Optimal Designs for the Carryover Model with Random Interactions Between Subjects and Treatments

The paper considers a model for crossover designs with carryover effects and a random interaction between treatments and subjects. Under this model, two observations of the same treatment on the same subject are positively correlated and therefore provide less information than two observations of the same treatment on different subjects. The introduction of the interaction makes the determination of optimal designs much harder than is the case for the traditional model. Generalising the results of Bludowsky's thesis, the present paper uses Kushner's method to determine optimal approximate designs. We restrict attention to the case where the number of periods is less than or equal to the number of treatments. We determine the optimal designs in the important special cases that the number of periods is 3, 4 or 5. It turns out that the optimal designs depend on the variance of the random interactions and in most cases are not binary. However, we can show that neighbour balanced binary designs are highly efficient, regardless of the number of periods and of the size of the variance of the interaction effects.     

Randomization of neighbour balanced generalized Youden designs

If a crossover design with more than two treatments is carryover balanced, then the usual randomization of experimental units and periods would destroy the neighbour structure of the design. As an alternative, Bailey [1985. Restricted randomization for neighbour-balanced designs. Statist. Decisions Suppl. 2, 237–248] considered randomization of experimental units and of treatment labels, which leaves the neighbour structure intact. She has shown that, if there are no carryover effects, this randomization validates the row–column model, provided the starting design is a generalized Latin square. We extend this result to generalized Youden designs where either the number of experimental units is a multiple of the number of treatments or the number of periods is equal to the number of treatments. For the situation when there are carryover effects we show for so-called totally balanced designs that the variance of the estimates of treatment differences does not change in the presence of carryover effects, while the estimated variance of this estimate becomes conservative.     

Practical approaches for design and analysis of clinical trials of infertility treatments: crossover designs and the Mantel–Haenszel method are recommended

Crossover designs have some advantages over standard clinical trial designs and they are often used in trials evaluating the efficacy of treatments for infertility. However, clinical trials of infertility treatments violate a fundamental condition of crossover designs, because women who become pregnant in the first treatment period are not treated in the second period. In previous research, to deal with this problem, some new designs, such as re‐randomization designs, and analysis methods including the logistic mixture model and the beta‐binomial mixture model were proposed. Although the performance of these designs and methods has previously been evaluated in large‐scale clinical trials with sample sizes of more than 1000 per group, the actual sample sizes of infertility treatment trials are usually around 100 per group. The most appropriate design and analysis for these moderate‐scale clinical trials are currently unclear. In this study, we conducted simulation studies to determine the appropriate design and analysis method of moderate‐scale clinical trials for irreversible endpoints by evaluating the statistical power and bias in the treatment effect estimates. The Mantel–Haenszel method had similar power and bias to the logistic mixture model. The crossover designs had the highest power and the smallest bias. We recommend using a combination of the crossover design and the Mantel–Haenszel method for two‐period, two‐treatment clinical trials with irreversible endpoints. Copyright © 2015 John Wiley & Sons, Ltd.     

CONSTRUCTION OF CROSSOVER DESIGNS WITH CORRELATED ERRORS

Crossover experiments are widely used, particularly where a sequence of treatments is given to subjects. Correlations between observations on the same subject are therefore likely and should be considered in both the design and analysis of crossover experiments. This paper presents an algorithm for the generation of efficient crossover designs with autoregressive and linear variance structures. The algorithm has been implemented as a module in the experimental design generation package CycDesigN (Release 3.0; CycSoftware, Hamilton, New Zealand). Output from the algorithm is compared with earlier work. Some results are given from the analysis of a crossover experiment assuming correlated errors.     

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.     

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.     

The construction of nearly balanced and nearly strongly balanced uniform cross-over designs

In this paper we consider the class of uniform cross-over designs. Existing results on the universal optimality of uniform cross-over designs are reviewed and a general method of construction is described. The constructed designs fall into four families, which include the balanced and strongly balanced designs as special cases: the remaining designs we refer to as nearly strongly balanced, a term first introduced by Kunert (Ann. Statist. 11 (1983)), and nearly balanced. The nearly strongly balanced and nearly balanced designs form an important family of uniform cross-over designs which provide designs where balanced or strongly balanced designs do not exist. The construction method can be easily generalized for any number of periods and subjects, as long as they are both a multiple of the number of treatments. Some illustrative examples are included.     

Cross-over Designs in the Presence of Higher Order Carry-overs

In cross-over experiments, where different treatments are applied successively to the same experimental unit over a number of time periods, it is often expected that a treatment has a carry-over effect in one or more periods following its period of application. The effect of interaction between the treatments in the successive periods may also affect the response. However, it seems that all systematic studies of the optimality properties of cross-over designs have been done under models where carry-over effects are assumed to persist for only one subsequent period. This paper proposes a model which allows for the possible presence of carry-over effects up to k subsequent periods, together with all the interactions between treatments applied at k + 1 successive periods. This model allows the practitioner to choose k for any experiment according to the requirements of that particular experiment. Under this model, the cross-over designs are studied and the class of optimal designs is obtained. A method of constructing these optimal designs is also given.     

Minimal balanced repeated measurements designs

Experimental designs in which treatments are applied to the experimental units, one at a time, in sequences over a number of periods, have been used in several scientific investigations and are known as repeated measurements designs. Besides direct effects, these designs allow estimation of residual effects of treatments along with adjustment for them. Assuming the existence of first-order residual effects of treatments, Hedayat & Afsarinejad (1975) gave a method of constructing minimal balanced repeated measurements [RM(v,n,p)] design for v treatments using n=2v experimental units for p [=(v+1)/2] periods when v is a prime or prime power. Here, a general method of construction of these designs for all odd v has been given along with an outline for their analysis. In terms of variances of estimated elementary contrasts between treatment effects (direct and residual), these designs are seen to be partially variance balanced based on the circular association scheme.     

Crossover designs for comparing test treatments to a control treatment when subject effects are random

We study crossover designs for the comparisons of several test treatments versus a control treatment and partially generalize the results of Hedayat and Yang (2005) to the situation in which subject effects are assumed to be random. More specifically, we establish lower bounds for the trace of the inverse of the information matrix for the test treatments versus control comparisons under a random subject effects model and show that most of the small size (3-, 4- and 5-period) designs introduced by Hedayat and Yang (2005) are highly efficient in the class of designs in which the control treatment appears equally often in all periods and no treatment is immediately preceded by itself.     

Testing treatment‐by‐period interaction in four‐period crossover trials

Statistical analyses of crossover clinical trials have mainly focused on assessing the treatment effect, carryover effect, and period effect. When a treatment‐by‐period interaction is plausible, it is important to test such interaction first before making inferences on differences among individual treatments. Considerably less attention has been paid to the treatment‐by‐period interaction, which has historically been aliased with the carryover effect in two‐period or three‐period designs. In this article, from the data of a newly developed four‐period crossover design, we propose a statistical method to compare the effects of two active drugs with respect to two response variables. We study estimation and hypothesis testing considering the treatment‐by‐period interaction. Constrained least squares is used to estimate the treatment effect, period effect, and treatment‐by‐period interaction. For hypothesis testing, we extend a general multivariate method for analyzing the crossover design with multiple responses. Results from simulation studies have shown that this method performs very well. We also illustrate how to apply our method to the real data problem.     

Optimal and efficient crossover designs for comparing test treatments to a control treatment under various models

We study the optimality, efficiency, and robustness of crossover designs for comparing several test treatments to a control treatment. Since A-optimality is a natural criterion in this context, we establish lower bounds for the trace of the inverse of the information matrix for the test treatments versus control comparisons under various models. These bounds are then used to obtain lower bounds for efficiencies of a design under these models. Two algorithms, both guided by these efficiencies and results from optimal design theory, are proposed for obtaining efficient designs under the various models.     

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.     

Designs with Repeated Measurements on Any Number of Units over Varying Periods

In the usual repeated measurements designs (RMDs), the subjects are all observed for the same number of periods and the optimum RMDs require specified numbers of subjects, usually depending on the number of treatments to be used. In practice, it is sometimes not feasible to meet these requirements. To overcome this problem, alternative designs are suggested where any number of available subjects may be used and they may be observed for different periods. These designs are based on suitable serially balanced sequences which are shown to be optimal. Moreover, besides the usual direct and residual effects, the model considered has an extra term due to the interaction effect between them. The recommended designs are universally optimal in a very general class.     

A nonparametric procedure for the analysis of balanced crossover designs

The authors propose nonparametric tests for the hypothesis of no direct treatment effects, as well as for the hypothesis of no carryover effects, for balanced crossover designs in which the number of treatments equals the number of periods p, where p ≥ 3. They suppose that the design consists of n replications of balanced crossover designs, each formed by m Latin squares of order p. Their tests are permutation tests which are based on the n vectors of least squares estimators of the parameters of interest obtained from the n replications of the experiment. They obtain both the exact and limiting distribution of the test statistics, and they show that the tests have, asymptotically, the same power as the F‐ratio test.     

Cost‐efficient higher‐order crossover designs for two‐treatment clinical trials

Higher‐order crossover designs have drawn considerable attention in clinical trials, because of their ability to test direct treatment effects in the presence of carry‐over effects. The important question, when applying higher‐order crossover designs in practice, is how to choose a design with both statistical and cost efficiencies from various alternatives. In this paper, we propose a general cost function and compare five statistically optimal or near‐optimal designs with this cost function for a two‐treatment study under different carry‐over models. Based on our study, to achieve both statistical and cost efficiencies, a four‐period, four‐sequence crossover design is generally recommended under the simple carry‐over or no carry‐over models, and a three‐period, two‐sequence crossover design is generally recommended under the steady‐state carry‐over models. Copyright © 2005 John Wiley & Sons, Ltd.     

The construction of multi-factor crossover designs in animal husbandry studies

For ethical reasons it is important to try to obtain as much useful information as possible from an animal experiment whilst minimizing the number of animals used. Crossover designs, where applicable, provide an ideal framework for achieving this. If two or more treatment factors are included in the crossover design then the reduction in total animal usage can be considerable. In this paper we consider such designs, defined as multi-factor crossover designs. The designs are applicable when there are several different treatment factors, each at t levels, to be applied to the experimental units. The motivation for investigating these designs was a study conducted at GlaxoSmithKline to determine the preference of male and female dogs for t=5 different types of bed and t=5 different bedding conditions. A construction method is given for forming universally optimal designs for t not too large. Also given is an example for the special case where the number of treatment levels t=6.     

An exact upper limit for the variance bias in a carry-over model with correlated errors

The analysis of crossover designs assuming i.i.d. errors leads to biased variance estimates whenever the true covariance structure is not spherical. As a result, the OLS F-test for the equality of the direct effects of the treatments is not valid. Bellavance et al. [1996. Biometrics 52, 607–612] use simulations to show that a modified F-test based on an estimate of the within subjects covariance matrix allows for nearly unbiased tests. Kunert and Utzig [1993. JRSS B 55, 919–927] propose an alternative test that does not need an estimate of the covariance matrix. Instead, they correct the F-statistic by multiplying by a constant based on the worst-case scenario. However, for designs with more than three observations per subject, Kunert and Utzig (1993) only give a rough upper bound for the worst-case variance bias. This may lead to overly conservative tests. In this paper we derive an exact upper limit for the variance bias due to carry-over for an arbitrary number of observations per subject. The result holds for a certain class of highly efficient balanced crossover designs.     

Estimation Bias in Complete-Case Analysis in Crossover Studies with Missing Data

Crossover designs are used often in clinical trials. It is not uncommon that subjects discontinue before completing all treatment periods in a crossover study. Despite availability of statistical methodologies utilizing all available data and software for obtaining valid inferences under the assumption of missing at random (MAR), naïve approaches, such as the complete case (CC) analysis, which is only valid with a strong assumption of missing completely at random are still widely used in practice. In this article, we obtain the analytical form of the estimation bias of treatment effects with CC for linear mixed models. We use simulation studies to examine the inflation of Type I error and efficiency loss in the inferences with CC under MAR. Invalidity and inefficiency of two other commonly used approaches for defining analyzed data in the presence of missing data, including data from at least two periods in three period crossover and available cases for a specific comparison of interest, are also demonstrated through simulation studies.     

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.