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.     

The impact of missing values in the concentration–time curve on the assessment of bioequivalence

A complication that may arise in some bioequivalence studies is that of ‘incomplete subject profiles’, caused by missing values that occur at one or more sampling points in the concentration–time curve for some study subjects. We assess the impact of incomplete subject profiles on the assessment of bioequivalence in a standard two‐period crossover design. The specific aim of the investigation is to assess the impact of four different patterns of missing concentration values on the coverage level of a 90% nominal two‐sided confidence interval for the ratio of geometric means and then to consider the impact on the probability of concluding bioequivalence. An overall conclusion from the results is that random missingness – that is, missingness for reasons unrelated to the bioavailability of the formulation involved or, more generally, to any aspect of the study design and conduct – has a damaging effect on the study conclusions only when the number of missing values is fairly large. On the other hand, a missingness pattern that potentially has a very damaging effect on the study conclusions is that which arises when values are missing ‘late’ in the concentration–time curve. Copyright © 2005 John Wiley & Sons, Ltd     

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.     

An extension of the placebo‐based pattern‐mixture model

Pattern‐mixture models provide a general and flexible framework for sensitivity analyses of nonignorable missing data in longitudinal studies. The placebo‐based pattern‐mixture model handles missing data in a transparent and clinically interpretable manner. We extend this model to include a sensitivity parameter that characterizes the gradual departure of the missing data mechanism from being missing at random toward being missing not at random under the standard placebo‐based pattern‐mixture model. We derive the treatment effect implied by the extended model. We propose to utilize the primary analysis based on a mixed‐effects model for repeated measures to draw inference about the treatment effect under the extended placebo‐based pattern‐mixture model. We use simulation studies to confirm the validity of the proposed method. We apply the proposed method to a clinical study of major depressive disorders. Copyright © 2013 John Wiley & Sons, Ltd.     

Handling of missing data in long‐term clinical trials: a case study

Missing data in clinical trials is a well‐known problem, and the classical statistical methods used can be overly simple. This case study shows how well‐established missing data theory can be applied to efficacy data collected in a long‐term open‐label trial with a discontinuation rate of almost 50%. Satisfaction with treatment in chronically constipated patients was the efficacy measure assessed at baseline and every 3 months postbaseline. The improvement in treatment satisfaction from baseline was originally analyzed with a paired t‐test ignoring missing data and discarding the correlation structure of the longitudinal data. As the original analysis started from missing completely at random assumptions regarding the missing data process, the satisfaction data were re‐examined, and several missing at random (MAR) and missing not at random (MNAR) techniques resulted in adjusted estimate for the improvement in satisfaction over 12 months. Throughout the different sensitivity analyses, the effect sizes remained significant and clinically relevant. Thus, even for an open‐label trial design, sensitivity analysis, with different assumptions for the nature of dropouts (MAR or MNAR) and with different classes of models (selection, pattern‐mixture, or multiple imputation models), has been found useful and provides evidence towards the robustness of the original analyses; additional sensitivity analyses could be undertaken to further qualify robustness. Copyright © 2012 John Wiley & Sons, Ltd.     

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.     

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.     

A Frailty Model in Crossover Studies with Time-to-Event Response Variable

In this article, we develop a model to study treatment, period, carryover, and other applicable effects in a crossover design with a time-to-event response variable. Because time-to-event outcomes on different treatment regimens within the crossover design are correlated for an individual, we adopt a proportional hazards frailty model. If the frailty is assumed to have a gamma distribution, and the hazard rates are piecewise constant, then the likelihood function can be determined via closed-form expressions. We illustrate the methodology via an application to a data set from an asthma clinical trial and run simulations that investigate sensitivity of the model to data generated from different distributions.     

An efficient analysis of covariance model for crossover thorough QT studies with period‐specific pre‐dose baselines

Baseline adjustment is an important consideration in thorough QT studies for non‐antiarrhythmic drugs. For crossover studies with period‐specific pre‐dose baselines, we propose a by‐time‐point analysis of covariance model with change from pre‐dose baseline as response, treatment as a fixed effect, pre‐dose baseline for current treatment and pre‐dose baseline averaged across treatments as covariates, and subject as a random effect. Additional factors such as period and sex should be included in the model as appropriate. Multiple pre‐dose measurements can be averaged to obtain a pre‐dose‐averaged baseline and used in the model. We provide conditions under which the proposed model is more efficient than other models. We demonstrate the efficiency and robustness of the proposed model both analytically and through simulation studies. The advantage of the proposed model is also illustrated using the data from a real clinical trial. Copyright © 2014 John Wiley & Sons, Ltd.     

Missing data in clinical trials: control‐based mean imputation and sensitivity analysis

In some randomized (drug versus placebo) clinical trials, the estimand of interest is the between‐treatment difference in population means of a clinical endpoint that is free from the confounding effects of “rescue” medication (e.g., HbA1c change from baseline at 24 weeks that would be observed without rescue medication regardless of whether or when the assigned treatment was discontinued). In such settings, a missing data problem arises if some patients prematurely discontinue from the trial or initiate rescue medication while in the trial, the latter necessitating the discarding of post‐rescue data. We caution that the commonly used mixed‐effects model repeated measures analysis with the embedded missing at random assumption can deliver an exaggerated estimate of the aforementioned estimand of interest. This happens, in part, due to implicit imputation of an overly optimistic mean for “dropouts” (i.e., patients with missing endpoint data of interest) in the drug arm. We propose an alternative approach in which the missing mean for the drug arm dropouts is explicitly replaced with either the estimated mean of the entire endpoint distribution under placebo (primary analysis) or a sequence of increasingly more conservative means within a tipping point framework (sensitivity analysis); patient‐level imputation is not required. A supplemental “dropout = failure” analysis is considered in which a common poor outcome is imputed for all dropouts followed by a between‐treatment comparison using quantile regression. All analyses address the same estimand and can adjust for baseline covariates. Three examples and simulation results are used to support our recommendations.     

Treatment policy estimands for recurrent event data using data collected after cessation of randomised treatment

In the past, many clinical trials have withdrawn subjects from the study when they prematurely stopped their randomised treatment and have therefore only collected ‘on‐treatment’ data. Thus, analyses addressing a treatment policy estimand have been restricted to imputing missing data under assumptions drawn from these data only. Many confirmatory trials are now continuing to collect data from subjects in a study even after they have prematurely discontinued study treatment as this event is irrelevant for the purposes of a treatment policy estimand. However, despite efforts to keep subjects in a trial, some will still choose to withdraw. Recent publications for sensitivity analyses of recurrent event data have focused on the reference‐based imputation methods commonly applied to continuous outcomes, where imputation for the missing data for one treatment arm is based on the observed outcomes in another arm. However, the existence of data from subjects who have prematurely discontinued treatment but remained in the study has now raised the opportunity to use this ‘off‐treatment’ data to impute the missing data for subjects who withdraw, potentially allowing more plausible assumptions for the missing post‐study‐withdrawal data than reference‐based approaches. In this paper, we introduce a new imputation method for recurrent event data in which the missing post‐study‐withdrawal event rate for a particular subject is assumed to reflect that observed from subjects during the off‐treatment period. The method is illustrated in a trial in chronic obstructive pulmonary disease (COPD) where the primary endpoint was the rate of exacerbations, analysed using a negative binomial model.     

Investigation of mixed model repeated measures analyses and non‐linear random coefficient models in the context of long‐term efficacy data

The longitudinal data from 2 published clinical trials in adult subjects with upper limb spasticity (a randomized placebo‐controlled study [NCT01313299] and its long‐term open‐label extension [NCT01313312]) were combined. Their study designs involved repeat intramuscular injections of abobotulinumtoxinA (Dysport®), and efficacy endpoints were collected accordingly. With the objective of characterizing the pattern of response across cycles, Mixed Model Repeated Measures analyses and Non‐Linear Random Coefficient (NLRC) analyses were performed and their results compared. The Mixed Model Repeated Measures analyses, commonly used in the context of repeated measures with missing dependent data, did not involve any parametric shape for the curve of changes over time. Based on clinical expectations, the NLRC included a negative exponential function of the number of treatment cycles, with its asymptote and rate included as random coefficients in the model. Our analysis focused on 2 specific efficacy parameters reflecting complementary aspects of efficacy in the study population. A simulation study based on a similar study design was also performed to further assess the performance of each method under different patterns of response over time. This highlighted a gain of precision with the NLRC model, and most importantly the need for its assumptions to be verified to avoid potentially biased estimates. These analyses describe a typical situation and the conditions under which non‐linear mixed modeling can provide additional insights on the behavior of efficacy parameters over time. Indeed, the resulting estimates from the negative exponential NLRC can help determine the expected maximal effect and the treatment duration required to reach it.     

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.     

A semi‐parametric approach to fitting a nonlinear mixed PK/PD model with an effect compartment using SAS

Modelling of the relationship between concentration (PK) and response (PD) plays an important role in drug development. The modelling becomes complicated when the drug concentration and response measurements are not taken simultaneously and/or hysteresis occurs between the response and the concentration. A model‐based approach fits a joint pharmacokinetic (PK) and concentration–response (PK/PD) model, including an effect compartment if necessary, to concentration and response data. However, this approach relies on the PK data being well described by a common PK model. We propose an algorithm for a semi‐parametric approach to fitting nonlinear mixed PK/PD models including an effect compartment using linear interpolation and extrapolation for concentration data. This approach is independent of the PK model, and the algorithm can easily be implemented using SAS PROC NLMIXED. Practical issues in programming and computing are also discussed. The properties of this approach are examined using simulations. This approach is used to analyse data from a study of the PK/PD relationship between insulin and glucose levels. Copyright © 2005 John Wiley & Sons, Ltd.     

Dose‐escalation strategies which use subgroup information

Dose‐escalation trials commonly assume a homogeneous trial population to identify a single recommended dose of the experimental treatment for use in future trials. Wrongly assuming a homogeneous population can lead to a diluted treatment effect. Equally, exclusion of a subgroup that could in fact benefit from the treatment can cause a beneficial treatment effect to be missed. Accounting for a potential subgroup effect (ie, difference in reaction to the treatment between subgroups) in dose‐escalation can increase the chance of finding the treatment to be efficacious in a larger patient population. A standard Bayesian model‐based method of dose‐escalation is extended to account for a subgroup effect by including covariates for subgroup membership in the dose‐toxicity model. A stratified design performs well but uses available data inefficiently and makes no inferences concerning presence of a subgroup effect. A hypothesis test could potentially rectify this problem but the small sample sizes result in a low‐powered test. As an alternative, the use of spike and slab priors for variable selection is proposed. This method continually assesses the presence of a subgroup effect, enabling efficient use of the available trial data throughout escalation and in identifying the recommended dose(s). A simulation study, based on real trial data, was conducted and this design was found to be both promising and feasible.     

A powerful test for Balaam's design

The crossover trial design (AB/BA design) is often used to compare the effects of two treatments in medical science because it performs within‐subject comparisons, which increase the precision of a treatment effect (i.e., a between‐treatment difference). However, the AB/BA design cannot be applied in the presence of carryover effects and/or treatments‐by‐period interaction. In such cases, Balaam's design is a more suitable choice. Unlike the AB/BA design, Balaam's design inflates the variance of an estimate of the treatment effect, thereby reducing the statistical power of tests. This is a serious drawback of the design. Although the variance of parameter estimators in Balaam's design has been extensively studied, the estimators of the treatment effect to improve the inference have received little attention. If the estimate of the treatment effect is obtained by solving the mixed model equations, the AA and BB sequences are excluded from the estimation process. In this study, we develop a new estimator of the treatment effect and a new test statistic using the estimator. The aim is to improve the statistical inference in Balaam's design. Simulation studies indicate that the type I error of the proposed test is well controlled, and that the test is more powerful and has more suitable characteristics than other existing tests when interactions are substantial. The proposed test is also applied to analyze a real dataset. Copyright © 2015 John Wiley & Sons, Ltd.     

A structured framework for assessing sensitivity to missing data assumptions in longitudinal clinical trials

The objective of this research was to demonstrate a framework for drawing inference from sensitivity analyses of incomplete longitudinal clinical trial data via a re‐analysis of data from a confirmatory clinical trial in depression. A likelihood‐based approach that assumed missing at random (MAR) was the primary analysis. Robustness to departure from MAR was assessed by comparing the primary result to those from a series of analyses that employed varying missing not at random (MNAR) assumptions (selection models, pattern mixture models and shared parameter models) and to MAR methods that used inclusive models. The key sensitivity analysis used multiple imputation assuming that after dropout the trajectory of drug‐treated patients was that of placebo treated patients with a similar outcome history (placebo multiple imputation). This result was used as the worst reasonable case to define the lower limit of plausible values for the treatment contrast. The endpoint contrast from the primary analysis was ? 2.79 (p = .013). In placebo multiple imputation, the result was ? 2.17. Results from the other sensitivity analyses ranged from ? 2.21 to ? 3.87 and were symmetrically distributed around the primary result. Hence, no clear evidence of bias from missing not at random data was found. In the worst reasonable case scenario, the treatment effect was 80% of the magnitude of the primary result. Therefore, it was concluded that a treatment effect existed. The structured sensitivity framework of using a worst reasonable case result based on a controlled imputation approach with transparent and debatable assumptions supplemented a series of plausible alternative models under varying assumptions was useful in this specific situation and holds promise as a generally useful framework. Copyright © 2012 John Wiley & Sons, Ltd.     

PARAMETRIC FRACTIONAL IMPUTATION FOR NON‐IGNORABLE CATEGORICAL MISSING DATA WITH FOLLOW‐UP

Incomplete data subject to non‐ignorable non‐response are often encountered in practice and have a non‐identifiability problem. A follow‐up sample is randomly selected from the set of non‐respondents to avoid the non‐identifiability problem and get complete responses. Glynn, Laird, & Rubin analyzed non‐ignorable missing data with a follow‐up sample under a pattern mixture model. In this article, maximum likelihood estimation of parameters of the categorical missing data is considered with a follow‐up sample under a selection model. To estimate the parameters with non‐ignorable missing data, the EM algorithm with weighting, proposed by Ibrahim, is used. That is, in the E‐step, the weighted mean is calculated using the fractional weights for imputed data. Variances are estimated using the approximated jacknife method. Simulation results are presented to compare the proposed method with previously presented methods.     

Choice of the primary analysis in longitudinal clinical trials

Missing data, and the bias they can cause, are an almost ever‐present concern in clinical trials. The last observation carried forward (LOCF) approach has been frequently utilized to handle missing data in clinical trials, and is often specified in conjunction with analysis of variance (LOCF ANOVA) for the primary analysis. Considerable advances in statistical methodology, and in our ability to implement these methods, have been made in recent years. Likelihood‐based, mixed‐effects model approaches implemented under the missing at random (MAR) framework are now easy to implement, and are commonly used to analyse clinical trial data. Furthermore, such approaches are more robust to the biases from missing data, and provide better control of Type I and Type II errors than LOCF ANOVA. Empirical research and analytic proof have demonstrated that the behaviour of LOCF is uncertain, and in many situations it has not been conservative. Using LOCF as a composite measure of safety, tolerability and efficacy can lead to erroneous conclusions regarding the effectiveness of a drug. This approach also violates the fundamental basis of statistics as it involves testing an outcome that is not a physical parameter of the population, but rather a quantity that can be influenced by investigator behaviour, trial design, etc. Practice should shift away from using LOCF ANOVA as the primary analysis and focus on likelihood‐based, mixed‐effects model approaches developed under the MAR framework, with missing not at random methods used to assess robustness of the primary analysis. Copyright © 2004 John Wiley & Sons, Ltd.     

Power and sample size for GEE analysis of incomplete paired outcomes in 2 × 2 crossover trials

The 2 × 2 crossover trial uses subjects as their own control to reduce the intersubject variability in the treatment comparison, and typically requires fewer subjects than a parallel design. The generalized estimating equations (GEE) methodology has been commonly used to analyze incomplete discrete outcomes from crossover trials. We propose a unified approach to the power and sample size determination for the Wald Z-test and t-test from GEE analysis of paired binary, ordinal and count outcomes in crossover trials. The proposed method allows misspecification of the variance and correlation of the outcomes, missing outcomes, and adjustment for the period effect. We demonstrate that misspecification of the working variance and correlation functions leads to no or minimal efficiency loss in GEE analysis of paired outcomes. In general, GEE requires the assumption of missing completely at random. For bivariate binary outcomes, we show by simulation that the GEE estimate is asymptotically unbiased or only minimally biased, and the proposed sample size method is suitable under missing at random (MAR) if the working correlation is correctly specified. The performance of the proposed method is illustrated with several numerical examples. Adaption of the method to other paired outcomes is discussed.