Testing for bioequivalence of highly variable drugs from TR‐RT crossover designs with heterogeneous residual variances

Traditional bioavailability studies assess average bioequivalence (ABE) between the test (T) and reference (R) products under the crossover design with TR and RT sequences. With highly variable (HV) drugs whose intrasubject coefficient of variation in pharmacokinetic measures is 30% or greater, assertion of ABE becomes difficult due to the large sample sizes needed to achieve adequate power. In 2011, the FDA adopted a more relaxed, yet complex, ABE criterion and supplied a procedure to assess this criterion exclusively under TRR‐RTR‐RRT and TRTR‐RTRT designs. However, designs with more than 2 periods are not always feasible. This present work investigates how to evaluate HV drugs under TR‐RT designs. A mixed model with heterogeneous residual variances is used to fit data from TR‐RT designs. Under the assumption of zero subject‐by‐formulation interaction, this basic model is comparable to the FDA‐recommended model for TRR‐RTR‐RRT and TRTR‐RTRT designs, suggesting the conceptual plausibility of our approach. To overcome the distributional dependency among summary statistics of model parameters, we develop statistical tests via the generalized pivotal quantity (GPQ). A real‐world data example is given to illustrate the utility of the resulting procedures. Our simulation study identifies a GPQ‐based testing procedure that evaluates HV drugs under practical TR‐RT designs with desirable type I error rate and reasonable power. In comparison to the FDA's approach, this GPQ‐based procedure gives similar performance when the product's intersubject standard deviation is low (≤0.4) and is most useful when practical considerations restrict the crossover design to 2 periods.     

Prediction in Some Poisson Errors in Variables Models

Predictive distributions are developed and illustrated for prediction in some Poisson errors in variables models. Two different situations in which multiplicative treatment effects are appropriate are considered within the context of predicting counts of road accidents. Hierarchical prior structures are investigated, and numerical integration and Gibbs sampling routines are used to derive the predictive and posterior probabilities. Examples of analyses are provided with data from road accidents in Sweden.     

Exact calculation of power and sample size in bioequivalence studies using two one‐sided tests

The number of subjects in a pharmacokinetic two‐period two‐treatment crossover bioequivalence study is typically small, most often less than 60. The most common approach to testing for bioequivalence is the two one‐sided tests procedure. No explicit mathematical formula for the power function in the context of the two one‐sided tests procedure exists in the statistical literature, although the exact power based on Owen's special case of bivariate noncentral t‐distribution has been tabulated and graphed. Several approximations have previously been published for the probability of rejection in the two one‐sided tests procedure for crossover bioequivalence studies. These approximations and associated sample size formulas are reviewed in this article and compared for various parameter combinations with exact power formulas derived here, which are computed analytically as univariate integrals and which have been validated by Monte Carlo simulations. The exact formulas for power and sample size are shown to improve markedly in realistic parameter settings over the previous approximations. Copyright © 2014 John Wiley & Sons, Ltd.     

Notes on estimation of the intraclass correlation under the AB/BA crossover trial

Under the AB/BA crossover trial, we focus our attention on estimation of the intraclass correlation in normal data. We develop both point and interval estimators in closed form for the intraclass correlation. We employ Monte Carlo simulation to study the performance of these estimators in a variety of situations. We note that the estimators developed here for the intraclass correlation remain valid even when there are possibly unexpected carry-over effects.     

Assessing robustness of crossover designsto subjects dropping out

In some crossover experiments, particularly in medical applications, subjects may fail to complete their sequences of treatments for reasons unconnected with the treatments received. A method is described of assessing the robustness of a planned crossover design, with more than two periods, to subjects leaving the study prematurely. The method involves computing measures of efficiency for every possible design that can result, and is therefore very computationally intensive. Summaries of these measures are used to choose between competing designs. The computational problem is reduced to a manageable size by a software implementation of Polya theory. The method is applied to comparing designs for crossover studies involving four treatments and four periods. Designs are identified that are more robust to subjects dropping out in the final period than those currently favoured in medical and clinical trials.     

Repeated measurements designs with unequal period sizes

Summary This paper is concerned with the designs in which each experimental unit is assigned more than once to a treatment, either different or identical. An easy method of constructing balanced minimal repeated measurements designs with unequal period sizes is presented whenever the number of periods is less than the number of treatments. Strongly balanced minimal repeated measurements designs with unequal period sizes are also constructed whenever the number of periods is less than the number of treatments.     

Genetic programming as a means for programming computers by natural selection

Many seemingly different problems in machine learning, artificial intelligence, and symbolic processing can be viewed as requiring the discovery of a computer program that produces some desired output for particular inputs. When viewed in this way, the process of solving these problems becomes equivalent to searching a space of possible computer programs for a highly fit individual computer program. The recently developed genetic programming paradigm described herein provides a way to search the space of possible computer programs for a highly fit individual computer program to solve (or approximately solve) a surprising variety of different problems from different fields. In genetic programming, populations of computer programs are genetically bred using the Darwinian principle of survival of the fittest and using a genetic crossover (sexual recombination) operator appropriate for genetically mating computer programs. Genetic programming is illustrated via an example of machine learning of the Boolean 11-multiplexer function and symbolic regression of the econometric exchange equation from noisy empirical data.Hierarchical automatic function definition enables genetic programming to define potentially useful functions automatically and dynamically during a run, much as a human programmer writing a complex computer program creates subroutines (procedures, functions) to perform groups of steps which must be performed with different instantiations of the dummy variables (formal parameters) in more than one place in the main program. Hierarchical automatic function definition is illustrated via the machine learning of the Boolean 11-parity function.     

Repeated measurements designs - a review

Any experiment in which one or more of the experimental units is used more than once is called a repeated measurements experiment. The associated design of a repeated measurements experiment is referred to as a repeated measurements design. This review covers some known results on repeated measurements designs. Emphasis is placed on the impact of optimal design theory. Some construction methods for these designs are presented. Hedayat and Afsarinejad (1975) has an extensive bibliography of earlier literature. A bibliography of these designs published after 1974 is provided at the end of this paper.     

Sample size determination for testing equality in frequency data under an incomplete block crossover design

When there are more than two treatments under comparison, we may consider the use of the incomplete block crossover design (IBCD) to save the number of patients needed for a parallel groups design and reduce the duration of a crossover trial. We develop an asymptotic procedure for simultaneously testing equality of two treatments versus a control treatment (or placebo) in frequency data under the IBCD with two periods. We derive a sample size calculation procedure for the desired power of detecting the given treatment effects at a nominal-level and suggest a simple ad hoc adjustment procedure to improve the accuracy of the sample size determination when the resulting minimum required number of patients is not large. We employ Monte Carlo simulation to evaluate the finite-sample performance of the proposed test, the accuracy of the sample size calculation procedure, and that with the simple ad hoc adjustment suggested here. We use the data taken as a part of a crossover trial comparing the number of exacerbations between using salbutamol or salmeterol and a placebo in asthma patients to illustrate the sample size calculation procedure.     

Nonparametric confidence intervals for Tmax in sequence-stratified crossover studies

Tmax is the time associated with the maximum serum or plasma drug concentration achieved following a dose. While Tmax is continuous in theory, it is usually discrete in practice because it is equated to a nominal sampling time in the noncompartmental pharmacokinetics approach. For a 2-treatment crossover design, a Hodges-Lehmann method exists for a confidence interval on treatment differences. For appropriately designed crossover studies with more than two treatments, a new median-scaling method is proposed to obtain estimates and confidence intervals for treatment effects. A simulation study was done comparing this new method with two previously described rank-based nonparametric methods, a stratified ranks method and a signed ranks method due to Ohrvik. The Normal theory, a nonparametric confidence interval approach without adjustment for periods, and a nonparametric bootstrap method were also compared. Results show that less dense sampling and period effects cause increases in confidence interval length. The Normal theory method can be liberal (i.e. less than nominal coverage) if there is a true treatment effect. The nonparametric methods tend to be conservative with regard to coverage probability and among them the median-scaling method is least conservative and has shortest confidence intervals. The stratified ranks method was the most conservative and had very long confidence intervals. The bootstrap method was generally less conservative than the median-scaling method, but it tended to have longer confidence intervals. Overall, the median-scaling method had the best combination of coverage and confidence interval length. All methods performed adequately with respect to bias.