Testing homogeneity of two zero-inflated Poisson populations.

The problem of testing treatment difference in the occurrence of a safety parameter in a randomized parallel-group comparative clinical trial under the assumption that the number of occurrence follows a zero-inflated Poisson (ZIP) distribution is considered. Likelihood ratio tests (LRT) for homogeneity of two ZIP populations are derived under the hypotheses that (i) there is no difference in inflation parameters, (ii) there is no difference in non-zero means; and (iii) there is no difference in both inflation parameters and non-zero means. Approximate formulas for sample size calculation are also obtained for achieving a desired power for detecting a clinically meaningful difference under the corresponding alternative hypotheses. An example concerning the assessment of the gastrointestinal (GI) safety in terms of the number of erosion counts of a newly developed compound for the treatment of osteoarthritis and rheumatoid arthritis is given for illustration purpose.

On power and sample size calculation for QT studies with recording replicates at given time point.

The problem of the impact on power and sample size calculation for routine QT studies with ECG recording replicates under a parallel-group design and a crossover design is examined. Replicate ECGs are defined as single ECG recorded within several minutes of a nominal time (PhRMA, 2003). Formulas for sample size calculations with and without adjustment for covariates such as some pharmacokinetic responses (e.g., AUC or C(max)), which are known to be correlated to the QT intervals, were derived under both the parallel-group design and the crossover design. The results indicate that the approach of replicates may require a smaller sample size for achieving the same power when the correlation coefficient between the recording replicates (or repeated measures) is close to 0 (i.e., these replicate ECGs are almost independent). On the other hand, if the correlation coefficient is close to 1, then there is not much gain regardless of whether replicate ECGs are considered. In this paper, an approach to identifying optimal allocation between the number of subjects and the number of replicates per subject is proposed for achieving the maximum power under a fixed budget constraint. The proposed approach can also be applied to minimize the cost for a given power.

Statistical assessment of QT/QTc prolongation based on maximum of correlated normal random variables.

To establish noninferiority in QT/QTc prolongation of a test drug with respect to either a placebo or an active control, a thorough QT/QTc study is recommended by ICH (ICH E14, ICH 2005) which concerns statistical inference on the maximal time-matched drug effect. The existing statistical methods for assessing such effects suffer either power loss or parameter restriction. In this paper, we propose a new asymptotic test with small sample correction based on distribution of maximum of correlated random variables under both a parallel-group design and a crossover design. Simulations indicate that our proposed test has adequate powers.

The effect of commonly used vehicles on canine hematology and clinical chemistry values.

Drug metabolism and pharmacokinetic (DMPK) studies are an important phase in drug discovery research. Compounds are administered via the intravascular or extravascular routes to animals to calculate various pharmacokinetic parameters. An important step in this process is dissolving the novel compound in a safe vehicle. This procedure is particularly challenging for compounds that must be administered intravenously, as the solution must be clear before injection. There are no published guidelines on which vehicles, or combination of vehicles, are acceptable in a particular species, nor are there published data on the effects these vehicles have on clinical chemistry or hematology parameters, particularly in dogs. In this study, 9 vehicles commonly used at sanofi-aventis USA (propylene glycol, polyethylene glycol 400, glycofurol, hydroxypropyl Beta-cyclodextrin, dimethyl sulfoxide, N-methyl-2-pyrrolidone, dimethylacetamide, ethyl alcohol, and saline) were tested for adverse clinical reactions (such as vomiting or diarrhea) and for their effect on hematology and clinical chemistry parameters. Each vehicle was administered to a group of 8 Beagles by slow intravenous infusion, and blood was collected prior to infusion and at 24 h and 7 d postinfusion. Of 8 dogs given propylene glycol, 2 developed mild gastrointestinal signs (vomitus, diarrhea) after their infusions. None of the vehicles tested induced significant hematology or serum clinical chemistry abnormalities, nor were significant clinical signs noted after administration. We conclude that at the dose, route, and manner described, all of the vehicles tested in this study are clinically safe to use and have no acute effects on hematology or serum chemistry parameters.

Statistical method for analysis of the disease curve in animals with experimental autoimmune encephalomyelitis.

Experimental autoimmune encephalomyelitis (EAE) is a procedure used in the laboratory to examine drugs that may have utility in treating multiple sclerosis (MS). The problem of modeling the disease curve in animals with EAE is studied. The classification of animals after each experiment is considered and the chi-square test is proposed to test a homogeneity between treatment groups. A mixture type of nonlinear mixed-effects model with repeated measurements is considered, assuming that the onset and/or remission of disease is the fixed effect as well as the random effect. Statistical inference on the parameters of the disease curves is discussed. The proposed model is shown to be efficient for comparing the disease curves with different treatments. Examples concerning the study of the effects of test compounds in EAE are presented to illustrate the proposed model and statistical methodologies.