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

A filtered polynomial approach to density estimation

In this paper, a little known computational approach to density estimation based on filtered polynomial approximation is investigated. It is accompanied by the first online available density estimation computer program based on a filtered polynomial approach. The approximation yields the unknown distribution and density as the product of a monotonic increasing polynomial and a filter. The filter may be considered as a target distribution which gets fixed prior to the estimation. The filtered polynomial approach then provides coefficient estimates for (close) algebraic approximations to (a) the unknown density function and (b) the unknown cumulative distribution function as well as (c) a transformation (e.g., normalization) from the unknown data distribution to the filter. This approach provides a high degree of smoothness in its estimates for univariate as well as for multivariate settings. The nice properties as the high degree of smoothness and the ability to select from different target distributions are suited especially in MCMC simulations. Two applications in Sects. 1 and 7 will show the advantages of the filtered polynomial approach over the commonly used kernel estimation metho

Natur - Raritäten : Moorfrösche sind bedroht

Der Moorfrosch gehört zu den bedrohten Tierarten Baden-Württembergs, für die das Land in besonderer Verantwortung steht. Ziel des Faltblattes ist, die Öffentlichkeit über Gefährdung und Maßnahmen zum Schutz dieser selten gewordenen Froschart zu informieren