On optimal designs for clinical trials: An updated review

Optimization of clinical trial designs can help investigators achieve higher qualityresults for the given resource constraints. The present paper gives an overviewof optimal designs for various important problems that arise in different stages ofclinical drug development, including phase I dose–toxicity studies; phase I/II studiesthat consider early efficacy and toxicity outcomes simultaneously; phase IIdose–response studies driven by multiple comparisons (MCP), modeling techniques(Mod), or their combination (MCP–Mod); phase III randomized controlled multiarmmulti-objective clinical trials to test difference among several treatment groups;and population pharmacokinetics–pharmacodynamics experiments. We find thatmodern literature is very rich with optimal design methodologies that can be utilizedby clinical researchers to improve efficiency of drug development

T-optimal designs formulti-factor polynomial regressionmodelsvia a semidefinite relaxation method

We consider T-optimal experiment design problems for discriminating multi-factor polynomial regression models wherethe design space is defined by polynomial inequalities and the regression parameters are constrained to given convex sets.Our proposed optimality criterion is formulated as a convex optimization problem with a moment cone constraint. When theregression models have one factor, an exact semidefinite representation of the moment cone constraint can be applied to obtainan equivalent semidefinite program.When there are two or more factors in the models, we apply a moment relaxation techniqueand approximate the moment cone constraint by a hierarchy of semidefinite-representable outer approximations. When therelaxation hierarchy converges, an optimal discrimination design can be recovered from the optimal moment matrix, and itsoptimality can be additionally confirmed by an equivalence theorem. The methodology is illustrated with several examples

Combining forecasts based on multiple encompassing tests in a macroeconomic core system

Copyright © 2010 John Wiley & Sons, Ltd. This is the accepted version of the following article: Costantini, M. and Kunst, R. M. (2011), Combining forecasts based on multiple encompassing tests in a macroeconomic core system. J. Forecast., 30: 579–596, which has been published in final form at http://onlinelibrary.wiley.com/doi/10.1002/for.1190/abstract.This paper investigates whether and to what extent multiple encompassing tests may help determine weights for forecast averaging in a standard vector autoregressive setting. To this end we consider a new test-based procedure, which assigns non-zero weights to candidate models that add information not covered by other models. The potential benefits of this procedure are explored in extensive Monte Carlo simulations using realistic designs that are adapted to UK and to French macroeconomic data, to which trivariate vector autoregressions (VAR) are fitted. Thus simulations rely on potential data-generating mechanisms for macroeconomic data rather than on simple but artificial designs. We run two types of forecast ‘competitions’. In the first one, one of the model classes is the trivariate VAR, such that it contains the generating mechanism. In the second specification, none of the competing models contains the true structure. The simulation results show that the performance of test-based averaging is comparable to uniform weighting of individual models. In one of our role model economies, test-based averaging achieves advantages in small samples. In larger samples, pure prediction models outperform forecast averages

Optimal designs for active controlled dose finding trials with efficacy-toxicity outcomes

Nonlinear regression models addressing both efficacy and toxicity outcomes are increasingly used in dose-finding trials, such as in pharmaceutical drug development. However, research on related experimental design problems for corresponding active controlled trials is still scarce. In this paper we derive optimal designs to estimate efficacy and toxicity in an active controlled clinical dose finding trial when the bivariate continuous outcomes are modeled either by polynomials up to degree 2, the Michaelis- Menten model, the Emax model, or a combination thereof. We determine upper bounds on the number of different doses levels required for the optimal design and provide conditions under which the boundary points of the design space are included in the optimal design. We also provide an analytical description of the minimally supported $D$-optimal designs and show that they do not depend on the correlation between the bivariate outcomes. We illustrate the proposed methods with numerical examples and demonstrate the advantages of the $D$-optimal design for a trial, which has recently been considered in the literature.Comment: Keywords and Phrases: Active controlled trials, dose finding, optimal design, admissible design, Emax model, Equivalence theorem, Particle swarm optimization, Tchebycheff syste

D-optimal designs formulti-response linear mixed models

Linear mixed models have become popular in many statistical applications duringrecent years. However design issues for multi-response linear mixed models are rarelydiscussed. Themain purpose of this paper is to investigate D-optimal designs formultiresponselinear mixed models. We provide two equivalence theorems to characterizethe optimal designs for the estimation of the fixed effects and the prediction of randomeffects, respectively. Two examples of the D-optimal designs formulti-response linearmixed models are given for illustration

Combining Forecasts Based on Multiple Encompassing Tests in a Macroeconomic Core System

We investigate whether and to what extent multiple encompassing tests may help determine weights for forecast averaging in a standard vector autoregressive setting. To this end we consider a new test-based procedure, which assigns non-zero weights to candidate models that add information not covered by other models. The potential benefits of this procedure are explored in extensive Monte Carlo simulations using realistic designs that are adapted to U.K. and to French macroeconomic data. The real economic growth rates of these two countries serve as the target series to be predicted. Generally, we find that the test-based averaging of forecasts yields a performance that is comparable to a simple uniform weighting of individual models. In one of our role-model economies, test-based averaging achieves some advantages in small samples. In larger samples, pure prediction models outperform forecast averages.Combining forecasts, encompassing tests, model selection, time series