摘要:

Some current approaches to modeling crossover trials in two treatments are critically reviewed from the perspective of the practical requirements of the drug developer. Particular attention is paid to the AB/BA design, and the inadequacies of the once popular two-stage procedure are discussed in detail. The use of baseline data is also examined. Both frequentist and Bayesian alternatives to approaches currently advocated are considered and critically compared. It is concluded that it is crucial for the applied statistician working in this field to have an appreciation of the practical medical and pharmacological background.

ISSN:1054-3406    

DOI:10.1080/10543409808835233

出版商:Marcel Dekker, Inc.    

年代:1998

数据来源: Taylor

ISSN:1054-3406    

DOI:10.1080/10543409808835234

出版商:Marcel Dekker, Inc.    

年代:1998

数据来源: Taylor

ISSN:1054-3406    

DOI:10.1080/10543409808835235

出版商:Marcel Dekker, Inc.    

年代:1998

数据来源: Taylor

ISSN:1054-3406    

DOI:10.1080/10543409808835236

出版商:Marcel Dekker, Inc.    

年代:1998

数据来源: Taylor

摘要:

Crossover designs are widely used in different medical investigations where a number of treatments have to be compared. Sequences of treatments are given to subjects, and in practice the observations within each subject are likely to be correlated. This paper is concerned with the construction of crossover designs for such cases. The design problem is nonlinear in the parameters, and design optimality depends on the parameters defining the correlation structure. When the correlation structure is known, local optimum designs are obtained. When the distribution of its parameters is known, optimum Bayesian crossover designs are constructed. The optimum sizes of the groups of subjects receiving the same sequence of treatments are also determined.

ISSN:1054-3406    

DOI:10.1080/10543409808835237

出版商:Marcel Dekker, Inc.    

年代:1998

数据来源: Taylor

摘要:

We discuss in this paper some issues related to the use of the ratio or the odds ratio of cure rates in therapeutic equivalence clinical trials with binary endpoints. Some two one-sided tests procedures are proposed and their fixed sample performances evaluated by Monte Carlo simulations. Sample size formulas are derived for most of these procedures. The con-sequences of applying acceptance limits proposed for pharmacokinetic responses in bioequivalence studies to clinical endpoints in therapeutic equivalence clinical trials are also described.

ISSN:1054-3406    

DOI:10.1080/10543409808835238

出版商:Marcel Dekker, Inc.    

年代:1998

数据来源: Taylor

摘要:

The purpose of this paper is to compare the Bayes factor and the likelihood ratio test in a pharmaceutical trial where the two treatments are a new drug and a control (a positive control or a placebo). The goal is to jointly answer the questions (1) is the new drug or the control toxic? (2) Is the new drug more effective and safer than the control? We consider a bivariate model where each treatment is characterized by a target effect (a continuous primary responsey) and by a side effect (a continuous supplementary response ξ). Using a Bayesian approach, we account for the uncertainty resulting from prediction of the side effect, by making use of the physician's prior inputs about the target-toxicity relationship and the maximum tolerated target effects that are considered to be safe. Finally, we consider an example about a sleeplessness drug, and we show that the Bayes factor provides a more flexible and informative tool than the likelihood ratio test in simultaneous testing. Advantages are greater when the number of experimental subjects is small.

ISSN:1054-3406    

DOI:10.1080/10543409808835239

出版商:Marcel Dekker, Inc.    

年代:1998

数据来源: Taylor

摘要:

Several statistical methods are available for the analysis of responses with ordinal categories or continuous distributionsfor the respective visits in longitudinal studies. This paper discusses an alternative nonparametric strategy for studies with more than two groups through Mann-Whitney rank measures of association for all pairs of groups. The proposed method is based on U-statistic theory, and it applies a linear or linear logistic model to the Mann-Whitney estimators for the probabilities of better response for each group relative to each of the others. In addition, the ways of adjusting for covariables and managing stratification factors are explained. Analysis of parallel dose-response relationships for two treatments isillustrated for the proposed method with data from a multicenter study with repeated measurements. A nonparametric estimator for relative potency is provided from the method.

ISSN:1054-3406    

DOI:10.1080/10543409808835240

出版商:Marcel Dekker, Inc.    

年代:1998

数据来源: Taylor

摘要:

Satterthwaite's approximation for the degrees of freedom of a linear combination of independent mean squares is extended to the case that the mean squares are correlated. The mean squares are sample variances where some of the experimental units have been used in more than one sample. The motivation for such an extension comes from pharmacokinetics. The observations, taken at different time points from a set of animals, are blood drug concentrations. Some animals were sampled at more than one time point. A linear combination of sample means provides an estimate of the population mean area under the concentration-versus-time curve, which is an indicator of drug exposure. An associated linear combination of sample variances provides an estimate of the variance of the area estimator. The behavior of confidence intervals based on the approximation was studied by simulation. The confidence interval for the population mean, constructed by assuming that the variance estimator has a chi-square distribution with the computed degrees of freedom, achieved close to its nominal 95% coverage, justifying the extension of Satterthwaite's approximation.

ISSN:1054-3406    

DOI:10.1080/10543409808835241

出版商:Marcel Dekker, Inc.    

年代:1998

数据来源: Taylor

摘要:

It is well known that the covariance matrix for the multinomial distribution is singular and, therefore, does not have a unique inverse. If, however, any row and corresponding column are removed, the reduced matrix is nonsingular and the unique inverse has a closed form. We elucidate some of the properties of the multinomial covariance matrix and its reduced forms. We state and prove a theorem that gives insight into the singularity and its removal. Based on these results, we establish that the covariance matrix for the multinomial distribution is positive semidefinite and that the reduced matrix is positive definite. In addition, we show that the determinant of the reduced matrix is invariant to the particular row and column that are removed. Goodness-of-fit statistics, including Pearson's chi-square, and justification of the degrees of freedom follow from the multivariate central limit theorem once the singularity is removed.

ISSN:1054-3406    

DOI:10.1080/10543409808835242

出版商:Marcel Dekker, Inc.    

年代:1998

数据来源: Taylor