sense approach to reducing exposure to polluted air is required It is an unquestionable fact that regular physical activity is beneficial to health and longevity. Accordingly, it is common practice for physicians and other health care professionals to encourage exercise. However, people exercising in urban regions may be unwittingly at risk because of exposure to concentrated automotive pollution, a known risk factor for cardiovascular and respiratory disease. The physiological changes that occur during exercise probably act to compound the toxic effects of environmental air pollution, and certain patient populations may have increased sensitivity. People should not be deterred from regular exercise, as it is of known benefit, but when prescribing exercise, clinicians should extend appropriate advice to patients to avoid areas with high pollutant concentrations. What, then, is the evidence to support such advice? Automotive exhaust comprises a heterogeneous mixture of suspended particles and gases, the most common gases being sulphur dioxide, nitrogen dioxide, carbon monoxide and ozone. Unburnt fuel emits volatile organic compounds (eg, benzene, toluene) and the fuel combustion process liberates many thousands of chemicals in addition to particulate matter of varying size and composition. Ultrafine particulate matter, with an aerodynamic diameter < 0.1µm, is thought to be particularly harmful to health, as it is readily inhaled and absorbed into the circulation.1 Epidemiological data have identified individual components of air pollution, or pollution collectively, as promoters of cardiovascular and respiratory disease.2,3 Some compounds are also known or suspected carcinogens.4 Harmful effects on the body from pollutants are multifactorial, with acute or chronic exposures increasing the cellular processes associated with atherogenesis (the underlying cause of most cardiovascular disease), impairing pulmonary function, provoking local and systemic inflammation, disrupting cardiac autonomic control and inducing vascular dysfunction. Deleterious health effects may result from exposure to pollutants at concentrations that are lower than recommended air quality standards.5 Indeed, research to date has failed to determine a “threshold” limit for which there is no adverse health effect.6 In general, most large-scale time series analyses of the physiological effects of air pollution find an exposure-dependent relationship that crosses socioeconomic boundaries and poses a significant threat to everyone’s health. Importantly, certain populations may be particularly vulnerable to the effects of polluted air, such as children;7 people with asthma,8 diabetes9 or acute lower respiratory disease; and frail or elderly people with pre-existing heart and lung conditions.10 Why may exercise in polluted areas be particularly hazardous? During aerobic exercise, even at relatively low intensities, inspired air is taken in predominantly through the mouth, and there is a major increase in minute ventilation and diffusion capacity. These factors augment the respiratory uptake of airborne contaminants, with increased penetration to the lower gas-exchange regions of the lung. Indeed, the total amount of ultrafine particulate matter deposited in the respiratory tract of humans during moderate exercise has been shown to be about five times that at rest.11 As would be expected, when the concentration of pollutants increases, so too does the amount of inhaled matter. Thus, habitual exercise in highly polluted localities, such as alongside busy roadways, may increase the overall intensity, duration and frequency of exposure, all of which are relevant to the evaluation of an individual’s risk profile for disease.6 Pulmonary function may markedly decline after inhalation of pollutants during exercise. In one study, when adolescents with asthma were exposed to sulphur dioxide and sodium chloride aerosol during treadmill running, many displayed symptoms of wheezing and shortness of breath.12 Several other studies have shown that poor air quality and acute exposures during exercise may induce symptoms in people with asthma, impair athletic performance in healthy people,13 and contribute to exercise-induced myocardial ischaemia in patients with stable coronary artery disease.14 This information should not be interpreted as a reason for people living in cities to stop exercising. Rather, a common-sense approach to reducing or avoiding exposure to polluted air during exercise is advisable. In summary, there is sound evidence for an exposure-dependent relationship between air pollution, morbidity and mortality, particularly in relation to cardiovascular and respiratory illnesses. Although regular aerobic exercise is recommended for good health, there may be adverse health consequences for people who habitually exercise in areas of high ambient pollution. Despite this, it is not uncommon to see people running or cycling alongside congested roadways, and clinicians should advise patients to exercise on quiet roads or in parks and recreation areas. The best time of day to exercise is early in the morning, before the build-up of traffic and when it is cooler. This is relevant because the combination of sunlight and heat with certain compounds increases ozone production. Importantly, certain groups may be acutely susceptible to the effects of air pollution, and clinicians should advise them accordingly.

James E Sharman BHM(Hons), PhD

Assessment of real cost effectiveness, with data linked to individual health outcomes while protecting patient privacy, is an essential challenge we need to meet Pharmacogenetics and pharmacogenomics — the use of genetic and genomic information, respectively, to tailor drugs to the treatment of individual patients — make it possible to use information from the human genome in ways that will radically transform the prevention and treatment of human disease.1,2 Over the past several years, Australians have been given access to several drugs which can be prescribed under a taxpayer-funded scheme only if the patient has a specific molecular disease target that predicts a good treatment outcome. The first such drug was trastuzumab for the treatment of breast cancer in women whose tumours over-express the HER2 protein. This drug was supplied by the government from December 2001 through a special program outside the Pharmaceutical Benefits Scheme (PBS). Another drug, imatinib, was also listed on the PBS in December 2001 for use in the accelerated and blast phases of chronic myeloid leukaemia, and in October 2002 for use in the chronic phase of that disease. In December 2004, gefitinib was listed for the treatment of non-small cell carcinoma of the lung in patients with evidence of an activating mutation in the epidermal growth factor receptor gene. These drugs are likely to be harbingers of a stream of drugs in which genetic information about individuals or their tumours (whether they result from DNA or RNA sequence changes, or protein alterations) will be used to maximise the efficacy of treatment. Funding the provision of new biological agents under the PBS will present a major financial outlay. Though the number of eligible patients may be small, the costs per patient are high (eg, more than $45 000 per patient per year for imatinib and more than $50 000 per year for gefitinib and trastuzumab). The high cost of providing these drugs to relatively small numbers of patients will add to the cost of the PBS when annual growth in government expenditure on pharmaceuticals averaged 10.5% between 1992–93 and 2002–03 (increasing from $1.883 billion to $5.121 billion).3 The Australian Pharmaceutical Benefits Advisory Committee (PBAC) makes recommendations to government on which drugs to list on the PBS on the basis of their comparative clinical efficacy, safety and cost-effectiveness.4 Given the high price of many of these new and existing biological agents, it has been argued that alternative models of access are needed, because they may only be cost-effective in a subgroup of patients with a disease.5 The PBAC has used a number of strategies that allow access to new biological agents while respecting the principle of cost-effectiveness. These options depend critically on identifying the subgroup of patients in whom the drug is cost-effective compared with the main available alternative treatment. Patient groups are defined by the presence of particular molecular markers of disease severity, underlying disease mechanism, or treatment prognosis.4 The PBAC has recently developed a collaborative model to enable the listing of the tumour necrosis factor-alpha inhibitor class of biological agents (including etanercept, adalimumab and infliximab) and anakinra, an interleukin-1 receptor antagonist, all of which are used in managing rheumatoid arthritis. Although molecular markers were not part of the restrictions for these drugs, the collaborative model that was developed can be applied more broadly. This model involves working with key stakeholders in the relevant medical specialty, representatives from the pharmaceutical company producing the drug, and consumer organisations to develop restrictions that will ensure that the drugs are used in ways that are the most cost-effective.4,6 These restrictions include detailed rules for initiation and continuation of therapy. The initiation rules may include a specified diagnostic test and/or evidence that the patient has failed to respond to existing treatments for the condition. Continuation of treatment requires evidence of adequate benefit on some appropriate clinical or biological test. Patients who start taking the drug are required to sign an agreement indicating that they understand and accept that PBS-subsidised treatment will cease if the criteria defining a satisfactory response to the drug are not achieved in the follow-up clinical assessment.6 An underlying difficulty (and additional cost) in listings with molecular targets is that the mechanism for identifying the target population is not coordinated with the drug development process. We need to evaluate the effects of genetically or genomically targeted drugs that are listed on the PBS on patient outcomes to improve the existing regulatory arrangements for these new drugs. Ideally, such evaluations should use data that link information on drug use and individual health outcomes. Linked data are currently very difficult to obtain for reasons of patient privacy and confidentiality, but methods should be put in place at the time of drug listing, with appropriate privacy safeguards, that enable the impact of these drugs to be assessed. The policy and economic challenges posed by these drugs also warrant wider public discussion. Increased public appreciation of the challenges that these drugs pose to the PBS is essential if we are to develop a broadly supported policy that will make these very expensive drugs available to patients who have the potential to benefit from them at a price that reflects their therapeutic value and at a cost that the government and the taxpayer are prepared to bear.

Wayne D Hall AM, PhD · Robyn Ward MB BS, FRACP, PhD · Winston S Liauw MB BS, MMedSci, FRACP · Jo-anne E Brien BPharm, BS(Pharm), PharmD · Christine Y Lu BPharm, MSc

In September 2004, the members of the International Committee of Medical Journal Editors (ICMJE) published a joint editorial aimed at promoting registration of all clinical trials.1 We stated that we will consider a trial for publication only if it has been registered before the enrolment of the first patient. This policy applies to trials that start recruiting on or after 1 July 2005. Because many ongoing trials were not registered at inception, we will consider for publication ongoing trials that are registered before 13 September 2005. Our goal then and now is to foster a comprehensive, publicly available database of clinical trials. A complete registry of trials would be a fitting way to thank the thousands of participants who have placed themselves at risk by volunteering for clinical trials. They deserve to know that the information that accrues from their altruism is part of the public record, where it is available to guide decisions about patient care, and deserve to know that decisions about their care rest on all of the evidence, not just the trials that authors decided to report and that journal editors decided to publish. We are not alone in pursuing this goal. The World Health Organization (WHO), through meetings in New York, Mexico City, and Geneva, has brought us close to the goal of a single worldwide standard for the information that trial authors must disclose. Around the world, governments are beginning to legislate mandatory disclosure of all trials. For example, among the bodies considering new legislation is the US Congress, where the proposed Fair Access to Clinical Trials (FACT) Act would expand the current mandate for registration of clinical trials. Many other journals have adopted our policy of requiring trial registration. These initiatives show that trial registration has become a public issue. But, as our deadline for registration approaches, trial authors and sponsors want to be sure that they understand our requirements, so that reports of their research will be eligible for editorial review. The purpose of this joint and simultaneously published editorial is to answer questions about the ICMJE initiative and to bring our position into harmony with that of others who are working toward the same end. Our definition of a clinical trial remains essentially the same as in our September 2004 editorial: “Any research project that prospectively assigns human subjects to intervention and comparison groups to study the cause-and-effect relationship between a medical intervention and a health outcome.” By “medical intervention” we mean any intervention used to modify a health outcome. This definition includes drugs, surgical procedures, devices, behavioural treatments, process-of-care changes, and the like. We update our 2004 editorial to state that a trial must have at least one prospectively assigned concurrent control or comparison group in order to trigger the requirement for registration. Among the trials that meet this definition, which need to be registered? The ICMJE wants to ensure public access to all “clinically directive” trials — trials that test a clinical hypothesis about health outcomes (eg, “Is drug X as effective as drug Y in treating heart failure?”). We have excluded trials from our registration requirement if their primary goal is to assess major unknown toxicity or determine pharmacokinetics (phase 1 trials). In contrast, we think the public deserves to know about trials that could shape the body of evidence about clinical effectiveness or adverse effects. Therefore, we require registration of all trials whose primary purpose is to affect clinical practice (phase 3 trials). Between these two extremes are some clinical trials whose prespecified goal is to investigate the biology of disease or to provide preliminary data that may lead to larger, clinically directive trials. We recognise that requiring public registration of trials whose prespecified goal is to investigate the biology of disease or to direct further research might slow the forces that drive innovation. Therefore, each journal editor will decide on a case-by-case basis about reviewing unregistered trials in this category. Authors whose trial is unregistered will have to convince the editor that they had a sound rationale when they decided not to register their trial. The ICMJE will maintain this policy for the next two years. We will then review our experience. Our September 2004 editorial specified the information that we would require for trial registration. Attendees at a recent meeting of the WHO registration advisory group identified a minimal registration dataset of 20 items (Box). The WHO-mandated items collectively address every key requirement that we established in our September 2004 editorial. The ICMJE supports the WHO minimal dataset and has adopted it as the ICMJE’s requirement: we will consider a trial for publication if the authors register it at inception by completing all 20 fields in the WHO minimal dataset. As individual editors, we will review the data in the registration fields when we decide whether to consider the trial for publication. We will consider a registration dataset inadequate if it has missing fields or fields that contain uninformative terminology. If an investigator has already registered a clinical trial in a publicly owned, publicly accessible registry using the data fields that we specified in our 2004 editorial, we will consider that registration to be complete as long as each field contains useful information. Acceptable completion of data fields is an important concern. It shouldn’t be, but it is. Many entries in the publicly accessible clinicaltrials.gov database do not provide meaningful information in some key data fields. A search conducted on May 4, 2005 (Deborah Zarin, MD, personal communication) indicates that certain pharmaceutical-company entries list a meaningless phrase (eg, “investigational drug”) in place of the actual name of the drug, even though a US law requires trial registrants to provide “intervention name” (http://www.fda.gov/cder/guidance/4856fnl.htm). Many companies and other entities are completing the data fields in a meaningful fashion. Data entries must include information that will be of value to patients and health professionals; the intervention name is needed if one is to search on that intervention. We recognise that clinical trial registries have many uses, but whatever the use, a worldwide uniform standard for a minimal database is necessary. We have participated in the WHO effort to establish a clinically meaningful trial registration process. The ICMJE supports this ongoing project. When it is complete we will evaluate the process, and if it meets our primary objectives, we will adopt it. We stated our requirements for an acceptable trial registry in the September 2004 editorial, and they remain the same. The registry must be electronically searchable and accessible to the public at no charge. It must be open to all registrants and not for profit. It must have a mechanism to ensure the validity of the registration data. The purpose of a clinical trials registry is to promote the public good by ensuring that everyone can find key information about every clinical trial whose principal aim is to shape medical decision-making. We will do what we can to help reach this goal. We urge all parties to register new and ongoing clinical trials. If in doubt about whether a trial is “clinically directive,” register it. Don’t use meaningless phrases to describe key information. Every trial participant and every investigator should be asking, “Is this clinical trial fully registered?” Minimal registration dataset* Item Comment 1. Unique trial number The unique trial number will be established by the primary registering entity (the registry). 2. Trial registration date The date of registration will be established by the primary registering entity. 3. Secondary IDs May be assigned by sponsors or other interested parties (there may be none). 4. Funding source(s) Name of the organisation(s) that provided funding for the study. 5. Primary sponsor The main entity responsible for performing the research. 6. Secondary sponsor(s) The secondary entities, if any, responsible for performing the research. 7. Responsible contact person Public contact person for the trial, for patients interested in participating. 8. Research contact person Person to contact for scientific inquiries about the trial. 9. Title of the study Brief title chosen by the research group (can be omitted if the researchers wish). 10. Official scientific title of the study This title must include the name of the intervention, the condition being studied, and the outcome (eg, The International Study of Digoxin and Death from Congestive Heart Failure). 11. Research ethics review Has the study at the time of registration received appropriate ethics committee approval (yes/no)? (It is assumed that all registered trials will be approved by an ethics board before commencing.) 12. Condition The medical condition being studied (eg, asthma, myocardial infarction, depression). 13. Intervention(s) A description of the study and comparison/control intervention(s) (For a drug or other product registered for public sale anywhere in the world, this is the generic name; for an unregistered drug the generic name or company serial number is acceptable). The duration of the intervention(s) must be specified. 14. Key inclusion and exclusion criteria Key patient characteristics that determine eligibility for participation in the study. 15. Study type Database should provide drop-down lists for selection. This would include choices for randomised vs. non-randomised, type of masking (eg, double-blind, single-blind), type of controls (eg, placebo, active), and group assignment, (eg, parallel, crossover, factorial). 16. Anticipated trial start date Estimated enrolment date of the first participant. 17. Target sample size The total number of subjects the investigators plan to enrol before closing the trial to new participants. 18. Recruitment status Is this information available (yes/no) (If yes, link to information). 19. Primary outcome The primary outcome that the study was designed to evaluate. Description should include the time at which the outcome is measured (eg, blood pressure at 12 months). 20. Key secondary outcomes The secondary outcomes specified in the protocol. Description should include time of measurement (eg, creatinine clearance at 6 months). * The data fields were specified at a meeting convened by the World Health Organization in April 2004; the explanatory comments are largely from the International Commitee of Medical Journal Editors.

Catherine D De Angelis · Jeffrey M Drazen · Frank A Frizelle · Charlotte Haug · John Hoey · Richard C Horton · Sheldon Kotzin · Christine Laine · Ana Marusic · A John P M Overbeke · Torben V Schroeder · Harold C Sox · Martin B Van Der Weyden

Trial registration, transparency and less reliance on industry trials are essential Over the past 20 years, politicians, hospital administrators and university deans have encouraged academic researchers to increase their participation in projects sponsored by the pharmaceutical industry, and the industry’s share of biomedical research has increased dramatically in that time (from 32% to 62% in the United States).1 Increasingly, the wisdom of this development has been challenged. It would be even better if testing drugs in patients was a public enterprise . . . The research agenda predominantly serves the interests of industry rather than those of patients. Surveys have shown that manipulation of clinical trials — whereby, if the results are published at all, the control treatment is disadvantaged by design, analysis, or interpretation2-5 — is common. Even when the results for the active and control therapies are no different, industry-sponsored trials come to a positive conclusion in favour of the sponsor’s drug five times more often than do not-for-profit-sponsored trials.4 This sponsor bias can have serious consequences. A meta-analysis supported by Merck concluded that there was no increased risk of arterial thrombosis with the company’s cyclo-oxygenase-2 (COX-2) inhibitor, rofecoxib.6 However, another meta-analysis, not sponsored by industry, showed an increased risk, which was apparent in publications available to the authors of the industry-sponsored meta-analysis 4 years before the drug was withdrawn because of thromboses.7 Such down-playing of harms in published papers has often required the collaboration, or acquiescence, of academic clinical researchers. It is likely that the widespread use of COX-2 inhibitors has caused thousands of premature deaths. An article by Henry and colleagues in this issue of the journal (page 557) reports important breaches in research integrity in industry-sponsored research, based on the experience of medical specialists in Australia.8 There are several reasons why the prevalence of the problems probably represents only the tip of the iceberg. Firstly, the authors note that their findings are limited by reliance on self-report, and only 39% responded. Secondly, while only about 9% of respondents reported one or more episodes of potentially serious research misconduct, the authors note that this is equivalent to 21% of those who had an active research relationship with industry. Thirdly, the authors did not consider protocol changes to be serious research misdemeanours. They need not be, but we found that at least one primary outcome was changed, introduced, or omitted while research was under way in 51 of 82 trials (62%).5 We think this is a serious problem as, with a median of 27 outcomes per trial,5 one would expect one outcome to become statistically significant by chance, even if the compared treatments were identical. Finally, 2% of respondents in the paper by Henry et al reported changes to study protocols while trials were under way.8 Our study comparing protocols with corresponding publications showed that formal changes submitted to scientific ethics committees are not common, but that informal changes are. We found that 86% of the respondents in a survey of triallists denied the existence of unreported outcomes, despite clear evidence to the contrary — we did not reveal to them until later that we had access to their trial protocols through the scientific ethics committees.5 Research misconduct and bias in intervention research could be markedly reduced if ongoing initiatives to register all trials at their inception, and ensure public access to trial protocols and all data generated by a trial, become successful. The International Committee of Medical Journal Editors have made a very positive and strong move towards this goal. They have agreed that after 1 July, 2005, its member journals, as a condition of considering a trial for publication, will require that it be registered in a public trials registry before patients enter the trial.9 Ethics committees would also have to play a central role to make this happen, and to ensure that commercial considerations will not be allowed to block access to the collected data, whether or not they are formally published. It would be even better, of course, if testing drugs in patients was a public enterprise (whether or not financed by industry) with blinding during data analysis and writing of manuscripts, till everyone involved had approved them.10 This would ensure that commercial influences on trial design, analysis, manuscript preparation and publication would no longer distort our views of the value of drugs and other treatments. It would also ensure that the comparison treatment was relevant, that the outcomes were directly relevant for patients, and that the patient population was relevant (eg, elderly patients in the case of COX-2 inhibitors, who are also those most likely to develop thromboses). A case in point is the publicly sponsored ALLHAT trial, the biggest trial ever performed on hypertension, which showed that the cheapest drug available was also the best.11 It is clear that governments could save money and treat patients better by investing much more in trials and academic trial centres than by relying on industry’s own trials and conclusions. Who would buy a washing machine that is five or 10 times more expensive than other machines just because its manufacturer has compared it with other machines and claims that it is the best? Unfortunately, such absurdities are often seen in health care, and are allowed to happen even in the absence of any direct head-to-head comparisons.

Peter C Gøtzsche MD, DrMedSci

We need to increase our investment to maintain and improve our position in the global knowledge economy Of all human endeavours, health and medical research arguably offers the greatest potential to improve human life. Research discoveries have extended and enhanced our lives, reduced the burden of many diseases in our society, and are changing the shape of health care. In an era of unparalleled promise offered by genomics, bioinformatics, stem-cell technology, biomedical devices, and therapeutic vaccines, the very nature of clinical practice could shift profoundly over the coming decades. There is, however, another very positive outcome of health and medical research — with the right support from government and industry, it could hold the key to Australia’s future prosperity in a global knowledge economy. The reality of this assertion is exemplified by the vibrant biotechnology and pharmaceutical industries so evident in the United States today. This powerhouse status is the outcome of political strategies put into place 25 years ago. The success of these strategies is reflected in a tenfold increase in the number of patents, royalty and licensing fees (amounting to one billion dollars US per year), strong links between academia and industry, and a fourfold increase in corporate research funding.1 Many overseas governments are now emulating this success by promoting the link between a country’s ability to foster and grow knowledge-based industries and its future economic prosperity. Developed countries, such as the US, Japan, Canada and the UK, are also implementing significantly resourced strategies to encourage citizens to become literate in science and technology, cultivate and attract the brightest minds, build infrastructure and capacity in basic sciences and research, develop commercial competence and grow new businesses. In April this year, the European Commission announced it would double its research budget to i70 billion over 7 years to bolster growth and competitiveness, catch up with American and Japanese spending on innovation, and transform the European Union (EU) into a knowledge-based economy.2 This spending is in addition to funds committed by the individual EU member states to support research within their own borders. The UK Medical Research Council (MRC), a taxpayer-funded organisation that supports and promotes biomedical research, lists among its goals “contributing to the wealth of the nation”. In the most recent financial year, the MRC spent nearly £450 million on research and earned about £15 million in licensing revenue. In Australia, the recommendations of the government’s 1999 Health and Medical Research Strategic Review (the “Wills Report”) were based on data showing that Australia had fallen behind other developed countries in its relative funding of health and medical research. The report found that additional investment would reap significant returns over the long term by improving the health of the Australian population, building the economy, and creating valuable jobs.3 Following its acceptance of the report, the government made an historic decision to increase National Health and Medical Research Council (NHMRC) funding over a 5-year period by injecting an additional $614 million, effectively doubling the annual NHMRC budget to about $412 million by 2005.4 State governments have focused on capturing the commercial potential of research outcomes and creating new business and industry. Initiatives like Queensland’s Smart State, BioMelbourne, BioInnovation SA and BioFirst NSW reflect the recognised importance and economic realities of catching the biotech wave. In December 2004, the Australian government released the report of the Investment Review of Health and Medical Research (the “Grant Report”) conducted by a committee of eminent experts from the commercial and research arenas.5 The government initiated this review to determine the impact of the additional investment made in response to the Wills Report and to revisit the Wills Report’s vision and assess if any changes of emphasis would be beneficial. Although it was carried out only 4 years after the government’s decision to accelerate the medical research investment cycle, the Grant Report’s independent assessment of the outcomes and returns generated by health and medical research showed that there had already been some successes, and that further commercial and health care benefits are likely in the near and long term. Two key success indicators are Australia’s comparatively high research productivity and quality, and the formation of 350 new businesses in the biomedical field from 1992 to 2003. Besides recommending continued strong growth in government funding to remain internationally competitive, the Grant Report also suggested that innovative new policies and incentives were needed to encourage greater private industry investment in research, targeting an increase in annual spending in Australia by multinational pharmaceutical and biotech companies from the current about $420 million6 to $1 billion. The Grant Report, completed in May 2004, was not released until December, and it has since slipped off the radar at this crucial time. If the Australian Government takes no further action, we could see Australia quickly drop away from the front-runners in biomedical research and innovation. Even flatline funding would be a reduction in real terms, and would see us fall further behind other countries as their investment and policy environments focus on optimising their leadership position. The Australian community supports increased health and medical research efforts. Research Australia’s annual health and medical research public opinion polls in 2003 and 2004 showed that most Australians wanted to see increased government and industry investment, and are prepared to contribute to that investment themselves.7 In fact, 47% of Australians said they would rather see surplus government funds invested in health and medical research than in tax cuts.8 Securing a strong, enduring, sustainable economic future for Australia requires a long-term view for building on the valuable investment to date. This will be achieved only by continued focus and leadership by national, state and territory governments in partnership with researchers, industry, and the community. Government commitment to the recommendations of the Grant Report would be a good first step towards showing this leadership.

Christine C Bennett MB BS, FRACP MPaed · Michael R Vitale PhD, MBA

We still have no national program for detecting this potentially lethal disorder In 1985, Brown and Goldstein were awarded the Nobel Prize in Physiology and Medicine for unravelling the regulation of cholesterol metabolism in man. A key feature of their work was the elucidation of the molecular mechanism for autosomal dominant familial hypercholesterolaemia (FH), a potentially lethal disorder caused by defective endocytosis of low-density lipoprotein (LDL) cholesterol by its receptor (LDLR).1 This, in turn, led to the development of “statin” drugs, which potently lower plasma LDL cholesterol and reduce coronary heart disease (CHD) mortality. But, 20 years later, what have we achieved in detecting and treating FH? FH is characterised by lifelong marked hypercholesterolaemia (LDL cholesterol > 5 mmol/L) that leads to tissue cholesterol deposition — in such forms as tendinous xanthomata (particularly involving the Achilles), corneal arcus and palpebral xanthomas — and greatly increased risk of fatal CHD.2 Unfortunately, most people with FH are at present undiagnosed or only diagnosed after their first coronary event. We estimate that, of the roughly 40 000 cases of FH in Australia, about 20% are diagnosed and less than 10% are being adequately treated. Atherosclerosis in FH begins in early childhood. Children with FH are known to have endothelial dysfunction (the earliest phase of atherosclerosis) and increased carotid intima media thickness (CIMT), both surrogate markers of cardiovascular disease.3,4 Carotid atherosclerosis in FH rapidly progresses during childhood, at a rate proportional to plasma LDL cholesterol levels.4 FH typically involves mutations in the LDLR gene, with homozygotes having a more severe phenotype that heterozygotes. To date, about 1000 mutations have been identified in the LDLR gene (www.ucl.ac.uk/fh), most being unique, which makes the search for an unknown mutation challenging and expensive. Although heterozygous FH affects about 1 in 500 people overall,2 it occurs much more frequently in some populations such as Afrikaners, Christian Lebanese and French Canadians2 because of “founder” effects that occur when a few members of a population migrate and start a new colony. FH can be caused by mutations in genes other than LDLR. A mutation in the apolipoprotein B gene (APOB) may result in a clinical and biochemical picture that is indistinguishable from classic FH, although cholesterol levels are generally not as elevated and tendon xanthomas are less common.5 An autosomal recessive form of FH has also been described.6 The clinical picture of this condition is similar to that of homozygous FH, although it is generally less severe and more variable, with greater responsiveness to therapy. Except in “founder” populations, homozygosity for any of these conditions is exceedingly rare (about 1/1 000 000 people), and, without special intervention, such as LDL aphaeresis and liver transplantation, is typically lethal at an early age. Early statin treatment in children with FH improves endothelial function.3 A recent 2-year randomised controlled trial of pravastatin treatment (40 mg daily) in 214 children aged 8–18 years with FH showed regression of carotid atherosclerosis with no adverse effects on growth, sexual maturation, hormone concentrations, or serum liver and muscle enzyme levels.7 Despite this, the long-term safety and efficacy of statin use in children with FH is yet to be established. The Atorvastatin versus Simvastatin on Atherosclerosis Progression trial compared the effect of “aggressive” lipid-lowering treatment in FH with “conventional” lipid-lowering therapy.8 Over 2 years, LDL cholesterol lowering by high-dose atorvastatin resulted in regression of CIMT, whereas reduction with conventional-dose simvastatin did not. Moreover, the change in CIMT was proportional to the reduction in LDL cholesterol. These results support the concept that intensive lowering of LDL cholesterol levels in patients with CHD is beneficial. Although heterozygous FH patients are responsive to statins, additional treatment in combination with statins (for example, statin plus cholestyramine) is often required to achieve the desired LDL-cholesterol-lowering target.9 Moreover, combination therapy often permits use of a lower statin dose, which can benefit patients in whom adverse effects have occurred. Ezetimibe, a new drug that specifically inhibits intestinal cholesterol absorption alone, can reduce plasma LDL cholesterol concentrations by about 18%. Used in combination with a statin, it can achieve a further 25% reduction in LDL cholesterol levels over statin alone, by reducing both cholesterol supply to the liver and cholesterol biosynthesis.10 The long-term effects of ezetimibe on FH cardiovascular morbidity and mortality are unknown. The most cost-effective strategy for finding subjects with FH is to screen close relatives of patients already diagnosed with FH. Screening involves measurement of plasma LDL cholesterol, combined with either a clinical examination and family history or molecular genetic testing.11 Children born to an affected parent have a one in two risk of inheriting FH, and should be screened, at least biochemically, after the age of 2–3 years, when a cholesterol-lowering diet can be safely implemented.12 It is important to appreciate that a normal lipid profile does not rule out heterozygosity for an FH-causing mutation, particularly in early childhood.13 International experience shows that a family screening program must incorporate ethically acceptable protocols for approaching and interacting with relatives, follow-up communication with family members and their health care practitioners, as well as access to genetic counselling services, if required. Despite all these advances, it remains a tragedy that after 20 years of burgeoning knowledge about FH and the parallel development of powerful cholesterol-lowering drugs, Australia does not have a national program for detecting the vast majority of patients with FH in our community, let alone diminishing their risk of CHD.

John R Burnett MD, PhD, FRCPA · David Ravine DM, FRACP, FRCPA · Frank M van Bockxmeer BSc(Hons), PhD · Gerald F Watts DSc, MD, FRACP

Questions of cost-effectiveness, vaccine efficacy and feasibility are yet to be answered In the United States, routine immunisation of all healthy children aged 6–23 months against influenza has recently been introduced. The principal justification for this is the relatively high morbidity and mortality from this disease in very young children.1 The United States is also considering routine influenza immunisation of all children aged over 6 months, in view of the herd protection it would provide to the adult population. Currently, Australian guidelines recommend immunisation of children in groups considered at high risk of severe influenza.2 Should Australia introduce universal childhood immunisation? There is no doubt that children have an extremely high incidence of influenza. It is estimated that, on average, 20%–43% of children are infected during typical influenza seasons.3-5 The incidence is highest in young children less than 2 years old, who are often hospitalised.1,3-5 The mortality due to influenza in infancy is second only to that in the most elderly patients.1 In the severe 2003–04 influenza season, 143 children died from influenza in the United States, of whom 58 (41%) were less than 2 years old and 65 (45%) had no underlying condition.1 These data emphasise the importance of protecting children with annual influenza immunisation, if feasible. Another reason to consider universal childhood influenza immunisation is herd protection. In what turned out to be an illuminating natural experiment, 50%–85% of Japanese schoolchildren were immunised annually against influenza from 1962 to 1987, but there was no routine immunisation of the elderly. When mandatory immunisation of schoolchildren was relaxed in 1987 and repealed in 1994 (because of doubts about safety and effectiveness), influenza immunisation rates dropped to very low levels. A retrospective study comparing excess mortality from pneumonia and influenza in Japan and the United States concluded that the vaccination of Japanese schoolchildren prevented about 37 000 to 49 000 deaths per year, mostly of elderly people. (This represented about one death for every 420 children vaccinated.)6 In considering the feasibility of universal childhood vaccination, vaccine efficacy is one of the factors that needs to be taken into account. In healthy adults under 65 years of age, inactivated influenza vaccine is 70%–90% effective when the match between vaccine and circulating viruses is close.1 However, the same vaccine may be less immunogenic in children. Studies in children aged 6 months to 15 years show a vaccine efficacy of 31%–91% against influenza A and 45% against influenza B.7,8 However, very few of the studies have examined children aged 6–23 months,9,10 the age group currently recommended for routine influenza vaccination in the United States. An alternative form of vaccine administration is on the horizon — live attenuated influenza vaccines. A recent systematic review10 suggested that live vaccines may be more effective than inactivated vaccines in children over 2 years of age (79% versus 65%). Live attenuated influenza vaccines have been licensed in the United States, and might be more acceptable because they are given intranasally.11 However, live vaccines cost a lot more and are not licensed for use in children under 5 years in the United States (because of limited safety data). They are not yet licensed in Australia for use in any age group. The high morbidity of influenza in children and the likely benefits due to herd immunity do make annual childhood influenza immunisation appear economically attractive. However, against this must be weighed the need to immunise with a new influenza vaccine each year, because of antigenic drift in influenza strains, and the need to give two doses of vaccine to children under 9 years in the first year they are immunised.1,2 In addition, the severity of influenza seasons varies unpredictably from mild to severe, and it costs as much to immunise in a mild year as in a severe one. In the United States, indirect costs (mainly days of work lost by parents) dominate economic analyses supporting the use of influenza vaccines in children.12 In Australia, by contrast, the Pharmaceutical Benefits Advisory Committee considers only direct costs of illness, so it is unlikely that a universal, publicly funded childhood immunisation program could be justified using such cost-effectiveness criteria. There may also be practical problems with attempts to introduce routine childhood immunisation. In 2004–05, the uptake of influenza vaccine for children aged 6–23 months in the United States, when the vaccine was recommended universally, was estimated to be only 48%.13 In Ontario, Canada, where all residents aged over 6 months have been offered free annual influenza immunisation since 2000,14 the 2003 uptake in children was only 27%.15 Parents of unimmunised children were more likely to believe that immunisation resulted in a flu-like illness, caused adverse effects more severe than the disease, or weakened the immune system.15 Such immunisation myths are common, although studies have repeatedly shown inactivated influenza vaccine align="right" to be safe, with low rates of adverse events and the benefits clearly outweighing the risks.1,2,9 Another practical issue is the question of how to fit the vaccine into an already crowded childhood vaccination schedule. In general, annual immunisation against influenza is recommended in autumn at the start of the influenza season; there is no fixed age of administration of vaccine. Implementing universal influenza vaccination would place a substantial extra burden on primary care practices.16 Considering all the available information, I believe that there is currently insufficient reason for introducing universal childhood vaccination for this disease in Australia. There are too many unanswered questions about the cost-effectiveness, efficacy and feasibility of universal immunisation of healthy children, whether infants or school-aged. For the time being, we should maintain a watching brief. Future data emanating from Ontario and the United States may provide us with a clearer answer as to whether large-scale programs of routine childhood influenza immunisation are feasible and effective. Further, if the US experience with live vaccines shows consistent immunogenicity and improved ease and acceptability of administration, live vaccines may yet prove to be a cost-effective way to implement universal childhood influenza immunisation in Australia. One thing is clear: influenza vaccination is most cost-effective for children considered at high risk of severe influenza, such as those with chronic cardiopulmonary and other chronic illness. These children should clearly be vaccinated annually against influenza.1,2 Yet vaccine coverage of high-risk groups aged 2–17 years is only 35% in the United States,13 and probably lower in Australia, although we lack age-specific data. Australian immunisation providers should redouble their efforts to ensure that children at high risk are immunised annually.2 Also, it should be remembered that the Australian immunisation handbook2 does not preclude vaccinating others who are not at high risk. It states that “influenza vaccine should be administered to any person who wishes to reduce the likelihood of becoming ill”.

David Isaacs MD, FRACP, FRCPCH

The past 12 months have brought considerable changes that affect the lives of Australia’s Indigenous people Five years ago, we began to deliberately cluster the publication of research reports on Aboriginal and Torres Strait Islander health in the second issue of the Journal in May, to coincide with National Sorry Day (26 May) and Reconciliation Week (26 May – 3 June). In the years that followed, the quantity and quality of papers related to Indigenous health grew, culminating this year in the inaugural MJA Indigenous Health issue. Some readers might question this initiative, considering that Indigenous Australians account for less than 3% of our population. However, we would counter that the social, economic and health disparities between Indigenous and non-Indigenous people in Australia are worse than in any other comparable country in the world,1 and that the MJA remains the only high level Australian research forum to regularly report these issues. Engaging with Indigenous people, and coping with our own feelings of impotence, guilt, frustration and fear as health professionals, must play a role in the healing process. The past 12 months have brought considerable changes that affect the lives of Australia’s Indigenous people. The Australian Government has completely overhauled its approach to Indigenous affairs:2 The Aboriginal and Torres Strait Islander Commission has been abolished, and a ministerial taskforce and a National Indigenous Council have been convened to advise on Indigenous affairs; Shared responsibility agreements are being forged with Indigenous communities; and, recently, Prime Minister John Howard has suggested changes to Aboriginal land rights, which would favour individual over communal ownership.3 In announcing the new arrangements for Indigenous affairs, Amanda Vanstone, the Minister for Immigration and Multicultural and Indigenous Affairs, promised,4 We will work with states and territory governments and Indigenous communities to find the best mechanism for input at the local and regional level. Our focus will continue to be on better service and better outcomes for Indigenous people. Despite widespread recognition that there were problems with the previous arrangements, some Indigenous leaders believe that the government’s move to “mainstreaming” threatens Indigenous Australians’ right to self-determination.5 Concerns have also been expressed that it will be more difficult for Aboriginal and Torres Strait Islander voices to be heard in health policy development.6 Disquiet about the place of shared responsibility or “mutual obligation” agreements in improving Indigenous health7 is echoed by Collard et al in this issue of the Journal (page 502). National Sorry Day was initiated in 1998, a year after the Bringing them home report focused public attention on the experiences of the Indigenous Australians who had been removed from their families. It was set aside as a day for acknowledging these people’s suffering and committing to assist them on their “journey of healing”. But this too has changed. The National Sorry Day committee has decided that the day will now be known as a “National Day of Healing — for all Australians”. In explaining the change, committee chairs Ray Minniecon and Gillian Brannigan noted:8 . . . the stolen generations cannot heal in isolation. Their healing depends on, and contributes to, healing among the wider Indigenous community. And healing among Indigenous Australians depends on, and contributes to, healing in the non-Indigenous community. This emphasis on the need for healing among all Australians should take us, as health professionals, beyond the usual perspective that the poor health of Indigenous Australians is about “them” — to look at ourselves, our society and our health care system. According to the National Sorry Day committee:8 If healing is to come, it will come through a grass-roots movement of people who feel each other’s pain across the gulfs which divide us, and commit themselves to work for justice. This was the experience of Gruen and Yee (page 538) after working for some time in a remote Aboriginal community. Engaging with Indigenous people, and coping with our own feelings of impotence, guilt, frustration and fear as health professionals, must play a role in the healing process. Some of the stories, pictures and vignettes in this special Indigenous Health issue may provide an avenue for such engagement. Health system problems also feature in this issue. A study published in the Journal in 2002 noted that Indigenous patients were less likely to receive diagnostic and therapeutic procedures in Australian hospitals.9 While the reasons for this differential treatment are complex, a similar shortfall has since been reported in the management of cancer patients,10 and, as reported by Coory and Walsh in this issue, in the rates of patients receiving percutaneous intervention or coronary artery bypass surgery after acute myocardial infarction (page 507). Whatever we make of these sobering findings the need for change is apparent. One of the reasons advanced by Coory and Walsh for their findings is the high prevalence of comorbidities in Indigenous patients, which, in turn, reflects social, economic and health care deficiencies in Indigenous communities. In a recent discussion paper Healing hands — Aboriginal and Torres Strait Islander workforce requirements, the Australian Medical Association identified lack of access to high quality primary health care as one of the major impediments to improving Indigenous health.11 The report revealed that these services were underfunded by $400 million per year, and there was a workforce shortfall of 430 doctors and 450 other health professionals. It also called for a commitment to increase the number of Indigenous people in the health workforce to levels proportionate to those of the general population — a project which requires training and support for an additional 928 doctors and 2570 nurses. An additional 2000 Aboriginal health workers are also required. Full resourcing of primary care for Indigenous people makes good sense, and should be achieved both through mainstream measures, such as the newly funded primary care item, Aboriginal and Torres Strait Islander health check,12 and via community-based projects achieved by partnerships with Aboriginal-controlled health organisations. An addendum to the AMA discussion paper included five “good news stories” of community-based clinical research projects that have achieved meaningful on-the-ground outcomes. Several such reports are also published in this issue: a decade-long retinal screening project in the Kimberley (Murray et al, page 520), point-of-care diabetes monitoring and feedback in a remote community (Martin et al, page 524), and a collaborative shared antenatal care project for urban Indigenous women (Panaretto et al, page 514). Such projects might seem at times like drops in an ocean of despair, but they are proof that an adequately resourced and carefully designed primary health care system for Indigenous people can make inroads into health inequity. So what do we make of Sorry Day, the National Day of Healing, and Reconciliation Week in 2005? Geoffrey Angeles, the winner of the first Dr Ross Ingram Memorial Essay Competition (page 541) should have the last word. There is nothing wrong with some of the old and a little bit of the new. Reconciliation comes in many forms, but basically it is about bringing together, compromise, resolution and understanding. Shaking hands and saying sorry is surface stuff. Examples of partnerships that work are more real. The Australian Government has adopted the rhetoric of partnership in Indigenous health. It now remains to be seen if rhetoric becomes reality, and whether we can come together as individuals, as a society and as a health system to form true and equitable partnerships. These partnerships should be based on hearing and understanding each other’s stories, healing relationships and an ongoing willingness, both personally and politically, to work together on upskilling, motivating and funding a health workforce that has Indigenous parity and is fit for the task. Editor, The Medical Journal of Australia, Sydney, NSW medjaustATampco.com.au

Ruth M Armstrong BMed · Martin B Van Der Weyden MD, FRACP, FRCPA

Demands for efficiency should not be met at the expense of equity Despite countless reports over decades about the health disadvantages of Indigenous Australians, attention has only recently been turned to remedying disparities in the provision and quality of health care. A report in this issue of the Journal by Coory and Walsh about access to coronary procedures (page 507)1 adds to a growing body of evidence that Indigenous Australians do not receive the same level of care as other Australians.2-4 How might clinicians be contributing inadvertently to this “treatment gap”? And how can they remedy it? The responsibility for reducing ethnic disparities rests primarily with the health care system and its providers. Clinical decisions are based on imperfect information. To each clinical encounter, doctors bring prior beliefs about the likely nature of the condition. These beliefs differ according to the patient’s age, sex, socioeconomic status and ethnicity. They influence diagnosis, investigations and treatment. With identical descriptions of pain, a doctor is more likely to diagnose cardiac ischaemia in an elderly, sedentary, obese man than in a young, active woman of normal weight. Such stereotyping is helpful — and, indeed, promotes efficient practice — when it is based on epidemiology, statistical likelihood and best evidence. However, when incorrect, inappropriate and often implicit beliefs about the behaviour or health of a particular group are applied to individuals, stereotyping can be harmful. Uncertainty increases with patients who speak a different language or belong to a different cultural group. This, in turn, can lead to unhelpful, even harmful stereotyping. The experience of an Aboriginal politician who recently underwent emergency surgery demonstrates this. “I have had problems with my stomach and my abdomen for years. They were saying it was a problem with my kidneys and now that I have had this surgery on my bowels, they have found out that my kidneys are perfect,” she said. “So when I have gone to doctors complaining about illness over many years, I suppose they have taken my genetic heritage as a Tiwi Islander and thought it was renal.”5 Delays in diagnosis and treatment caused by such stereotyping might be partly responsible for Indigenous Australians’ poorer health outcomes. In the United States, concerns about the quality of health care received by racial and ethnic minorities compared with white Americans prompted Congress to request an investigation by the Institute of Medicine (IOM). Their landmark report, Unequal treatment: confronting racial and ethnic disparities in health care, found convincing evidence that racial and ethnic disparities exist across a wide range of conditions and health services and are associated with poorer outcomes.6 The report made several recommendations relevant to Australia, including cross-cultural training, use of interpreter services, and training more health care providers from ethnic and racial minority backgrounds.6 However, this might not suffice. Doctors who treat black Americans are less likely than those who treat white Americans to be “board certified” (ie, fully qualified) specialists. They are also more likely to report difficulty in arranging access to consultants, diagnostic imaging, and non-emergency hospital admission.7 In other words, doctors who treat black patients have less power, fewer resources, and possibly less training than doctors who treat whites. Is this also true in Australia? The IOM report defined disparities as racial or ethnic differences in the quality of health care not due to clinical need, patient preference or appropriateness of intervention.6 In Australia, these three factors have repeatedly been suggested as reasons for the treatment gap. Coory and Walsh suggest that the prevalence and severity of comorbidities may have a major impact on lower rates of coronary procedures and make providers question the appropriateness of such interventions.1 They note that selection favours lower-risk patients. However, even after controlling for the presence of comorbidities, Indigenous Australians still had significantly fewer interventions. With respect to patient preference, some commentators have suggested that, because Aboriginal people treated for chronic kidney disease fare poorly, they prefer not to be treated,8 but this hypothesis is contradicted by growing community activism to secure dialysis services in remote areas.9,10 A crucial issue is the increasing conflict between “efficiency” and equity. With increasing demands on health services, doctors attempt to maximise efficient use of scarce resources. Based on the mantra of “evidence-based medicine”, doctors perform more selective procedures and strive for lower rates of complications. A recent editorial suggested that people who cannot stop smoking should be excluded from a range of therapeutic interventions because of their higher risk of postoperative complications.11 Similar exclusions could also be applied to other groups, such as obese people. While this approach might increase “efficiency”, applying such standard criteria would greatly reduce Indigenous Australians’ access to beneficial interventions. Perhaps a higher complication rate is acceptable in the overall context of Indigenous Australians’ relative need for health care. Recovery from postoperative complications might be preferable to death without surgery. The responsibility for reducing ethnic disparities rests primarily with the health care system and its providers. System-level changes are clearly required, such as adequate funding for primary care, an adequate Indigenous health workforce, and improvements in the interface between primary care and specialist services.1,6,12 Clinicians have a central role to play in advocating for such changes. Because patients should be part of the solution, the IOM report recommends the development of appropriate education for patients in areas such as when and how to access health care, and how to participate effectively in clinical decision-making.6 However, most patients, in particular Indigenous Australian patients, are relatively powerless compared with doctors and “the system”. In Australia, the political debate about Indigenous health and development is framed in terms of “mutual obligation”. If we clinicians and researchers are to fulfil our obligation, we must first understand how we might inadvertently be contributing to the problem and then take steps to bridge the treatment gap.

Joan Cunningham ScD · Alan Cass PhD, FRACP · Peter C Arnold BSc, MB BCh, BA

Obstetric services need to be women-centred and based on mutual respect and collaboration Obstetricians and midwives have complementary roles in the care of pregnant women, and each group would find survival without the other difficult. Nor would women necessarily receive the best care if access to one or other of these professions were restricted. Having complementary roles, though, has not prevented hostility or “turf” wars between the two groups, with midwives claiming that maternity services are over-medicalised,1 and obstetricians counter-claiming that there is no demand for midwife-led care.2 So what is the current modus vivendi for obstetricians and midwives, and to where feasibly could it evolve by 2020? By 2020, it can only be hoped that an Australian National Maternity Policy will be in place. Maternity services in Australia in 2005 provide much choice for women, including private or public care by obstetricians, general practitioners and midwives. These services can take place in traditional hospital obstetric units, birthing centres and, now less frequently, at home. Australia has not followed the New Zealand model of care in allowing women to choose a midwife as a “lead maternity carer” as a mainstream option in the public health system. However, in some Australian states, this may soon change.3 If this were to eventuate, Australia would do well to look at the lessons learned from the experience in New Zealand. Across the Tasman many positive changes have resulted from maternity services reform, such as significant improvement for many women in continuity of maternity caregiver, and greater availability of non-medically based models of care for those women wanting them. But negative changes have also occurred, such as the effective loss of the option for women to have a GP involved in their maternity care, and an initial exodus of experienced midwives out of the public hospital system. In particular, the sheer pain of major change, for both women and care providers, could have been minimised by thorough and consultative planning. Given all this choice, why should there be hostility between obstetricians and midwives? The main criticisms from midwives stem from a perception that obstetric care in Australia is too medicalised and that obstetric intervention rates are too high.4 Because better continuity of care from a known midwife may lead to fewer obstetric interventions5 and greater certainty for women, there has been a strong push by midwives and consumer groups, such as the Maternity Coalition, for funded midwife-led care.6 On the other hand, obstetricians point to an established system of care, with low rates of maternal and perinatal morbidity as well as generally high levels of community satisfaction.2 Provision of maternity services in Australia has also been made more difficult by workforce issues. The average age of obstetricians in Australia is 51 years7 and of midwives 41 years.8 The workforce survey carried out by the Royal Australian and New Zealand College of Obstetricians and Gynaecologists (RANZCOG) in 2003 revealed that a quarter of Australian Fellows were now aged 60 or more.7 The same workforce survey also highlighted the possibility of a major shortage of obstetricians in the next 10 years, due to retirements, new RANZCOG Fellows not wishing to practise obstetrics, increased feminisation of the obstetric workforce, and problems associated with safe working hours.7 There has also been a major decrease in GPs practising obstetrics, especially in rural areas, for lifestyle reasons and because of the cost of medical indemnity.9 The shortage of midwives is also a problem. The Australian Health Workforce Advisory Committee estimates a current national shortage of 1850 midwives, and this is expected to increase over the remainder of the decade.8 Problems with recruiting and retaining midwives seem to be related to midwives’ perceptions of a lack of professional recognition, stress and workload issues, as well as limited opportunities for midwives to practise as primary carers and provide continuity of care to women.10 To facilitate discussion between maternity care providers, the RANZCOG re-established the Joint Committee for Maternity Services in 2002. This has representatives from the RANZCOG, the Australian College of Midwives, the Royal Australian College of General Practitioners, and the Australian College of Remote and Rural Medicine, as well as consumer representation. Each representative feeds back to his or her governing body, with the committee proving useful in airing problems and encouraging a collaborative approach to maternity care provision. The committee has made some progress in reviewing international clinical guidelines for possible use in Australia, but has been hampered by lack of funding, obstetricians suspicious of change, and midwives frustrated by lack of change. Difficulties have arisen in reconciling differences between obstetricians, GPs and midwives in how to provide safe evidence-based care that will not diminish current levels of safety. By 2020, it can only be hoped that an Australian National Maternity Policy will be in place. At present, there is none. If this is to occur, obstetricians, GPs and midwives must work to develop collaborative policies that are women-centred, not provider-centred, and which will ensure individualised care to meet the particular needs of each pregnant woman. The development of adequate continuing professional development programs (CPD) for all maternity care providers should be mandatory, and the development of some joint CPD programs crossing profession groups would be useful. There should be development of systems of care that allow for continuity of care for women during pregnancy, labour and postnatally, but which protect against burnout of care providers. There are already good examples of effective services in various places across Australia, ranging from large metropolitan units, such as the Adelaide Women’s and Children’s Hospital Community Midwifery Program, to rural services, such as those provided at Wangaratta Hospital in Victoria, that are women-centred and based on mutual respect and collaboration between obstetricians and midwives. The challenge is to make this the norm for the benefit of mothers and babies as well as their care providers.

Edward W Weaver MB BS, FRACOG · Kenneth F Clark MB ChB, FRANZCOG · Barbara A Vernon BA(Hons), PhD

Do we have a clear enough picture to guide rational health and social policy responses? Australia’s economic prosperity has long brought incremental health gains through better living conditions, sanitation, education, medical care and vaccination.1 The effects on child health and mortality have been striking. The latest report from the Australian Institute of Health and Welfare (AIHW), A picture of Australia’s children, documents this continuing trend. Infant and child mortality rates halved again in the past 20 years.2 The fall in deaths from sudden infant death syndrome (SIDS) to a third of 1991 rates is a tribute to outstanding Australian child health research, as well as the work of child and family health nurses and the SIDS Council of Australia.3 A steady decline in deaths from injury in later childhood has also contributed to lower childhood mortality. Judged by these indices, the present generation of Australian children is the healthiest ever. Key findings of A picture of Australia’s children The infant mortality rate in Australia halved over the past two decades, from 9.6 per 1000 livebirths in 1983 to 4.8 in 2003. The Indigenous infant mortality rate also declined by 3.3% per year, but was still 2.5 times that of other Australian infants. Rates of non-communicable health problems, such as obesity and mental disorders, appear to be rising, but lack of up-to-date national data makes it difficult to accurately assess the current rates. Rates of vaccination among children aged 1 and 2 years have increased over time, with the coverage in 2004 being over 90%. Between 1990 and 2000, children’s dental health improved, with a decrease in the mean number of decayed teeth in 6 year olds (from 2.1 to 1.7), and 12 year olds (from 1.4 to < 1). However, since 2000, tooth decay in Australian children seems to be on the increase again. The number of children on care and protection orders has risen almost 50% in the past 6 years, with the rates sixfold higher in Indigenous children. The proportion of children placed in out-of-home care also rose from 3 per 1000 children in 1997 to 5 per 1000 in 2004. Economic progress has also altered the lives of children through changing the social context of development. The transformation of Australian families has been striking. Fewer children, smaller households, older parents, working mothers, and parental separation and divorce, all affect the way in which families provide a nurturing and secure base.4 There are concerns that a greater investment in fewer children, tied with heightened parental anxieties, has produced a “bubble-wrap generation”. The effects of limiting independent exploration, risk taking and physical activity on children’s physical, cognitive and emotional development may be profound.5 Socioeconomic changes have also affected child health in other ways, such as altering material consumption and lifestyle. Industries, ranging from fashion to food and entertainment, now market to children, regarding them not only as the consumers of tomorrow but as major agents of influence on family spending.6 In this changing social context, the AIHW report attempted to capture a broad picture of the health and development of our children (Box). In preparing the report, emerging morbidities, such as childhood obesity, were to be an important focus. Obesity not only poses risks for later cardiovascular disease and diabetes, but also profoundly affects children’s quality of life and self-concept.7 However, the best available national data are 10 years old, from a time when around one in five children were overweight or obese. Moreover, national data are not available on patterns of physical activity or nutrition. Because of longer-term effects on adult health and prosperity, the socioeconomic circumstances of childhood are central in social policy considerations.8 Nowhere are these continuities between childhood circumstances and adult health clearer than in Aboriginal and Torres Strait Islanders. For this reason the report attempted to capture broader data on family functioning, local neighbourhoods, educational attainment, and the welfare of children in contact with health and social services. Some of the trends revealed by the study provide food for thought. The number of children on care and protection orders has increased almost 50% in 6 years, and rates in Indigenous children are over sixfold higher. The proportion of children in out-of-home care (ie, having to live away from their parents) has risen over 60% in the same period. Around one in ten families with children currently report that their neighbourhoods feel unsafe at least some of the time. This experience is three times commoner in poorer families. What effects these trends may be having on the mental health and emotional development of children is uncertain. Again our picture is incomplete, with the best available national data on child mental health now 7 years old.9 Data from this 7-year-old study suggested that, at any point in time, one in eight children had a diagnosable mental or behavioural disorder. These rates were twice as high in sole parent and blended families (ie, families formed by second marriages between parents with children). Thus, in attempting to paint a bigger picture of child health, development and wellbeing, the AIHW report has exposed huge gaps in the information needed for rational health and social policy responses. Perhaps the clearest gaps concern the emerging non-communicable illnesses of childhood. A need for up-to-date national data on the social and geographic distribution of childhood obesity and mental disorders stands out as a priority. What data we have suggest that these problems vary greatly according to geographic location and socioeconomic status and are worsening. If current social changes persist, the worsening trends in obesity and mental disorders seem likely to continue, and the children most affected will be those in disadvantaged and disrupted families. The federally funded Longitudinal Study of Australian Children will address some of the gaps by providing a better understanding of how current social and family contexts affect children.10 However, the study is of two cohorts separated by 4 years and will not be able to adequately capture the continuing and ongoing changes in the social context of childhood that we may expect to see in the coming years. Other gaps relate to our service systems for children and families. The aggregation of service system data to create ongoing national minimum datasets for areas such as juvenile justice, child protection and children’s services is an important first step in understanding how these systems are working. But much more is needed. The development of brief measures of development and social context in early and later childhood11,12 heralds the possibility of efficiently capturing ongoing shifts in the lifestyles, social development and health of our children. The new health problems of childhood are complex in their origins and likely to be complex in their solutions. A clearer picture of our children is needed to guide our responses — whether these be through priority research, informed government policy, better functioning of our service systems or, most importantly, the efforts of Australia’s parents, schools and local communities.

George C Patton MD, FRANZCP · Sharon R Goldfeld FRACP · Indrani Pieris-Caldwell PhD · Meredith Bryant MA · Graham V Vimpani FRACP

Most cases are caused by a single mutation, paving the way for therapeutic advances for this fatal disease Friedreich ataxia (FRDA), an autosomal recessive disease, is the commonest of the inherited ataxias’, affecting around 1 in 30 000 people.1 With an average age of onset of 10 years, those affected by this condition become wheelchair-bound on average 10 years after onset. The symptom that heralds onset in the vast majority of cases is increasing incoordination. Onset after 30 years of age is rare. Death ensues, on average, 36 years after disease onset and is largely due to hypertrophic cardiomyopathy.2 Other sources of morbidity in FRDA include an increased incidence of diabetes mellitus, dysarthria, swallowing difficulties, scoliosis, optic atrophy, hearing loss and foot deformity.1 FRDA is caused by mutations in the FRDA gene which encodes the protein frataxin. The pathogenic mutation is an expanded GAA triplet repeat in intron one of the FRDA gene in 98% of mutant alleles.1 The other 2% are point mutations. The fact that one mutation accounts for the vast majority of FRDA means that there is a relatively simple diagnostic test available for this disease. The genetic basis of FRDA was elucidated in 1996, and much has since been learnt about its pathogenesis. The first evidence of the role of frataxin came serendipitously, when the yeast equivalent of the FRDA gene (yfh1) was removed and increased levels of mitochondrial iron were detected.3 Human studies have confirmed that FRDA is indeed a disease of mitochondria. The accumulated evidence suggests that the marked reduction in frataxin results in decreased production of iron–sulfur cluster-containing proteins, which leads to deficiencies of some of the mitochondrial respiratory chain complexes and to secondary iron accumulation.2 Oxidative damage has been strongly implicated, although recent evidence brings this into question.4 These genetic and molecular findings have led to a number of therapies being proposed for FRDA. Interventions to maximise quality of life are of paramount importance, while the quest to find disease-modifying therapies continues. Hopes for the obvious prospect of iron chelation therapy have been tempered because none of the current iron chelators approved for clinical use preferentially reduce the levels of iron in mitochondria without also reducing cytosolic iron levels.5 Antioxidant therapy has shown the most promise. High-dose coenzyme Q10 and vitamin E has been shown to reverse the surrogate marker of reduced energy production in muscle magnetic resonance spectroscopy.6 Idebenone, an analogue of coenzyme Q10, reduces cardiac hypertrophy, although it has not been shown to relieve the neurological aspects of FRDA.7 A multicentre placebo controlled trial of idebenone is to start soon in the United States. An antioxidant targeted at mitochondria, mitoquinone, has been developed in New Zealand.8 Because mitochondria have a very strong membrane potential of about 150 mV (positive outside, negative inside), the drug is concentrated in mitochondria about 500-fold compared with antioxidants without a mitochondrial-targeting moiety. Clinical trials of this agent are planned to commence this year. Another approach that has promise is identifying agents that increase frataxin expression.9 The rationale for this approach is that all patients with FRDA produce low levels of normal frataxin, and, in experimental animal models, production of 25% of normal levels is enough to prevent development of disease. Therefore, a 5–10 fold increase in frataxin production may be therapeutic for most patients, while lower levels of induction may still produce significant amelioration of the disease.2 A small number of pharmacological agents have been screened thus far, causing up to a 2.5-fold induction in frataxin expression. It is hoped that high throughput screening of approved drugs and chemical libraries will lead to the identification of more effective and safe inducers. A major challenge facing FRDA clinical investigation is the development of appropriate outcome measures for clinical trials.10 FRDA is rare, and its rate of progression is not predictable, but occurs in a step-wise fashion. Therefore, a multicentre approach is vital to enable development of scales to measure the effects of therapies so that pharmacological discoveries can be quickly translated to patient benefit. The discovery of the underlying genetic mechanism for FRDA has led rapidly to better understanding of its pathogenesis. It is likely that this expanding knowledge will lead to therapies that slow the progression of, and ultimately cure, this fatal disease.

Martin B Delatycki MB BS, FRACP, PhD · Panos A Ioannou PhD · Andrew J Churchyard MB BS, FRACP, PhD

Unrealistic expectations may overshadow genuine advances and focus attention more on failures For many years, scientists and clinicians have sought to harness the power of genes for treating disease. The potential for gene therapy to cure otherwise untreatable conditions, and to offer a completely new strategy where conventional medicine has limited efficacy, has attracted huge interest and investment of time and money from both academic and commercial biotechnology sectors. The field of gene therapy has therefore grown rapidly. However, unrealistic expectation has overshadowed genuine advances and focused attention more on clinical failures and unnecessary mistakes. Only recently, federal law enforcement officials announced a substantial settlement with the University of Pennsylvania after the death of a patient in a gene therapy trial in 1999. Consequently, gene therapy has been viewed with suspicion, and the tight regulatory control on the conduct of clinical studies has to some extent restricted progress. But is the frequently cited accusation that gene therapy has failed to deliver in the clinical arena justified, or is it another manifestation of unrealistic expectation? At the start of the 1990s, the first clinical trials of gene therapy were attempted for an inherited severe combined immunodeficiency (SCID) caused by deficiency of the intracellular enzyme adenosine deaminase (ADA).1-4 In the absence of definitive treatment, SCID of any molecular type is usually fatal within the first year of life, although patients with ADA deficiency can be supported by administration of exogenous bovine enzyme. Even so, this is often only partially effective, and is extremely expensive. The rationale for the development of gene therapy for SCID therefore derives from the severity of the illness, the inadequacy of conventional therapy, and the considerable morbidity and mortality associated with stem-cell transplantation, particularly from a mismatched donor. Efficacy in these early studies was limited, but a decade further on, gene transfer technology and cell handling protocols had been refined sufficiently to produce real clinical benefit. Four recent studies have demonstrated highly effective gene therapy for the X-linked form of SCID (SCID-X1) and ADA deficiency, using retroviruses to deliver the therapeutic genes into haemopoietic stem cells ex vivo5-8 (also Gaspar and Thrasher, unpublished data). Bearing in mind the outcome and adverse effects of conventional therapy, these are remarkable results and the first clear indication that gene therapy can offer a cure for some human diseases. In a few patients, including one reported in this issue of the Journal (page 458),9 the treatment has failed, indicating that there is more to learn about the effective dose of corrected cells and the potential for host factors to influence immune cell development.10 Many different types of vector have been tested in laboratory experiments to deliver therapeutic genes, and their effectiveness is largely determined by the host and tissue type. For stable gene transfer to dividing cells, such as haemopoietic cells, the new genetic material has to be retained through cell division and passed on to daughter cells. Although retroviruses are highly effective for this, their dependence on chromosomal integration brings with it the risk of inadvertent gene activation or inactivation. Having initially achieved successful immunological reconstitution, three patients with SCID-X1 (out of a total of 18 SCID-X1 and seven ADA-deficient patients treated to date) developed T cell lymphoproliferative disease about 3 years after the gene therapy pro-cedure. 11 In two of these patients, the enhancer sequences in the retroviral vector, which are responsible for effective transgene expression, had activated the LMO-2 proto-oncogene. There are likely to be other factors that contributed to cell transformation, but they have not yet been defined. It is therefore unclear whether all patients are at significant risk, or whether this is restricted to a few with SCID-X1. All this makes decision-making by regulatory authorities very difficult, as it would be unfortunate to withdraw potentially life-saving therapy from patients who have few rational alternatives. It is also difficult for families faced with deciding whether to participate in a new therapy with proven curative potential but an element of uncertainty in the longer term. In light of the third adverse event reported earlier this year, regulatory authorities in both France and the United States have put ongoing SCID-X1 studies on hold, although the US Food and Drug Administration have preserved the potential to treat patients in whom allogeneic transplantation has failed. Having considered all options, UK authorities have allowed trials to continue as before, with case-by-case review. This response seems to offer the most flexibility, as patients in whom conventional therapy is judged to be of very high risk can continue to benefit from gene therapy. Importantly, it also empowers families to participate, with informed consent, in the decision-making process. The Australian position is outlined in this issue of the journal (page 441).12 Fortunately, it is likely that much can be done to improve efficiency and safety of current protocols, and these developments are expected to enter clinical trial quite soon. The design of vectors used for gene delivery is clearly important, and modifications are possible that limit the risks of mutagenesis, such as incorporation of DNA and RNA insulator sequences in integrating vectors; use of self-inactivating vectors in which the powerful viral enhancer sequences are deleted; or targeting of safe regions in the genome. Ultimately, the development of homologous recombination or gene repair to accurately correct genetic mutations, or the construction of mitotically stable extrachromosomal vectors, would obviate many of these problems, but current technologies are inefficient. The potential for gene therapy to treat human disease is clear, and the clinical evidence is beginning to emerge. The time between concept and delivery of therapeutic success is really no different from that of other significant medical advances, and the continuing occurrence of side effects associated with established approaches, such as organ and bone-marrow transplantation, should not be forgotten. Undoubtedly, similar strategies will be applied to other severe conditions, but also to a larger number of non-lethal conditions associated with significant disability. In this latter case, the risks of therapy have to be more clearly defined in biologically relevant model systems. The expectation that this exciting new therapeutic modality will produce major immediate effects in the absence of either predictable or unexpected adverse events is unrealistic. More than ever, human clinical trials are necessary to establish the efficacy of gene therapy and to inform future technological development.

Adrian J Thrasher

The NHMRC has set up the Gene and related Therapies Research Advisory Panel (GTRAP) to oversee gene therapy research The cornerstone of clinical research involving humans in Australia is the HREC (Human Research Ethics Committee). All studies must be approved by an HREC at the investigators’ institute(s). The demands on these committees are considerable, particularly when cutting-edge technology is involved. This was the situation in 1994 when the National Health and Medical Research Council (NHMRC) formed GTRAP (Gene and related Therapies Research Advisory Panel). The function of GTRAP was to provide the NHMRC, researchers, clinicians and HRECs with advice on medical, scientific and technical issues related to gene therapy,1 a novel form of treatment that had just been introduced in the United States. Its use in Australia — to treat severe combined immunodeficiency (SCID) — is described in this issue of the Journal (page 458).2 The NHMRC, through its Australian Health Ethics Committee, required that HRECs not give final approval for a gene therapy trial unless that trial had also been reviewed and approved by GTRAP. In Australia, gene therapy requires both local HREC and national GTRAP oversight. The reason for this was the novelty of the treatment, which does not involve traditional drugs or chemicals, but cells that have been genetically modified. Risks such as insertional mutagenesis, now tragically seen after gene therapy of SCID-X1, were known in the early 1990s to be possible. 3 Another concern was the unintentional involvement of germ cells, although the original targets for gene transfer were somatic cells. Genetic errors in somatic cells would harm the patient, but those in germ cells could be passed on to future generations. GTRAP works closely with the Therapeutic Goods Administration (Australia’s equivalent of the US Food and Drug Administration [FDA]), the Office of the Gene Technology Regulator and the Australian Health Ethics Committee through members in common. The “and related” component of GTRAP’s title reflects the growing use that will be made of cellular therapies in clinical practice. The NHMRC has recently expanded the GTRAP terms of reference to include cell therapies in the broader sense, given the future possibility that genetically engineered stem cells (or xenotransplants) will be trialled in clinical research. This move parallels the Therapeutic Goods Administration’s proposed new regulatory framework for tissues and emerging biological therapies.4 Because of the inherent uncertainty surrounding these novel therapies, GTRAP requires that all treated patients (or their families) be contactable should problems develop in the longer term. All studies require the sponsors or investigators to provide annual reports, notifications of adverse events, and a final report on completion of the study. GTRAP’s current position on trials of gene therapy for X-linked SCID or other therapy involving potential risk combinations (retroviral vectors and stem cell targets) is similar to that followed by the FDA, outlined in this issue of the Journal.5 For SCID-X1, this means that gene therapy can still be considered as an option if there are no alternative treatments, such as a suitable allogeneic bone marrow transplantation, or if such transplantation has failed. In the case of the potential risk combinations outlined above, gene therapy could continue after review of the risk–benefit analysis, ongoing monitoring which now would need to include 6-monthly integration-site analysis (analysis of the patient’s cells to detect any potential oncogenic events early), and inclusion in the patient information sheet and consent form the information that acute leukaemia has occurred in children as a complication of gene therapy. In Australia, the clinical investigator and sponsor of two ongoing gene therapy studies involving SCID-X12 and HIV, respectively, placed their studies on voluntary clinical hold when two cases of leukaemia were reported in children who had received gene therapy for SCID-X1. Since then, the SCID-X1 clinical study has remained on voluntary hold. The HIV study, which uses a retroviral vector targeted to haemopoietic stem cells, came off voluntary hold when reassessed by GTRAP. This reassessment included a review of the risk–benefit analysis, implementation of the additional monitoring requirement, and rewording of the consent documents, as described above. Following the report of a third leukaemia complication, the HIV study, which is also being conducted in the United States, has continued pending further advice from the FDA as well as GTRAP. At present, there are no additional scientific data available to GTRAP that would require a clinical hold on the HIV study, although the patient information sheet and consent forms must again be changed to reflect three, rather than two, leukaemia cases. More information on GTRAP (including a list of all gene therapy studies undertaken in Australia) can be found on the NHMRC website (www.nhmrc.gov.au/research/gtrap.htm).

Ronald JA Trent PhD, FRACP, FRCPA

Better coordination costs no more and improves the lot of patients How is it that Australia’s mental health services are in disarray? A Senate inquiry is mooted, and the press run stories of concern almost every week. Most of the stories are about failures in public-sector acute-care services that are the responsibility of the state and territory governments. Christopher Pyne, the Australian Government’s Parliamentary Secretary for Health said that “Australia’s states and territories stand condemned for their failure to deliver adequate mental health services . . . perhaps it is time for them to cede their responsibility for mental health to the Commonwealth”.1 So, while more money might make things easier, lack of money is not the cause of the crisis. Part of this rhetoric should be viewed in the light of federal–state relationships. However, part does reflect the uncoordinated way we fund our health systems — Medicare and Pharmaceutical Benefits at the federal level, private health insurance, the state and territory provision of public-sector services, and rising out-of-pocket expenses at the individual level. A coordinated funding system would be preferable. There are six contributors to Australia’s mental health service — general practitioners, private psychiatrists, private psychologists, private hospitals, state inpatient and community services, and non-government charitable organisations. The work of these contributors is poorly coordinated. It is like a six-horse chariot with six horsemen who seldom communicate. Coordination of health care is vital. In Canada, when Saskatoon, Edmonton and Calgary realised that a wave of influenza was coming, they had GPs give antiviral injections in nursing homes, made room in hospital intensive care units and had ambulances check their oxygen units. The wave of influenza came, there was no crisis and there were no unnecessary deaths. In Toronto, there was no such coordination — nursing homes closed, emergency rooms and intensive care units became full, ambulances circled the block and many people died unnecessarily.2 Coordinating the elements of a health system is important. The chariot needs a single horseman. In this issue of the Journal (page 396), Whiteford and Buckingham detail the achievements of the Australian Health Ministers’ Advisory Council’s National Mental Health Strategy 1993–2003, an attempt at federal–state coordination to which they contributed.3 The achievements have been considerable,4 but there are some reservations: While expenditure on mental health has increased, it has only increased in line with expenditure on other health services. Acute public-sector inpatient beds are at a satisfactory 18 per 100 000, but hospitals often are unable to admit critically ill patients because the number of rehabilitation beds and beds in the community is one quarter of the 50 per 100 000 recommended.5 Services that can’t discharge can’t admit. Community mental health services have grown as the number of hospital places has decreased. However, the absence of rehabilitation and community beds means that staff are being asked to care for people in the community who should be in supervised residential places. There have been few area-wide attempts to integrate the work of GPs, private psychiatrists and psychologists with the work of state inpatient and community services. Also in this issue of the Journal (page 401), Hickie and colleagues provide a manifesto for change, asking for money to establish national targets for mental health outcomes, to promote early intervention in the young, provide effective treatment in primary care, maximise rehabilitation opportunities, and invest in sustainable innovation.6 These are good aims, but won’t necessarily solve the present crisis. They do not address the issue of governance, how to enable the six contributors to work together, and how to remedy the deficiency in supervised accommodation. How did this crisis come about? Australia’s burden of mental illness (anxiety, depression, substance misuse and psychosis) is similar to that of other developed countries. Our coverage (proportion of people with a current mental disorder who seek treatment) is better than in most such countries. Our trained workforce is good. We have a strong consumer and carer movement and a powerful lobby in the Mental Health Services Conference <http://www.themhs.org>. We have very good data and know who is treated in each care sector.7 We have calculated that optimal care at current coverage would cost no more, but would be twice as effective as current care.8 So, while more money might make things easier, lack of money is not the cause of the crisis. The current crisis is most evident in the inability of the acute-care units to admit emergency cases, but there is a much more worrying problem looming — psychiatrists and nurses do not want to work in public-sector inpatient and community services.3 Psychiatrists in training, who staff state hospital and community services, find it uncongenial and resolve to leave the public system; and nurses who are no longer trained within the system resolve not to enter it. Information from new brain-imaging strategies and from the human genome project is changing our understanding of mental disorders. One would think that this impending avalanche of information would produce clinicians eager to be involved. In much of medicine, any physician hoping for an appointment at a teaching hospital will be doing a research doctorate. This is not happening in psychiatry. Patients deserve better. What to do? Is there any evidence that integrating the elements can improve services? There is. Projects in three health areas were funded by the federal government in 1999 to improve linkages between disparate parts of the mental health system. In each area, patient care improved, there was no increase in expenditure, and provider collaboration continued after the trial was over.9 Is Christopher Pyne right? Would things be better if there was a single payer and a single source of governance? Tony Abbott, Minister for Health and Ageing said “speculation about structural change is likely to dominate this year’s health debate”,10 which at least suggests that the matter is still on the table. The Constitution probably precludes the federal government forcibly taking over the states’ responsibility for health, but a way around this impasse has been suggested, arguing for an “Australian Health Commission” that could take responsibility for all health services and provide a patient-focused health care system which would be to everyone’s benefit.11 If something like this happens, the chariot would have one horseman, and the recurring crises in mental health might gradually ease.

Gavin Andrews MD

The most important need is for a change of attitude and approach Transition is “the purposeful, planned movement of adolescents and young adults with chronic physical and medical conditions from child-centred to adult-orientated health care systems”.1 The importance of transition of young people with chronic health conditions from paediatric to adult care is finally being recognised, but it needs to be addressed in a coordinated and integrated way. In Australia, as internationally, there are some well established and potentially effective transition programs. However, little is known about the efficacy of such programs, as there is little published evaluation.2 What is clear, both anecdotally and with some modest support in the literature, is that the journey faced by young people with chronic and disabling conditions is a complex one.3,4 The majority will face obstacles that arise from the lack of infrastructure and precedent in this specialised area of health care. Current approaches are rarely ideal, the most likely options being abrupt transfer to adult services, staying in the paediatric setting longer than is appropriate, or leaving medical supervision altogether. 5 The study at the Royal Children’s Hospital, Melbourne, reported by Lam and colleagues6 in this issue of the Journal (page 381) revealed a doubling in admissions of young adults aged 18 and over between 1992 and 2001, along with an overall increase in the numbers of adolescents admitted. In a more detailed analysis of a cohort of 247 young adults admitted during 2001, the authors also examined disease complexity and discovered a paucity of transition planning, particularly in surgical units. While some medical services (eg, Endocrinology, Respiratory Medicine) appeared to effect transition of adolescents with complex health issues efficiently, this was definitely not the norm. With increasing prevalence of some diseases and improved survival rates for previously fatal childhood conditions, pressures on all tertiary care facilities continue to rise. In paediatric hospitals, one possible outcome is pressure to improve facilities for adolescents. A psychosocial survey of Australian hospitals undertaken in 2004 by the Association for the Welfare of Child Health showed an increase in the number of “adolescent units” since the previous survey in 1994. 7 Hospitalised and ambulatory young people require developmentally appropriate health care supported by psychosocial services — needs that are usually better served in dedicated adolescent facilities. While the impact of this trend on transition practices is yet to be determined, the broader challenge is to consider transition needs in the coordinated planning of health care services. Until transition to adult care is recognised by the adult health care system as requiring a demonstrable change in attitude and resources, little real progress will be possible. Older adolescents deserve to be treated more as adults than as children. Keeping young adults in the paediatric system is working against this goal on many levels. A sense of maturity and hope for the future are implied in “moving on”, 8 but one of the prerequisites for an effective transition program is “an interested and capable adult service”. By allowing young adults to stay on in the paediatric system (which carries its own set of problems, including the inappropriate collocation of young children with “adults”), the development of such services is effectively stifled, and adult physicians and surgeons are not encouraged to develop their skills in the area. The article by Lam et al asks, “Why are they there?” It has been proposed that paediatric services may hold onto patients because of mistrust of adult services9 or through failure to promote independence and autonomy in health-care seeking. 10 Some other probable reasons are less strongly supported by the literature. One is that paediatric services are family-focused, while adult services treat patients as independent adults. This is problematic for young adults who still require family involvement because of the nature or severity of their disease or disability. Doctors and other staff in adult services may have limited knowledge and understanding of childhood chronic illnesses in young people who survive into adulthood, or of developmental issues in adolescents. Furthermore, young people are “diluted” in the adult health care system and their special needs may be largely overlooked in individual services. There are inherent difficulties in discovering, accessing and negotiating adult services for young people and their carers. The implications of “failed transition” for young people range from a lack of continuity of care and reliance on crisis services to “falling through the gap”, with significant adverse health consequences. 11 We agree with Lam and colleagues that the solution to the problems of young adults in children’s hospitals lies more in a greater focus on the infrastructure supporting transition than in admission policies per se. Unfortunately, there are no established, evaluated transition programs described in the literature on which such an infrastructure could be based. In New South Wales, the Transitional Care for Young People with Chronic Childhood Illnesses Group (part of the Greater Metropolitan Clinical Taskforce) is developing a state-wide strategy to address transition, which may serve as a blueprint for a national process (Box). Data collection, “gap” identification and the use of transition coordinators based in adult hospitals are all part of this initiative. Australia urgently needs to develop a national policy on transitional care that articulates the critical role of transition coordinators as well as the coordination of transitional care between paediatric and adult services. Success will also depend on educating health professionals and families about the value of coordinated transition; developing appropriate attitudes and expertise, particularly in adult services; comprehensively evaluating transition programs; examining health outcomes and cost–benefit issues; and involving consumer advisory groups.12,13 While additional resources may be needed, the overwhelming need is for a change of attitude and approach. Transition plan for young people and their families/carers*† * Based on a strategy being developed by the Transitional Care for Young People with Chronic Childhood Illnesses Group of the Greater Metropolitan Clinical Taskforce. †This model will require adjustment to meet the needs of special groups.

David L Bennett FRACP, FSAM · Susan J Towns FRACP · Kate S Steinbeck FRACP

Next to nothing is known about physical findings’ impact on patient care Young physicians today seem confused about physical examination. In the United States, many of them do not know how to do it and do not see why they should. Asymptomatic patients do not seem to need it; the US Preventive Services Task Force found insufficient evidence to recommend periodic physical examination of the breast, prostate, heart or anything else. Sick patients do not seem to benefit much from it either, most of them tested to death regardless of their physical findings. It is hard to say which is the chicken or the egg here, but physical diagnosis instruction in many US medical schools now is either out of date (emeritus faculty members teaching useless arcana like percussion of Traube’s space), out of touch (junior faculty members making rounds in a conference room, not at the bedside), or both. Young physicians trained outside the US are bewildered about this, too. Many of them, meticulously trained in physical examination, are appalled upon first encountering the “hands off” culture of US medicine. But they learn quickly, in the process often unlearning much of what they had learned before. The pace and clinical impact of this remarkable phenomenon is unknown because no one has studied it, a bewildering thing in itself. Many medical professionals claim to be bothered by this trend, but you would not know it from reading the medical literature. Although laudable research has clarified the accuracy (likelihood ratios) and reliability (kappa statistics) of particular physical findings,1 next to nothing is known about physical findings’ impact on patient care.2 In fact, you can count on one hand the number of studies ever published about this issue, not one of them large, controlled or externally funded.2-6 This inattention by researchers to medicine’s core clinical skills seems especially striking in this era of evidence-based medicine, in sharp contrast to the glut of acronymic mega-trials funded by “Big Pharma” to achieve statistically significant (but often clinically trivial) results. Some say not to worry about the lack of published evidence, the clinical value of physical examination is self-evident. To these true believers, we recommend a brief visit to any US teaching hospital today. The National Board of Medical Examiners, not so sanguine, plans to test the bedside skill of US medical students as a new requirement for graduation. This is a wise plan — in part because it has worked well in other countries — but not worth the bother if it ends there. What more can we do? In addition to evaluating how well our physicians learn the basics,7 we must continuously question what we teach them and why. For example, which physical findings have clinical utility in which clinical contexts? Palpating the carotid artery is essential in a patient with angina and a systolic murmur,1 less important in a patient with neck pain. Which physical findings, when shared with radiologists or pathologists, improve interpretation of diagnostic images or biopsies? Contrary to popular belief, the sensitivity and specificity of technological diagnostic tests may not be independent of patients’ clinical findings, knowledge of which may improve test performance.8 Conversely, which aspects of physical examination are useless (inaccurate, unreliable, redundant) or cost-inefficient when compared with technological testing? Thus, the real dilemma today is uncertainty about the “value added” by particular aspects of physical examination to the quality of patient care. If more attention were paid to this issue, more effort could be devoted to maintaining and improving particular bedside skills throughout physicians’ professional careers. Instead, the strongest praise many observers can offer is their feeling that the “laying on of hands” improves communication and trust between doctors and patients, somehow “connecting” them better, not just physically but otherwise. Despite its New Age vibrations, this feeling rings true to us, at least in the sense that careful physical examination focuses the physician, intently and singularly, on this patient now. (As one expert examiner put it, “The stethoscope allows you to connect not only your ears, but also your mind, to the patient.”9) This phenomenon is notable, and deserves further study, but it is not enough to convince the bewildered or sceptical among us about the value of physical examination. Proving scientifically physical examination’s clinical utility is difficult because this requires strict control of potential confounders. But to “isolate” the contribution of physical examination to diagnosis or prognosis — controlling methodologically and analytically for the patient’s history, test results and other confounders — makes little sense clinically. Physical findings add value precisely because they interact with and complement these other sources of information.3-6 For this reason, clinical epidemiologists commonly describe physical findings as “tests” whose result, when combined with a pre-test probability (based on prevalence, the clinical history or both), generates a post-test probability.1 This Bayesian approach makes it easier to describe the accuracy of physical findings, but there is scant evidence that physicians use this kind of reasoning when making clinical decisions. More promising, in our view, are clinical decision rules which, based on multivariate analysis of all potential clinical predictors (including physical findings), quantify the predictive power of the few key determinants of the outcome of interest.10 When impact analysis of such decision rules demonstrates that particular physical findings help to improve patient outcomes (for example, in the management of suspected pulmonary embolism or acute cardiac ischaemia),11,12 sceptics best take heed: these are things we all need to know. Much more research is needed in this area. In the end, we find ourselves bewildered by the need to say these things, bothered by the medical profession’s reticence about them. Together with the history, physical examination is the doctor’s best kept secret — powerful, portable, fast, cheap, durable, reproducible and fun — but it must be allowed out of the closet. We admit we are biased about this, perhaps even bewitched. How could we not be? Like other experienced clinicians, we cannot forget those memorable moments when a careful physical examination yielded magical results: neck veins that resurrected a young mother, moribund from pericardial constriction; a tender temple that rejuvenated an octogenarian, wasted by months of fever; a Babinski reflex that saved an Olympian, his brain tumor too early to see. And more, many more. Such anecdotes prove nothing, of course, but they are . . . bewitching. Modern medicine — bewitched by technology, bothered by its cost, bewildered by those who need it but cannot afford it — would do well to step back, re-examine itself. We recommend a thorough check-up. Preferably by a doctor who takes the time to look, listen, even touch. This should not be difficult to arrange. There are many such doctors out there. Good ones. For now, anyway.

Brendan M Reilly MD · Christopher A Smith MD · Brian P Lucas MD

They reduce rates of restenosis but not mortality or infarction — so are they worth it? The development of drug-eluting coronary stents has proven to be a quantum advance in interventional cardiology, rivalling the impact of stenting itself. Drug-eluting coronary stents deliver effective local concentrations of antiproliferative drugs (thus avoiding systemic toxicities), without substantially modifying the technique of percutaneous coronary intervention (PCI). Two of the drugs used are sirolimus and paclitaxel. Sirolimus is an inhibitor of the G1-phase of the cell cycle, while paclitaxel inhibits microtubule formation, both of which are necessary for cell division. Thus, they inhibit the natural healing mechanisms — endothelial cell migration and extracellular matrix formation — that produce intimal hyperplasia, resulting in restenosis. Randomised clinical trials of patients with stents that elute these agents have demonstrated reduced angiographic restenosis rates when compared with patients with bare-metal stents.1,2 These individual trials are supported by a recent meta-analysis of 11 randomised clinical trials involving 5103 patients; this showed that, in patients with drug-eluting stents (compared with those receiving bare-metal stents), there was a significant reduction in the proportion of patients requiring target lesion revascularisation (Box).3 Thus, within the context of randomised trials, and when all other things are equal, drug-eluting stents are clearly superior in preventing restenosis, which is the most significant late morbidity associated with coronary intervention. But, not all things are equal — these stents come at an approximately threefold increase in economic cost. As a consequence of this cost differential, the benefits of this new technology need to be considered critically. While the meta-analysis confirmed that drug-eluting stents decrease rates of restenosis and target lesion revascularisation,3 there was no evidence that they reduced deaths and myocardial infarction rates. However, given the nature of the innovation, this would not be expected. Furthermore, from the patient’s perspective, the impact of drug-eluting stents on the more relevant endpoint of “any” coronary revascularisation (as opposed to “target lesion” revascularisation) has not been highlighted and will be eroded by the development of de novo disease in other areas of the coronary vasculature.6 Among cardiologists and patients, this technology has been embraced with substantial enthusiasm. Drug-eluting stents are now being implanted in patients in subgroups and with lesion types beyond those evaluated by randomised trials.7 Some clinicians have also proposed that multi-vessel PCI using drug-eluting stents provides a comparable alternative to coronary artery bypass grafting.8 This preference is best illustrated by the disparate rates of drug-eluting stent implantation in the private and public sectors, estimated at > 75% and < 25%, respectively, reflecting the difference in who is paying for this technology. Several issues make it difficult to compare the cost-effectiveness of the two types of stents. First, without a benefit in terms of mortality, assessment of cost-effectiveness by cost-per-life-year saved is precluded. To circumvent this issue, a published cost-effectiveness analysis from the SIRIUS trial of sirolimus-eluting stents in elective PCI used quality-adjusted life-year (QALY) data drawn from a trial of bare-metal stenting for reperfusion therapy after myocardial infarction.4 Whether these QALY data are applicable to the patients in the SIRIUS trial, and to Australian patients, is uncertain. Given the potential lack of generalisability of clinical trial data to clinical practice, the use of QALY data from patients treated within a different clinical context may lead to a cost-effectiveness extrapolation not relevant to our local context. The time has come for the Australian cardiology community to develop national systems that routinely assess the long-term clinical outcomes of all patients undergoing PCI and coronary artery bypass grafting. Such data should yield several benefits. First, actual local data on effectiveness are essential for locally relevant cost-effectiveness estimates. Second, data on specific patient and lesion subsets inadequately studied in randomised trials will allow us to apply this innovation to patients most likely to benefit from it.9 Such data are vital to the rational development of practice guidelines and reimbursement strategies for optimal patient outcomes and health care expenditure. Third, as with any emerging therapy or technology, routine evaluation of long-term safety remains a priority; this has been highlighted by the recent report of very late stent thrombosis associated with drug-eluting stents.10 Routine systems of evaluation would provide an effective infrastructure for surveillance of unexpected adverse events occurring after a new technology has been approved, and would be less reliant on physicians for recognition and reporting. Problems relating to the costs of data collection and the difficulties of risk adjustment remain to be solved before nationwide registries can be implemented. However, the clinical and economic consequences of inappropriate application of this and other technologies would exceed these costs, potentially by orders of magnitude. The resource burden associated with assessing implementation of a new technology should not be used as an argument against its conduct, but rather should encourage the incorporation of this activity into routine clinical practice and funding. It has been argued that, with time, the cost of drug-eluting stents will fall, clinical experience will grow, and the application of this technology to clinical practice will be optimised.11 Over the past 10 years, the cost of bare-metal stents has declined by approximately 60%. Yet, interventional practice remains heterogeneous, and outcomes remain uncertain. Registries designed to assess practice, outcomes and cost will offer essential objective data to inform rational choices — until the time when all things become equal. Summary of evidence related to drug-eluting stents A Bayesian meta-analysis* of 11 randomised controlled trials comparing drug-eluting stents with bare-metal stenting3 showed the former had: — No effect on mortality rates (odds ratio, 1.11; 95% credible interval*, 0.61–2.06)3 — No effect on rates of myocardial infarction (odds ratio, 0.92; 95% credible interval*, 0.66–1.25)3 — Substantially lower rates of target lesion revascularisation (odds ratio, 0.26; 95% credible interval*, 0.14–0.45)3 — Fewer major adverse cardiac events when death, myocardial infarction, and target vessel revascularisation are combined (odds ratio, 0.42; 95% credible interval*, 0.32–0.53)3 In a randomised comparison of sirolimus-eluting versus bare-metal stents in elective percutaneous coronary intervention, the incremental cost-effectiveness ratio was estimated to be US$27 540 per quality-adjusted life-year gained.4 This reflects the money that needs to be spent to gain a benefit of one quality-adjusted life-year with this technology. Up to 50% of patients undergoing percutaneous coronary intervention have characteristics that would have led to their exclusion from clinical trials of drug-eluting stents in the US Dynamic Registry, a comprehensive angioplasty registry sponsored by the National Heart, Lung and Blood Institute.5 * In a Bayesian meta-analysis, “credible interval” corresponds to confidence interval.

Derek PB Chew MB BS, MPH, FRACP