Providing Australian children and adolescents with equitable access to new and emerging therapies through clinical trials: a call to action

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Opportunities for children to benefit from novel therapies have increased substantially over the past decade. Change is needed to maximise these opportunities, particularly in the paediatric trial environment. Investment and a coordinated national approach are needed to prevent Australian children falling behind their international peers. There is international recognition that collaborative approaches and strategic investment in paediatric clinical trials reap benefits in terms of access to clinical trials and new therapies. This article exemplifies a multi-state collaboration and presents a united call to action to prioritise paediatric clinical trials, by strategically investing in effective governance and infrastructure, and a shift in culture that embeds clinical trials in the core business of paediatric health care and academic institutions. Recently, numerous life-changing and life-saving therapies have emerged, with many more in the drug development pipeline (Box 1).1-4 Phenotypic drug discovery has been revolutionised by advanced methods for pre-clinical screening: disease models using induced pluripotent stem cell technologies, organoids, gene-editing tools and imaging assay technologies.5 Between 2010 and 2020, 440 innovative drugs were approved for marketing by the United States Food and Drug Administration,2 including an increasing number of gene and other advanced therapeutics.1 New and truly transformative paediatric therapies include highly effective modulator therapy in cystic fibrosis,6 gene therapies for spinal muscular atrophy,7 and chimeric antigen receptor T-cell therapy for cancer.8 Access to novel therapies through clinical research is increasingly seen as optimal care for children affected by devastating and previously untreatable disease. Many of these diseases are rare, affecting fewer than 5 in 10 000 people.9 About two million Australians live with a rare disease, most first experienced in childhood. One-third of children affected by a rare disease will not live to see their fifth birthday.10, 11 Children managed at hospitals that support advanced therapeutic trials — including gene therapies — have been able to access potentially transformative therapies years before regulatory approval and subsequent reimbursement make them broadly available. For progressive or life-limiting conditions, this can mean major direct benefit. Ideally, clinical research should be embedded into clinical practice, as has long been in the case for paediatric oncology. Oncology provides an exemplar for disciplines that can provide effective overarching treatment paradigms that incorporate numerous subsets of very targeted treatment pathways.12, 13 Additionally, while most advanced therapies are currently sponsored by overseas-based pharmaceutical companies, experience in trials provides opportunities to develop research pipelines that enable the development, evaluation and translation of novel Australian therapies. Nevertheless, considerable challenges to delivering high quality clinical trials in children and adolescents remain (Box 2).14-17 Internationally, these challenges have led to the development of paediatric clinical trials networks.18 A Bill is currently before the US House of Representatives, promoting the establishment and maintenance of a paediatric trials network, supported by substantial grant funding from 2024 to 2029.19 Mismatch between costs that study sites recover from trials, and the time and resources required: In Australia, the challenges in delivering clinical trials in children is further compounded by distance, with less concentrated populations and large distances between capitals, and our position outside of the major global regulators, particularly the US Food and Drug Administration and the European Medicines Agency. It is the responsibility of tertiary and quaternary paediatric centres to provide equitable and streamlined access to early phase and emerging treatments for every Australian child affected by disease or disability, regardless of rarity of disease, socio-economic status, or geographical location. This aligns with the articulated objective of Australia's National Strategic Action Plan for Rare Diseases, which aims to enable all Australians to have equitable access to the best available health technology.20 This shift away from the traditional separations between clinical care and clinical research into a seamless clinical interface requires reconsideration of the funding models that have previously been utilised for clinical trials. Just as excellent clinical care involves investment beyond a physical bed and staff at the bedside — with resourcing for education, professional development, and capacity building — these same pillars of sustainability are essential in the clinical trials sphere.21 A thriving and expanding advanced therapeutics service cannot be established by haphazard revenue generated by pharmaceutical company-funded clinical trials alone. Increased support can ensure: recruitment and retention of expert personnel in both paediatrics and clinical trials; high quality local infrastructure to support novel therapies along with workflow processes, quality assurance and control mechanisms; and adequate staffing and resources to meet site performance and data standards, as recommended prerequisites for high quality trials. This cannot occur without the same support that international networks have received to grow collaborative networks, site infrastructure and resources.22 We recommend the development of a national collaborative community of paediatric trials centres, enabling clinicians and researchers to exchange excellence and experience in the strategy and implementation of clinical trials and advanced therapeutics. This will provide an efficient, national approach to paediatric clinical trials and advanced therapeutic delivery that potentiates the health, economic and social impacts for all paediatric hospitals in Australia. Given the rarity of many paediatric diseases and the complexity of emerging therapies, a national approach for complex trials in paediatrics is imperative. This compliments the priorities identified in the National Strategic Action Plan for Rare Diseases,20 which promotes the importance of a national rare disease workforce strategy as well as the National Clinical Trials Governance Framework21 and is in line with other nationally coordinated approaches such as the National Health Genomics Policy Framework.23 We have established a collaboration across the Sydney Children's Hospitals Network, the Royal Children's Hospital Melbourne and Murdoch Children's Research Institute campus, Monash Children's Hospital, Queensland Children's Hospital, and university partners, with a view to eventually creating a national network of paediatric clinical trial centres. The rate at which advanced and targeted therapeutics are moving through scientific pipelines to trials and clinical care requires rapid enhancements in knowledge and skillset. Mapping of expertise allows streamlined access for both industry and referring clinicians. The lessons learnt from a gene replacement therapy in neuromuscular disease will inform implementation of future gene therapy trials. With a collaborative approach, the complications experienced from chimeric antigen receptor T-cell therapy at one centre can provide benefit in managing complications at another. Our collaboration of Australian paediatric trials centres remains informal but has been effective in sharing ideas for best practice, written resources and educational material; however, greater resources and core funding are required to achieve its full potential. The European Union has recognised the importance of such networks and funded a paediatric trials network with a substantial Horizon 2020 grant.24 We recommend the delivery of precision medicine that is transformative and disease specific, by combining and developing world class paradigms

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