Gamma failure‐time mixture models: yet another way to establish efficacy

Using a Yamaguchi‐type generalized gamma failure‐time mixture model, we analyse the data from a study of autologous and allogeneic bone marrow transplantation in the treatment of high‐risk refractory acute lymphoblastic leukaemia, focusing on the time to recurrence of disease. We develop maximum likelihood techniques for the joint estimation of the surviving fractions and the survivor functions. This includes an approximation to the derivative of the survivor function with respect to the shape parameter. We obtain the maximum likelihood estimates of the model parameters. We also compute the variance‐covariance matrix of the parameter estimators. The extended family of generalized gamma failure‐time mixture models is flexible enough to include many commonly used failure‐time distributions as special cases. Yet these models are not used in practice because of computational difficulties. We claim that we have overcome this problem. The proposed approximation to the derivative of the survivor function with respect to the shape parameter can be used in any statistical package. We also address the issue of lack of identifiability. We point out that there can be a substantial advantage to using the gamma failure‐time mixture models over nonparametric methods. Copyright © 2003 John Wiley & Sons, Ltd.     

Adaptive Crossover Design for Normal Responses

In a response-adaptive design, we review and update the trial on the basis of outcomes in order to achive a specific goal. In clinical trials our goal is to allocate a larger number of patients to the better treatment. In the present paper, we use a response adaptive design in a two-treatment two-period crossover trial where the treatment responses are continuous. We provide probability measures to choose between the possible treatment combinations AA, AB, BA, or BB. The goal is to use the better treatment combination a larger number of times. We calculate the allocation proportions to the possible treatment combinations and their standard errors. We also derive some asymptotic results and provide solutions on related inferential problems. The proposed procedure is compared with a possible competitor. Finally, we use a data set to illustrate the applicability of our proposed design.     

Progressively censored tests for clinical experiments and life testing problems based on weighted empirical distributions

In the context of time-sequential studies, progressively censored tests for a simple regression model based on weighted empirical distributions are considered for ungrouped as well as grouped data situations. Early decision rules based on such tests are formulated. The asymptotic theory of the proposed tests rests on a construction of suitable empirical processes and their convergence (in distribution) to appropriate Gaussian functions. Critical values of the proposed test statistics are obtained by simulation, For a hypothetical example (of practical interest), a comparative study is made for the empirical powers and stopping times for some rival tests.     

Assessing multiple endpoints with ordered alternatives

Nonparametric approaches to the analysis of multiple endpoints in clinical studies can be of particular value when the endpoints are heterogeneous or distributional assumptions are suspect. We describe a multivariate Terpstra-Jonckheere U-statistic for assessing multiple endpoints with ordered alternatives, and illustrate its use with data arising from a recent clinical study.     

An efficient sequential design of clinical trials

We propose an efficient group sequential monitoring rule for clinical trials. At each interim analysis both efficacy and futility are evaluated through a specified loss structure together with the predicted power. The proposed design is robust to a wide range of priors, and achieves the specified power with a saving of sample size compared to existing adaptive designs. A method is also proposed to obtain a reduced-bias estimator of treatment difference for the proposed design. The new approaches hold great potential for efficiently selecting a more effective treatment in comparative trials. Operating characteristics are evaluated and compared with other group sequential designs in empirical studies. An example is provided to illustrate the application of the method.     

Issues in blinded sample size re-estimation

The utility of blinded sample size re-estimation for clinical trials depends on the ability to estimate variability without providing information about the true treatment difference, and on some reasonable assurance that the method is not likely to cause the sample size to be increased when the treatment effect is better than anticipated. We show that violations of these properties are unlikely to occur in practice.     

Tables of the cramér-von mises distributions

Tables of the one- and two-sample unweighted Cramer-von Mises statistics are given, and compared with the limiting distribution. The two-sample statistic may be useful in (for example) clinical trials when a proportional hazards assumption (which leads to the use of the log-rank test) is unjustified: see, for example, Schumacher (1984). It is often possible to stop clinical trials early if the Cramer-von Mises test (rather than say, the log-rank test) is employed.