Designed Extension of Survival Studies: Application to Clinical Trials with Unrecognized Heterogeneity

It is well known that unrecognized heterogeneity among patients, such as is conferred by genetic subtype, can undermine the power of randomized trial, designed under the assumption of homogeneity, to detect a truly beneficial treatment. We consider the conditional power approach to allow for recovery of power under unexplained heterogeneity. While Proschan and Hunsberger (1995) confined the application of conditional power design to normally distributed observations, we consider more general and difficult settings in which the data are in the framework of continuous time and are subject to censoring. In particular, we derive a procedure appropriate for the analysis of the weighted log rank test under the assumption of a proportional hazards frailty model. The proposed method is illustrated through application to a brain tumor trial.

A SURVEY OF THE LIKELIHOOD APPROACH TO BIOEQUIVALENCE TRIALS

Bioequivalence trials are abbreviated clinical trials whereby a generic drug or new formulation is evaluated to determine if it is "equivalent" to a corresponding previously approved brand-name drug or formulation. In this manuscript, we survey the process of testing bioequivalence and advocate the likelihood paradigm for representing the resulting data as evidence. We emphasize the unique conflicts between hypothesis testing and confidence intervals in this area - which we believe are indicative of the existence of the systemic defects in the frequentist approach - that the likelihood paradigm avoids. We suggest the direct use of profile likelihoods for evaluating bioequivalence and examine the main properties of profile likelihoods and estimated likelihoods under simulation. This simulation study shows that profile likelihoods are a reasonable alternative to the (unknown) true likelihood for a range of parameters commensurate with bioequivalence research. Our study also shows that the standard methods in the current practice of bioequivalence trials offers only weak evidence from the evidential point of view.