Clinical trials have led to significant advances in health outcomes. For example, much of the continued decline in cardiovascular mortality since 2000 has been attributed to the evidence that established the various treatment strategies now in common use.1 However, as the costs of both medical care and clinical trials continue to rise, are our current clinical trials good value for money? In this article, the last in a series based on the MJA Clinical Trials Research Summit, we discuss the need for an innovative funding model for investigator-led clinical trials.

Through clinical trial evidence, treatments that are expensive yet no more effective than cheaper alternatives can be abandoned, while more cost-effective treatments
or programs can be introduced. Studies casting doubt on widely practised and costly clinical interventions demonstrate the value of investigator-initiated research. Recent Australian examples include trials of vertebroplasty for osteoporotic vertebral fractures, which showed no advantage compared with a sham procedure,2 and of craniectomy for closed head injury, which surprisingly had worse outcomes than conservative management.3 The ENIGMA (Evaluation of Nitrous Oxide in the Gas Mixture for Anaesthesia) trial showed previously unrecognised harms of nitrous oxide in anaesthesia,4 and showed that using nitrous oxide-free anaesthesia could potentially
save A$300 million per year in Australia.5 Giving immunoglobulin to neonates at risk of infection to prevent later disability was advocated until the International Neonatal Immunotherapy Study (INIS) established that
it did not make a difference.6 Were it not for the evidence provided by such trials, many millions of dollars would
be spent annually on ineffective interventions.

Just as importantly, many Australian trials have identified cost-effective treatments and preventive strategies. The recent ASPIRE (Aspirin to Prevent Recurrent Venous Thromboembolism) trial showed
that patients who had had unprovoked venous thromboembolism and were no longer candidates for anticoagulation could be protected from recurrence
with daily low-dose aspirin, a treatment applicable to thousands of patients worldwide.7 The cost of this trial (about A$4.5 million) is likely to be recouped within the next 1 to 2 years through savings in thromboembolism treatment costs. Lipid lowering with statin drugs has reduced cardiovascular mortality and morbidity, especially over the past decade. Its efficacy and cost-effectiveness were demonstrated particularly in the LIPID trial for patients with coronary heart disease and average cholesterol levels, leading to Pharmaceutical Benefits Scheme (PBS) subsidy of these drugs for many Australians.8 The cost of each additional quality-adjusted life-year (QALY) related to treatment was estimated at
just A$6300.9 Evidence from this trial has improved the treatment of thousands of patients. The cost of the trial itself was A$40 million, and when the cost of treatment for patients in Australia (as a result of trial evidence) is added, the total cost equates to less than A$7000 per QALY — considerably lower than the cost of many funded health care programs.

Many potentially worthwhile studies miss out on adequate public funding, and paradoxically some of these could be undertaken at no extra cost to the health system, for example, whether 3 months of adjuvant chemotherapy for patients with colorectal cancer is as effective as the current 6 months of treatment.10 The costs of undertaking this trial could be immediately recovered from the cost saving to the PBS.11

Not all trials will produce clear evidence of a benefit
or harm so, in terms of value for money, the full range of trials and their results must be considered. The National Institutes of Health program of trials in stroke and neurological disorders showed that a portfolio of 28 trials costing US$335 million (a mix of positive and negative trials) resulted in more effective care being identified and implemented, at an estimated total cost of US$7700 per QALY. Clearly, such research programs and subsequent treatments represent better value for money than some of the programs our health care budget currently pays for.12

Can we afford to pay for clinical trials? In 2003, McNeil and colleagues suggested a budget for large-scale public-good clinical trials of A$100 million per year, which at the time amounted to 0.2% of public health expenditure.13 By 2011, National Health and Medical Research Council (NHMRC) research grants for trials did total about A$100 million. But the cost of a large multicentre trial may exceed A$1.5–2 million per year over several years, or about twice the highest NHMRC grant in 2011. The combination of
an ageing population, the increasing cost of health care and new technological advances will lead to further cost increases, making it imperative for research to identify the most effective and efficient approaches to medical care within a constrained total budget.

Another challenge in sustaining research in Australia is the cost incurred by the complexity of the regulatory environment. Ethics and governance arrangements are cumbersome, requiring time-consuming ethical and contractual procedures, complex documentation, and detailed adverse event reporting.14 Hospitals are under pressure and increasingly reluctant to contribute to local costs of data collection. Also, clinical trials infrastructure (eg, coordinating centres available to multiple clinical trial groups) is underfunded, in spite of its potential to ultimately reduce costs.

We propose a new model for funding investigator-initiated studies. A strong clinical trial program must be embedded within and financed as part of the health system. A proportion of health care funding should be provided for cost-effective clinical trials for public good, as part of high-quality health care delivery, allocated on the basis of scientific quality, impact on future practice and whether a trial is expected to produce useful information. This has already begun in the United States and United Kingdom. The US academic health science centre (AHSC) model, in which institutions integrate translational research and care delivery systems, may have the potential to achieve these goals.15,16 In the UK, the National Institute for Health Research (NIHR) has injected
£1 billion into clinical and health outcomes research undertaken in National Health Service institutions.17 The NIHR ensured, by commissioning specific projects, that research funds would not be subsumed into operations. We propose that a pool of competitive funding could support the research costs of hospitals, which would be accountable through performance indicators for the hospital executive.

In addition, sufficient funding for clinical trials infrastructure nationally would allow economies of scale in areas such as data management, project coordination and biostatistical support, an investment that would reduce the costs of future research.

We believe that an additional 0.5% of total health care funding (about A$600 million), increasing to 1% in 2030, would allow clinical research advances and improvements in health outcomes to be achieved within projected national health care costs.18

These costs could also be offset by steps to make trials less expensive than they are now. This would rely, first, on efficient research design, such as judicious use of surrogate outcomes and prospectively designed meta-analysis of existing evidence and, second, on relief from some of the current regulatory requirements. If trials are part of usual health care, the less onerous and less expensive legal, ethical and reporting requirements used in health care would also apply to research.

Primary health care and the private health system
are important components of health care provision in Australia, and their potential contributions to effective health research should be considered.19 Public support should also be strengthened through a concerted campaign directed at patients, encouraging them to
take part in trials.

An independent national body overseeing clinical research and evaluation, with representatives from health departments, the NHMRC and industry, is needed to lead these innovations.20

With this leadership, and if our funding model includes integrating trials into the health care system, financing
a proportion of trials from the health care dollar and supporting investigator networks (Box), value for money in research in Australia will be within reach. If we do not do this, we will miss our opportunity for better health outcomes.

Lymphangioleiomyomatosis (LAM) is a rare genetic disease affecting women of childbearing age. It may occur either as sporadic LAM (sLAM), or in association with tuberous sclerosis complex (TSC) (TSC–LAM).1 Although LAM is classically characterised by progressive, cystic destruction of the lung parenchyma, it also has extrapulmonary manifestations including chylous collections (in the abdomen and pleura), lymphadenopathy, benign tumours of the kidney (angiomyolipomas [AMLs]), and abdominopelvic cystic masses (lymphangioleiomyomas).1–4

In LAM, abnormal cells of smooth muscle lineage infiltrate the lungs and lymphatic system, and circulate through the blood.2 This has resulted in the characterisation of LAM as a benign metastatic tumour by some researchers. Accumulation of these cells in the lymphatic ducts results in obstruction and consequently chylous ascites and pleural effusions, and may also underlie the formation of lymphangioleiomyomas. The origin of the LAM cells is unknown. Predicting a prognosis for patients is difficult, but a 10-year survival from time of diagnosis has been estimated at about 80%–90%.5

The genetic mutation in women with LAM lies in one of two functionally related genes: the TSC1 gene (coding for hamartin on chromosome 9q34) or the TSC2 gene (coding for tuberin on chromosome 16p13). A mutation on the TSC2 gene is more common in sLAM.1,3 Loss of function of the hamartin–tuberin complex leads to inappropriate downstream constitutive activation of mammalian target of rapamycin (mTOR), a key regulatory protein in cell proliferation and lymphangiogenesis.1,2 Accordingly, there has been much recent interest in mTOR inhibitors as potential therapeutic agents in TSC and LAM.

One recent randomised controlled trial has confirmed that the mTOR inhibitor sirolimus is effective in stabilising decline in lung function in LAM.3 Sirolimus has also been associated with shrinkage of lymphangioleiomyomas and chylous effusions, in case reports6,7 and in one longitudinal series,8 as well as with shrinkage of renal AMLs.9,10 Temsirolimus has been linked to shrinkage of abdominal tumours in a single case report.11 The mTOR inhibitor everolimus has been associated with reductions in the size of giant cell astrocytomas and seizure frequency in patients with TSC,12 and has recently been accepted by the United States Food and Drug Administration (FDA) for treatment of renal AMLs in TSC.13 Everolimus has not been reported in the treatment of lymphangioleiomyomas or chylous ascites.

We describe a series of five women with sLAM, all of whom had clinically significant lymphangioleiomyomas. All five women had a dramatic shrinkage and, in some cases, resolution of their tumours during therapy with everolimus.

Although LAM frequently presents with respiratory symptoms, abdominal involvement occurs in up to 70% of cases,14 with abdominal lymphangioleiomyomas in 16% of cases.2 Women may present with abdominal pain and swelling, and refractory chylous ascites, or with non-specific signs such as infertility or perimenstrual abdominal discomfort.4 Treatment is generally unsatisfactory, with medical therapies ineffective, and repeated abdominocentesis resulting in fluid reaccumulation, protein loss and potential infection.

The use of mTOR therapy in LAM is a targeted approach to an abnormality arising from a genetic mutation affecting multiple systems. The 2011 MILES trial showed that treatment with sirolimus in LAM was associated with a slower decline in lung function, improvement in quality of life and shrinkage of renal AMLs, but abdominal LAM was not the focus of that trial.3 To date, single-case reports and one observational series have documented regression of abdominal lymphangioleiomyomas with sirolimus or temsirolimus treatment,6–9,11 but there are no reports on everolimus. Our case series suggests that the efficacy of mTOR inhibitors extends to everolimus, and that this has good effect on abdominal LAM, which has been very difficult to treat in the past. Previous studies have shown that mTOR inhibitor treatment needs to be continued in TSC, but longitudinal data in LAM are limited.3,7 This is the first study to report everolimus treatment for LAM for several years, with all five women continuing on everolimus therapy. This is significant because the efficacy of mTOR inhibitors appears to rely on sustained therapy.3,11

Everolimus is a derivative of sirolimus and has a very similar side-effect profile. It has a shorter elimination half-life (about 30 hours) and greater relative bioavailability, compared with sirolimus.15 We used a lower dose of everolimus than the dose of sirolimus that was used in the MILES trial. The everolimus dose we used was consistent with the lower range of doses used in lung transplantation in our centre, with the aim of producing fewer side effects. Overall, everolimus was well tolerated and side effects, although significant, were within its described profile.

In summary, all women with sLAM showed a good response to treatment, with disappearance or shrinkage of abdominal lymphangioleiomyomas in four of five of cases, and clinical resolution of the lymphangioleiomyoma in the fifth. Abdominal symptoms resolved. Cessation of the therapy in one patient resulted in recurrence of ascites, and reinstitution of treatment resulted in resolution again. This is similar to the MILES trial, in which continued treatment was required.3 We suggest that everolimus treatment may be an effective long-term therapy for lymphangioleiomyomas and chylous ascites, which requires further evaluation in an appropriately designed controlled trial.

2 Abdominal computed tomography scans of Patient 1 showing (A) a baseline coronal view with a large multilobulated mass (measuring 8.3 cm × 4.3 cm axially and 17.5 cm longitudinally) in the para-aortic region (arrow), consistent with lymphangioleiomyoma; and (B) marked regression of the mass after 9 months of everolimus therapy

At 2 pm on Monday, 17 June 2013, His Holiness
the Dalai Lama arrived at Westmead Hospital in Sydney, not as a patient (thank goodness) but as a distinguished guest. Surrounded by a swirl of 10 police escort motorcycles and four security cars worthy of President Jed Bartlet from The West Wing, His Holiness landed and then embraced, smiled at and bestowed long white silk scarves upon the members of his welcoming party.

Security men spoke into tiny microphones at their wrists, and freaked out as the Dalai Lama strode into the waiting crowds. Dozens of cameras clicked as he made his way to the overflowing John Loewenthal Auditorium for
a colloquium on current ethical questions — about individual and social responsibility in a world loaded
with inequality, about Indigenous health and the interface between politics and health care. In welcoming him, I remarked that I could not imagine gathering an audience of this size to discuss our budget. The audience smiled their agreement and then they listened and questioned.

No doubt the Dalai Lama has his own political agenda. But for an hour on that wintry afternoon, staff who each day commit their lives to caring for others were inspired not by his politics, not by his grasp of economics, but by the optimism he exuded, by his spirituality and goodwill, by his warm humour and canny pragmatism.

“It’s the economy, stupid!” may be true and politicians forget it at their peril, but for many voters there is a desire that politicians address us also at our deepest level, honouring our sense of destiny and moral commitment. We want a vision, and we want to hear a story of our progress to date and what its next chapter might be, how things can be better in the future and how we can help. Only a positive view of the future, connected to our moral purpose and to how we want to be, will lead to effective and inclusive policy. But such a vision on its own is
not enough. It will inevitably also need to take account
of material, social and organisational reality.

Vision, of course, means looking forward. We do not need threatening and dire statements about how bad things are (they aren’t): imagine, a friend said to me recently, the outcome if Martin Luther King had announced, “I have a nightmare!” We need a dream
that guides future developments. We also need policies
to turn that dream into daytime reality.

Between now and the federal election scheduled for 14 September this year, we have the opportunity to reflect on the health reforms of the past 4 years and consider what has been achieved, and what has not been achieved. Importantly, we need to use that discussion to know what we need to do next.

We can have a vision and plan to transform it into action and results. But policies are not neat prose or detailed architectural plans to be easily and faithfully followed. Public policy formation is a complex phenomenon, with many players and multiple agendas unfolding. As a way forward, evidence from the real world may be a more defined and stable base from which to work. For this reason, many of us yearn for more evidence-based policy. But as social scientist Brian Head argues, the idea of “evidence-based” policy can be challenged and may
be an unrealistic expectation.1

Policy debate and decision making are inherently political and value-based. “Policy decisions are not deduced primarily from facts and empirical models”, Head states, “but from politics, judgement and debate. Policy domains are inherently marked by the interplay of facts, norms and desired actions. Some policy settings are
data-resistant owing to governmental commitments.”1

Evidence-based policy is also challenged because “information is perceived and used in different ways,
by actors looking through different ‘lenses’. From this perspective, there is more than one type of relevant ‘evidence’”.1 Head speaks of “three lenses” of evidence — political know-how, systematic research, and professional practice. “The three-lenses approach suggests that there may be importantly divergent perspectives on whether and how to increase mutual understanding and shared objectives.”1

So policy may not yield all the results we seek, but
we can at least be clear about what we, as health care professionals, value and wish to see enhanced. We can contribute. We can be at the policy table. Between now and 14 September, the Journal will publish a series of opinions by health leaders, each a page long, about the future and what we should consider in relation to health policy.

We hope that these short essays will contribute to the formation of useful policy by those who compete to lead us through the next 4 years. And may the vision be 20/20!