Second Paediatric Strategy Forum for anaplastic lymphoma kinase (ALK) inhibition in paediatric malignancies: ACCELERATE in collaboration with the European Medicines Agency with the participation of the Food and Drug Administration.

The first (2017) and sixth (2021) multistakeholder Paediatric Strategy Forums focused on anaplastic lymphoma kinase (ALK) inhibition in paediatric malignancies. ALK is an important oncogene and target in several paediatric tumours (anaplastic large cell lymphoma [ALCL], inflammatory myofibroblastic tumour [IMT], neuroblastoma and hemispheric gliomas in infants and young children) with unmet therapeutic needs. ALK tyrosine kinase inhibitors have been demonstrated to be active both in ALK fusion-kinase positive ALCL and IMT. ALK alterations differ, with fusions occurring in ALCL, IMT and gliomas, and activating mutations and amplification in neuroblastoma. While there are many ALK inhibitors in development, the number of children diagnosed with ALK driven malignancies is very small. The objectives of this ALK Forum were to (i) Describe current knowledge of ALK biology in childhood cancers; (ii) Provide an overview of the development of ALK inhibitors for children; (iii) Identify the unmet needs taking into account planned or current ongoing trials; (iv) Conclude how second/third-generation inhibitors could be evaluated and prioritised; (v) Identify lessons learnt from the experience with ALK inhibitors to accelerate the paediatric development of other anti-cancer targeted agents in the new regulatory environments. There has been progress over the last four years, with more trials of ALK inhibitors opened in paediatrics and more regulatory submissions. In January 2021, the US Food and Drug Administration approved crizotinib for the treatment of paediatric and young adult patients with relapsed or refractory ALCL and there are paediatric investigation plans (PIPs) for brigatinib and for crizotinib in ALCL and IMT. In ALCL, the current goal is to investigate the inclusion of ALK inhibitors in front-line therapy with the aim of decreasing toxicity with higher/similar efficacy compared to present first-line therapies. For IMT, the focus is to develop a joint prospective trial with one product in children, adolescents and adults, taking advantage of the common biology across the age spectrum. As approximately 50% of IMTs are ALK-positive, molecular analysis is required to identify patients to be treated with an ALK inhibitor. For neuroblastoma, crizotinib has not shown robust anti-tumour activity. A focused and sequential development of ALK inhibitors with very good central nervous system (CNS) penetration in CNS tumours with ALK fusions should be undertaken. The Forum reinforced the strong need for global academic collaboration, very early involvement of regulators with studies seeking possible registration and early academia-multicompany engagement. Innovations in study design and conduct and the use of 'real-world data' supporting development in these rare sub-groups of patients for whom randomised clinical trials are not feasible are important initiatives. A focused and sequenced development strategy, where one product is evaluated first with other products being assessed sequentially, is applicable for ALK inhibitors and other medicinal products in children.

Termites of Solidarity in the House of Austerity: Undermining Fiscal Governance in the European Union.

European Union (EU) fiscal governance, especially the European Semester, is an ambitious new governance architecture involving surveillance and discipline, across both Eurozone and non-Eurozone member state policies, in pursuit of fiscal rigor. It is the most recent of several attempts to expand EU powers over member state policy with the goal of austere budgeting, and one that has led to remarkable claims of authority by the EU over member state health policies as detailed as medical school admissions and the role of primary care. It is expected that it would be resisted not just by those who object to an EU role in the organization and delivery of health care but also by those who object to a particular austere approach to health policy. How well is it working? Using two waves of interviews and documentary analysis, and health as a policy case study, the authors document three key techniques that opponents use to undermine the semester's governance architecture: broadening goals, expanding the scope of conflict, and disputing and nuancing indicators. The result is that opponents of a narrow fiscal governance agenda are again successfully undermining the narrow focus of the semester.

What Is EU Public Health and Why? Explaining the Scope and Organization of Public Health in the European Union.

Public health is notoriously difficult to define, and that is the case for public health in the European Union as much as other political systems. In this article, the authors try to identify the actual scope and meaning of public health as it is institutionalized in the EU political system. Using a mixture of historical policy and legal analysis, the authors show how the evolution of the institutional space called public health in the EU has been shaped by the EU's distinctive constitutional nature, its focus on regulation, and the legacy of its focus on market making as well as the preferences of its political leaders. The European Union does have an increasingly large space named "public health," in which health ministers, the health directorate-general, and invocation of its public health treaty article 168 can be found, as well as a much broader and older area of activities justified by the need to manage adverse health consequences of market-making policies in other areas such as labor standards and agriculture. The COVID-19 crisis of 2020 not only led to a strengthening of EU public health but also showed that the EU is one of the many political systems in which the legal and bureaucratic domain of public health is far smaller than the actual issues affecting the public's health.

Health "Brexternalities": The Brexit Effect on Health and Health Care outside the United Kingdom.

The principal effects of Brexit on health and health care will fall within the United Kingdom, and all forms of Brexit have overwhelmingly negative implications for health care and health within the UK. This article focuses on the external effects of Brexit ("Brexternalities") for health and health care. The EU is a particularly powerful institutional and legal arrangement for managing economic and political externalities in health policy as in any other policy. Equally, when a state leaves the EU, the manner of leaving will result in better or worse management of relevant externalities. Brexternalities thus involve questions about policy legitimacy and accountability. Health Brexternalities do not fall equally in all EU countries. They are felt more distinctly in the context of those elements of health policy that are most closely entwined with the UK's health policy (e.g., on the island of Ireland, certain areas of Spain, and other parts of southern Europe). Some health Brexternalities, such as in medicine safety, will be imposed on the whole population of the EU. And some health Brexternalities, such as communicable disease control, will be felt globally.

Networked Health Care Governance in the European Union.

The European Union (EU) increasingly resorts to new forms of governance to establish unified health and welfare policies without member states having to transfer their sovereignty to a supranational level. European Administrative Networks are important instruments in the toolbox of new forms of governance, dealing with rulemaking, rule monitoring, and rule enforcement. Operating beyond, but not above, the state, European networks of national administrative units allow for interaction and exchange to coordinate national responses to increased interaction across their borders. The authors use social network analysis to uncover the pattern of interaction among national representatives in two central EU health care networks. Their analysis finds not only that the network in the area of pharmacovigilance has more competences, resources, and capacity to improve the enforcement of EU rules than the network regarding cross-border health care but also that the driving forces behind network interaction appear to differ quite a bit as well. While the supranational character becomes apparent in the former network, network interactions in the latter seem aimed at mitigating the impact of patient mobility rather than improving cross-border health care take up.

Health, federalism and the European Union: lessons from comparative federalism about the European Union.

Bringing together the results of a large-scale review of European Union (EU) policies affecting health and a large-scale analysis of social policy and federalism, this paper uses comparative federalism to identify the scope and tensions of EU health policy at the end of the Juncker Commission. Viewing health care and public health policy through the lens of comparative federalism highlights some serious structural flaws in EU health policy. The regulatory state form in which the EU has evolved makes it difficult for the EU to formulate a health policy that actually focuses on health. Of the three faces of EU health policy, which are health policy, internal market policy and fiscal governance, health policy is legally, politically and financially the weakest. A comparison of the EU to other federations suggests that this creates basic weaknesses in the EU's design: its key powers are regulatory and its redistribution minimal. No federal welfare state so clearly pools risks at a low level while making markets so forcefully or creating rights whose costs are born by other levels of government. This structure, understandable in light of the EU's history and development, limits its health and social policy initiatives and might not be stable over the long term.

Challenges to sovereign ambitions: forces of convergence and divergence within the global pharmaceutical sector and the UK's withdrawal from the European Union.

This paper maps key regulatory, governance and legal challenges associated with the UK's withdrawal from the European Union (EU) in terms of convergent and divergent pressures within the global pharmaceutical sector. These include (i) convergent regulatory pressures associated with the European framework for pre-market licensing; (ii) convergent and divergent industry pressures with regard to drug discovery and manufacturing; and (iii) divergent and convergent market pressures associated with the supply, pricing and assessment of medicines. The UK's sovereign ambitions risk a loss of influence over the licensing and surveillance of pharmaceuticals under convergent regulatory and industry pressures to engage in unilateral participation in the European regime. Further, they also risk a loss of influence over processes for pricing and assessing the effectiveness of new treatment regimens under divergent market pressures from larger pharmaceutical markets outside the EU, notably the United States.

A tribute to the foot soldiers: European health agencies in the fight against antimicrobial resistance.

The prevention of antimicrobial resistance (AMR) has been a flagship of the EU's health policy since the early 2000s, leading the European Commission to mandate three European agencies to cooperate in the fight against AMR: EMA (the European Medicines Agency), ECDC (European Centre for Disease Prevention and Control) and EFSA (the European Food Safety Agency). This article is at the intersection of EU health policy and the burgeoning scholarship on bureaucratic reputation. Little is known on the role played by reputational incentives on inter-agency cooperation. This empirical work supports the claim that cooperation creates incentives for agencies to protect their reputational uniqueness vis-à-vis each other. However, rather than threatening their cooperation, it amounts to a process of sense-making of their respective roles in the integrated fight against AMR. Evidence is generated through the agencies' textual sources, as well as in-depth interviews and analysed through a narrative analysis. From the early days of inter-agency cooperation, to recent legislative work, this paper offers in-depth insights on the EU's governance against AMR.