Integrating Phase 2 into Phase 3 based on an Intermediate Endpoint While Accounting for a Cure Proportion -- with an Application to the Design of a Clinical Trial in Acute Myeloid Leukemia

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, discuss historical data that informed the simulation model, and operational challenges when implementing it.Comment: 23 pages, 3 figures, 3 tables. All code is available on github: https://github.com/numbersman77/integratePhase2.gi

MIRROS: a randomized, placebo-controlled, Phase III trial of cytarabine ± idasanutlin in relapsed or refractory acute myeloid leukemia.

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: NCT0254528

Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome associated with COVID-19: An Emulated Target Trial Analysis.

RATIONALE: Whether COVID patients may benefit from extracorporeal membrane oxygenation (ECMO) compared with conventional invasive mechanical ventilation (IMV) remains unknown. OBJECTIVES: To estimate the effect of ECMO on 90-Day mortality vs IMV only Methods: Among 4,244 critically ill adult patients with COVID-19 included in a multicenter cohort study, we emulated a target trial comparing the treatment strategies of initiating ECMO vs. no ECMO within 7 days of IMV in patients with severe acute respiratory distress syndrome (PaO2/FiO2 <80 or PaCO2 ≥60 mmHg). We controlled for confounding using a multivariable Cox model based on predefined variables. MAIN RESULTS: 1,235 patients met the full eligibility criteria for the emulated trial, among whom 164 patients initiated ECMO. The ECMO strategy had a higher survival probability at Day-7 from the onset of eligibility criteria (87% vs 83%, risk difference: 4%, 95% CI 0;9%) which decreased during follow-up (survival at Day-90: 63% vs 65%, risk difference: -2%, 95% CI -10;5%). However, ECMO was associated with higher survival when performed in high-volume ECMO centers or in regions where a specific ECMO network organization was set up to handle high demand, and when initiated within the first 4 days of MV and in profoundly hypoxemic patients. CONCLUSIONS: In an emulated trial based on a nationwide COVID-19 cohort, we found differential survival over time of an ECMO compared with a no-ECMO strategy. However, ECMO was consistently associated with better outcomes when performed in high-volume centers and in regions with ECMO capacities specifically organized to handle high demand. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Turkey and the European Union: the implications of a specific enlargement. Egmont European Affairs Paper, April 2006

Turkey has been an associate member of the EU since 1963 and an official candidate to EU membership since 1999. The European Council of December 2004 finally scheduled to open negotiations in view of Turkish accession to the EU on 3rd October 20052. The December decision provoked intense reactions all across political forces as well as among European citizens. The debate over Turkey’s accession has been a far more intense one than that which surrounded the start of negotiations with the accession countries of Central and Eastern Europe (CEECs) in 1998. Irrational reactions from the public opinion in EU Members States – or real response to the specificities of the Turkish enlargement? After presenting a brief history of the EU-Turkish relationship (§1) and examining whether the Turkish enlargement bears either political, economic, geopolitical or cultural particularities (§ 2), this paper explores the grounds on which the European Commission recommended the opening of the negotiations (§ 3). Finally, in light of the specificities of the Turkish enlargement highlighted in part 2, the implications of the Council Decision to open negotiations in view of Turkey’s accession to the EU are discussed (§ 4)

The construction process of EU cultural policy : explaining Europeanisaton and EU policy formation

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Dynamic Multi-Level Governance – Bringing the Study of Multi-level Interactions into the Theorising of European Integration

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.integration theory; neo-functionalism; intergovernmentalism; multilevel governance; negative integration; positive integration; social policy; political science

The Politics of Values in EU Governance. Occurrences, Effects and Modes of Regulation of Values

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