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Existing research points to the presence of philanthropists in global governance as funders of programmes and partners. Through an in-depth exploration of global health governance, we highlight that philanthropic organizations now shape governance by acting as producers of knowledge. Practicing 'knowledge philanthropism', they collect, produce and assemble the data, calculations and research which is used by International Organizations (IOs) to govern problems. In addition, philanthropies craft tools of interpretation, whether concepts, vocabularies, or concrete technological devices that embed these, which are being used for the treatment of the knowledge they themselves produce. While performing such activities, they reify their own role and enable their deeper entanglement in the knowledge machinery of global governance, fashioning data-centric activities as the solution to global health problems, and themselves as the necessary partners in this resource-intensive data collection effort. The epistemic power of philanthropists produces political effects, on health interventions and modes of governing, which deeply participate to the transformation of all matters into objects of investments for financial returns. We explore these processes in relation to global health governance, with a specific focus on medical hypertension, fashioned as a top global health priority and a necessary 'investment' by the World Health Organization (WHO) and other sites of global governance. [ABSTRACT FROM AUTHOR]

This article opens up the blackbox through which evidence is selected and assessed in the making of guidelines and recommendations in global governance, through an exploration of "methods regimes." Methods regimes are a special kind of sociomaterial arrangement, which govern the production and validation of knowledge, by establishing a clear hierachy between alternative forms of research designs. When such regimes become inscribed in processes of global governance, they shape and control what knowledge is deemed valid and thus relevant for policy. We shed light that through a mode of operation that relies on a discourse of procedurality, a dispersed but powerful network of epistemic operators, and a dense web of infrastructures, methods regimes constitute and police the making of "policy-relevant knowledge" in global governance. Through an examination of the case of "GRADE" (Grading of Recommendations, Assessment, Development, and Evaluation), a standardized system that evaluates and grades the quality of evidence in global health, we show that its dominance has worked to the effect of empowering a new cast of methodologists, seen as more objective and portable across domains, sidelining certain forms of evidence that do not conform with its own methodological criteria of scientificity, and "clinicalizing" research in medicine and beyond. [ABSTRACT FROM AUTHOR]

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The reasons behind why and how the communitarisation of the policy debate on book prices took place in Europe are explained. It is argued that once the locus of the decision-making process had shifted de facto towards the EU level, the diversity of actors' preferences, decision rules and the nature of the status quo made it impossible for the tenants of dirigiste solutions to impose their policy preferences.

International bureaucracies can expand their activities into new domains, even when these are remote from their formal mandates. Asking how they do this, this article reveals that expansion often goes unnoticed, because international secretariats typically start new activities in a way which is informal, mundane and depoliticized. Through an examination of UNESCO's and WHO's expansion into the domain of bioethics, the article argues that international bureaucratic tactics revert to a three-fold strategy mixing technicalization, expertization and naturalization. This suggests that international bureaucracies' autonomy does not depend on their fixed characteristics, as defined by their legal-institutional mandates, capacities, or level of expertise. Expansion takes place, rather, when such resources are efficiently activated, assembled, or developed, thus shedding light on the need to examine what international bureaucracies 'do', rather than what they 'are', in order to capture their influence in global governance. [ABSTRACT FROM AUTHOR]

Patients with refractory or relapsed acute myeloid leukemia (R/R AML) have a poor prognosis, with a high unmet medical need. Idasanutlin is a small-molecule inhibitor of MDM2, a negative regulator of tumor suppressor p53. By preventing the p53-MDM2 interaction, idasanutlin allows for p53 activation, particularly in patients with TP53 wild-type (WT) status. MIRROS (NCT02545283) is a randomized Phase III trial evaluating idasanutlin + cytarabine versus placebo + cytarabine in R/R AML. The primary end point is overall survival in the TP53-WT population. Secondary end points include complete remission rate (cycle 1), overall remission rate (cycle 1) and event-free survival in the TP53-WT population. MIRROS has an innovative design that integrates a stringent interim analysis for futility; continuation criteria were met in mid-2017 and accrual is ongoing. Trial registration number: NCT02545283. [ABSTRACT FROM AUTHOR]

For a trial with primary endpoint overall survival for a molecule with curative potential, statistical methods that rely on the proportional hazards assumption may underestimate the power and the time to final analysis. We show how a cure proportion model can be used to get the necessary number of events and appropriate timing via simulation. If phase 1 results for the new drug are exceptional and/or the medical need in the target population is high, a phase 3 trial might be initiated after phase 1. Building in a futility interim analysis into such a pivotal trial may mitigate the uncertainty of moving directly to phase 3. However, if cure is possible, overall survival might not be mature enough at the interim to support a futility decision. We propose to base this decision on an intermediate endpoint that is sufficiently associated with survival. Planning for such an interim can be interpreted as making a randomized phase 2 trial a part of the pivotal trial: If stopped at the interim, the trial data would be analyzed, and a decision on a subsequent phase 3 trial would be made. If the trial continues at the interim, then the phase 3 trial is already underway. To select a futility boundary, a mechanistic simulation model that connects the intermediate endpoint and survival is proposed. We illustrate how this approach was used to design a pivotal randomized trial in acute myeloid leukemia and discuss historical data that informed the simulation model and operational challenges when implementing it. [ABSTRACT FROM AUTHOR]

This article challenges the assumption that ethics committees introduce democratic control in policy areas where scientific expertise and ethical concerns collide. The claim is that politicians or bureaucrats are likely to resort to the use of ethical expertise when they face a specific type of dilemma: the impossibility, on the one hand, of yielding a consensus on controversial value-based issues via the democratic route and the need, on the other, to legitimize controversial policy choices in these areas. The article examines this dynamic with regard to the European Union's medical biotechnology policy, a contested policy domain where ethical specialists are awarded expert status. The article finds that establishing ethical experts as a new category of expertise alongside scientific experts actually bolsters the technocratic domain in areas where it is contested, thus reinforcing the authority of experts and bureaucrats in the policy process, rather than democratic control. [ABSTRACT FROM AUTHOR]

This article addresses debates on the formulation of public policy, building upon a body of literature which has focused on the interconnectedness between the venues of policy action and the way issues are defined. It does so by focusing on the strategic role of policy actors in a policy subfield and their attempts at manipulating either frames or venues in order to shape policy. The novelty here consists in pointing to the involvement of regulators in such strategic action. An emerging body of research has indeed shown that the activity of formally independent regulators is not necessarily limited to the implementation of delegated regulatory competencies and that they are increasingly engaged in policy-making activities. Thus, by resorting to the agenda-setting and framing literature, the article sheds light on novel pathways through which regulators intervene in policy-making activities, making a claim that they have very good 'tools' at their disposal in order to shape policy. These dynamics are examined in the case of the last piece of the EU's pharmaceutical framework - the 2004 Directive on Traditional Herbal Medicines - which provoked intense debate among manufacturers of herbals, retailers, consumers, and both EU-level and domestic-level regulatory authorities. [ABSTRACT FROM AUTHOR]

After the 2004 eastern enlargement, the European Union has become a terrain of competition between different memory narratives. At the core of the debate is the status of the Holocaust and its role in the identity-definition process of European societies. This article asks why similar memory debates have resulted in different policy outcomes when taking place in different institutional settings at the EU level. It finds, along with Schattschneider's analysis of policy conflicts, that the choice of the venue of the conflict determined what the conflict was about and how people were divided. Policy outcomes were determined by which of the different possible conflicts gained the dominant position and this, in turn, depended on 'losers' in the policy debate being able to choose the right venue for the defence of their concerns. [ABSTRACT FROM AUTHOR]

Over the last few years, EU institutions have taken on the task of promoting an ‘active European remembrance’ of Europe's twentieth century totalitarian experiences. At stake in this process is the possibility of constructing an EU-wide historical narrative. However, EU-level debates on the remembrance of European history are permeated by struggles between policy actors who vie for control over the telling of Europe's past. Using insights from the agenda-setting and framing literatures, the article examines the conditions under which memory narratives are able to become prominent or, conversely, lose ground in the EU's overall discourse. It concludes that, although the constellation of actors in place was a key factor in explaining fluctuations in the EU's remembrance discourse, the weight of their arguments also depended on how well their discourse resonated with existing memory cultures at the domestic and the EU levels. [ABSTRACT FROM PUBLISHER]

A new discourse in which culture is increasingly integrated into a policy agenda dealing with innovation policy, and the fostering of growth and economic competitiveness more generally, is currently gaining ground at the EU level. Surprisingly, it is the Directorate-General for Culture, Youth and Education (DG Culture) of the European Commission that has initiated and promoted this policy agenda in an attempt to gain control over policy. The new agenda differs radically from the programmatic discourses formerly promoted by DG Culture, which laid the emphasis on the value of culture for its own sake. By identifying the factors that enabled a small, hardly influential DG to reframe culture as a key factor of economic competitiveness and to impose this programmatic solution both within the Commission and at the intergovernmental level, this article sheds light on the key dynamics of agenda-setting in the EU institutional context. It focuses, essentially, on the nature of the discourse itself, the specificities of conflict expansion strategies at the EU level and the characteristics of the EU political and institutional context. [ABSTRACT FROM PUBLISHER]

This article aims to fill a gap in the theoretical literature on European integration by providing a dynamic and multi-level explanatory framework of the dynamics of European integration - defined as the locus of governance shifts from the national to the European level. While with the development of governance approaches, the multi-actorness of the EU has been taken into account, the objective of understanding how interactions between different actors explain dynamics of integration has been abandoned. Thus, the article shows that by focusing on dynamic patterns of interaction between subnational, state and supranational actors, some core dynamics of the European integration process can be better captured. A dynamic and multi-level model of interaction, termed 'reversed intergovernmentalism', is proposed here. The model posits that governments' intervention at the EU level often takes place as a reaction to developments orchestrated by Community institutions, but that, through their reaction, states in turn foster both the process of integration and another form of EU intervention in such a way that the very nature of EU integration can also divert from initial EU agendas. Setting itself against existing theories of European integration, the argument shows that integration dynamics can only be fully understood within a process of interaction and reciprocal feedback between actors at different levels of governance. [ABSTRACT FROM AUTHOR]

The European Union (EU) began to develop copyright policies as early as the 1980s even though no competence existed in the Treaties. The formulation of EU policies in the area of intellectual property has been the object of heated policy debates between a diverse range of stakeholders, at the heart of which are some fundamentally different conceptions about the nature of intellectual property and its role in the information economy. Thus, EU copyright policy is the complex outcome of the interplay between subnational, national and EU-level policy actors that were all trying to ‘frame the policy debate’ in order to control policy and policy outcomes . This article explains why certain policy choices were made in the formulation of EU policies, when several policy options were, in principle, available. It argues, essentially, that insofar as the locus of decision-making shifted towards the EU level as a result of European institutions' use of their agenda-setting and judiciary powers , policy outcomes were, in a second stage, more likely to favour liberal policy solutions. [ABSTRACT FROM AUTHOR]

\n Objectively measuring Parkinson’s disease (PD) signs and symptoms over time is critical for the successful development of treatments aimed at halting the disease progression of people with PD.To create a clinical trial simulation tool that characterizes the natural history of PD progression and enables a data-driven design of randomized controlled studies testing potential disease-modifying treatments (DMT) in early-stage PD.Data from the Parkinson’s Progression Markers Initiative (PPMI) were analyzed with nonlinear mixed-effect modeling techniques to characterize the progression of MDS-UPDRS part I (non-motor aspects of experiences of daily living), part II (motor aspects of experiences of daily living), and part III (motor signs). A clinical trial simulation tool was built from these disease models and used to predict probability of success as a function of trial design.MDS-UPDRS part III progresses approximately 3 times faster than MDS-UPDRS part II and I, with an increase of 3 versus 1 points/year. Higher amounts of symptomatic therapy is associated with slower progression of MDS-UPDRS part II and III. The modeling framework predicts that a DMT effect on MDS-UPDRS part III could precede effect on part II by approximately 2 to 3 years.Our clinical trial simulation tool predicted that in a two-year randomized controlled trial, MDS-UPDRS part III could be used to evaluate a potential novel DMT, while part II would require longer trials of a minimum duration of 3 to 5 years underscoring the need for innovative trial design approaches including novel patient-centric measures.To develop effective medicines that can slow down or stop the progression of Parkinson’s disease (PD), it is important to accurately understand how the disease worsens over time. We used data from an observational study, led by the Michael J. Fox Foundation, called the Parkinson’s Progression Markers Initiative (PPMI) to understand the natural progression of  PD. We simulated clinical trials on a computer using different scales to measure the progression of PD. We specifically looked at a physician-reported measure MDS-UPDRS part III, and at a patient-reported measure MDS-UPDRS part II of how PD symptoms worsen over time. To measure the effect of a new medicine slowing down the progression of PD using patient-reported measure MDS-UPDRS part II, we estimate that we may need to conduct a clinical trial of at least 3 to 5 years. On the other hand, to measure an effect using physician-reported measure MDS-UPDRS part III, the duration of the trial could be shorter than 2 years. We were also able to show that worsening recorded by the physician-reported measure MDS-UPDRS part III could be predictive of a later worsening recorded by the patient-reported measure MDS-UPDRS part II. We concluded that MDS-UPDRS part III may be a good endpoint for a clinical trial of a reasonable duration and that MDS-UPDRS part II could be measured in longer studies, for example, open-label extensions. [ABSTRACT FROM AUTHOR]