Some practical considerations in three‐arm non‐inferiority trial design

Non‐inferiority trials aim to demonstrate whether an experimental therapy is not unacceptably worse than an active reference therapy already in use. When applicable, a three‐arm non‐inferiority trial, including an experiment therapy, an active reference therapy, and a placebo, is often recommended to assess assay sensitivity and internal validity of a trial. In this paper, we share some practical considerations based on our experience from a phase III three‐arm non‐inferiority trial. First, we discuss the determination of the total sample size and its optimal allocation based on the overall power of the non‐inferiority testing procedure and provide ready‐to‐use R code for implementation. Second, we consider the non‐inferiority goal of ‘capturing all possibilities’ and show that it naturally corresponds to a simple two‐step testing procedure. Finally, using this two‐step non‐inferiority testing procedure as an example, we compare extensively commonly used frequentist p ‐value methods with the Bayesian posterior probability approach. Copyright © 2016 John Wiley & Sons, Ltd.     

Design and analysis of a 3‐arm noninferiority trial with a prespecified margin for the hazard ratio

A 3‐arm trial design that includes an experimental treatment, an active reference treatment, and a placebo is useful for assessing the noninferiority of an experimental treatment. The inclusion of a placebo arm enables the assessment of assay sensitivity and internal validation, in addition to the testing of the noninferiority of the experimental treatment compared with the reference treatment. In 3‐arm noninferiority trials, various statistical test procedures have been considered to evaluate the following 3 hypotheses: (i) superiority of the experimental treatment over the placebo, (ii) superiority of the reference treatment over the placebo, and (iii) noninferiority of the experimental treatment compared with the reference treatment. However, hypothesis (ii) can be insufficient and may not accurately assess the assay sensitivity for the noninferiority of the experimental treatment compared with the reference treatment. Thus, demonstrating that the superiority of the reference treatment over the placebo is greater than the noninferiority margin (the nonsuperiority of the reference treatment compared with the placebo) can be necessary. Here, we propose log‐rank statistical procedures for evaluating data obtained from 3‐arm noninferiority trials to assess assay sensitivity with a prespecified margin Δ. In addition, we derive the approximate sample size and optimal allocation required to minimize the total sample size and that of the placebo treatment sample size, hierarchically.     

Estimating the variance for heterogeneity in arm‐based network meta‐analysis

Network meta‐analysis can be implemented by using arm‐based or contrast‐based models. Here we focus on arm‐based models and fit them using generalized linear mixed model procedures. Full maximum likelihood (ML) estimation leads to biased trial‐by‐treatment interaction variance estimates for heterogeneity. Thus, our objective is to investigate alternative approaches to variance estimation that reduce bias compared with full ML. Specifically, we use penalized quasi‐likelihood/pseudo‐likelihood and hierarchical (h) likelihood approaches. In addition, we consider a novel model modification that yields estimators akin to the residual maximum likelihood estimator for linear mixed models. The proposed methods are compared by simulation, and 2 real datasets are used for illustration. Simulations show that penalized quasi‐likelihood/pseudo‐likelihood and h‐likelihood reduce bias and yield satisfactory coverage rates. Sum‐to‐zero restriction and baseline contrasts for random trial‐by‐treatment interaction effects, as well as a residual ML‐like adjustment, also reduce bias compared with an unconstrained model when ML is used, but coverage rates are not quite as good. Penalized quasi‐likelihood/pseudo‐likelihood and h‐likelihood are therefore recommended.     

Empirical Likelihood Inference for the Rao‐Hartley‐Cochran Sampling Design

The Hartley‐Rao‐Cochran sampling design is an unequal probability sampling design which can be used to select samples from finite populations. We propose to adjust the empirical likelihood approach for the Hartley‐Rao‐Cochran sampling design. The approach proposed intrinsically incorporates sampling weights, auxiliary information and allows for large sampling fractions. It can be used to construct confidence intervals. In a simulation study, we show that the coverage may be better for the empirical likelihood confidence interval than for standard confidence intervals based on variance estimates. The approach proposed is simple to implement and less computer intensive than bootstrap. The confidence interval proposed does not rely on re‐sampling, linearization, variance estimation, design‐effects or joint inclusion probabilities.     

Assessing the treatment effect in a randomized controlled trial with extensive non‐adherence: the EVOLVE trial

Intention‐to‐treat (ITT) analysis is widely used to establish efficacy in randomized clinical trials. However, in a long‐term outcomes study where non‐adherence to study drug is substantial, the on‐treatment effect of the study drug may be underestimated using the ITT analysis. The analyses presented herein are from the EVOLVE trial, a double‐blind, placebo‐controlled, event‐driven cardiovascular outcomes study conducted to assess whether a treatment regimen including cinacalcet compared with placebo in addition to other conventional therapies reduces the risk of mortality and major cardiovascular events in patients receiving hemodialysis with secondary hyperparathyroidism. Pre‐specified sensitivity analyses were performed to assess the impact of non‐adherence on the estimated effect of cinacalcet. These analyses included lag‐censoring, inverse probability of censoring weights (IPCW), rank preserving structural failure time model (RPSFTM) and iterative parameter estimation (IPE). The relative hazard (cinacalcet versus placebo) of mortality and major cardiovascular events was 0.93 (95% confidence interval 0.85, 1.02) using the ITT analysis; 0.85 (0.76, 0.95) using lag‐censoring analysis; 0.81 (0.70, 0.92) using IPCW; 0.85 (0.66, 1.04) using RPSFTM and 0.85 (0.75, 0.96) using IPE. These analyses, while not providing definitive evidence, suggest that the intervention may have an effect while subjects are receiving treatment. The ITT method remains the established method to evaluate efficacy of a new treatment; however, additional analyses should be considered to assess the on‐treatment effect when substantial non‐adherence to study drug is expected or observed. Copyright © 2015 John Wiley & Sons, Ltd.     

Confidence intervals for nonparametric quantile regression: an emphasis on smoothing splines approach

In this paper we consider the problem of constructing confidence intervals for nonparametric quantile regression with an emphasis on smoothing splines. The mean‐based approaches for smoothing splines of Wahba (1983) and Nychka (1988) may not be efficient for constructing confidence intervals for the underlying function when the observed data are non‐Gaussian distributed, for instance if they are skewed or heavy‐tailed. This paper proposes a method of constructing confidence intervals for the unknown τth quantile function (0<τ<1) based on smoothing splines. In this paper we investigate the extent to which the proposed estimator provides the desired coverage probability. In addition, an improvement based on a local smoothing parameter that provides more uniform pointwise coverage is developed. The results from numerical studies including a simulation study and real data analysis demonstrate the promising empirical properties of the proposed approach.     

Pseudo‐empirical likelihood ratio confidence intervals for complex surveys

The authors show how an adjusted pseudo‐empirical likelihood ratio statistic that is asymptotically distributed as a chi‐square random variable can be used to construct confidence intervals for a finite population mean or a finite population distribution function from complex survey samples. They consider both non‐stratified and stratified sampling designs, with or without auxiliary information. They examine the behaviour of estimates of the mean and the distribution function at specific points using simulations calling on the Rao‐Sampford method of unequal probability sampling without replacement. They conclude that the pseudo‐empirical likelihood ratio confidence intervals are superior to those based on the normal approximation, whether in terms of coverage probability, tail error rates or average length of the intervals.     

Self‐normalization for Spatial Data

This paper considers inference for both spatial lattice data with possibly irregularly shaped sampling region and non‐lattice data, by extending the recently proposed self‐normalization (SN) approach from stationary time series to the spatial setup. A nice feature of the SN method is that it avoids the choice of tuning parameters, which are usually required for other non‐parametric inference approaches. The extension is non‐trivial as spatial data has no natural one‐directional time ordering. The SN‐based inference is convenient to implement and is shown through simulation studies to provide more accurate coverage compared with the widely used subsampling approach. We also illustrate the idea of SN using a real data example.     

Sensitivity to censored‐at‐random assumption in the analysis of time‐to‐event endpoints

Over the past years, significant progress has been made in developing statistically rigorous methods to implement clinically interpretable sensitivity analyses for assumptions about the missingness mechanism in clinical trials for continuous and (to a lesser extent) for binary or categorical endpoints. Studies with time‐to‐event outcomes have received much less attention. However, such studies can be similarly challenged with respect to the robustness and integrity of primary analysis conclusions when a substantial number of subjects withdraw from treatment prematurely prior to experiencing an event of interest. We discuss how the methods that are widely used for primary analyses of time‐to‐event outcomes could be extended in a clinically meaningful and interpretable way to stress‐test the assumption of ignorable censoring. We focus on a ‘tipping point’ approach, the objective of which is to postulate sensitivity parameters with a clear clinical interpretation and to identify a setting of these parameters unfavorable enough towards the experimental treatment to nullify a conclusion that was favorable to that treatment. Robustness of primary analysis results can then be assessed based on clinical plausibility of the scenario represented by the tipping point. We study several approaches for conducting such analyses based on multiple imputation using parametric, semi‐parametric, and non‐parametric imputation models and evaluate their operating characteristics via simulation. We argue that these methods are valuable tools for sensitivity analyses of time‐to‐event data and conclude that the method based on piecewise exponential imputation model of survival has some advantages over other methods studied here. Copyright © 2016 John Wiley & Sons, Ltd.     

Semiparametric Quantile Regression Analysis of Right‐censored and Length‐biased Failure Time Data with Partially Linear Varying Effects

Right‐censored and length‐biased failure time data arise in many fields including cross‐sectional prevalent cohort studies, and their analysis has recently attracted a great deal of attention. It is well‐known that for regression analysis of failure time data, two commonly used approaches are hazard‐based and quantile‐based procedures, and most of the existing methods are the hazard‐based ones. In this paper, we consider quantile regression analysis of right‐censored and length‐biased data and present a semiparametric varying‐coefficient partially linear model. For estimation of regression parameters, a three‐stage procedure that makes use of the inverse probability weighted technique is developed, and the asymptotic properties of the resulting estimators are established. In addition, the approach allows the dependence of the censoring variable on covariates, while most of the existing methods assume the independence between censoring variables and covariates. A simulation study is conducted and suggests that the proposed approach works well in practical situations. Also, an illustrative example is provided.     

GRAPHICAL SENSITIVITY ANALYSIS WITH DIFFERENT METHODS OF IMPUTATION FOR A TRIAL WITH PROBABLE NON‐IGNORABLE MISSING DATA

Graphical sensitivity analyses have recently been recommended for clinical trials with non‐ignorable missing outcome. We demonstrate an adaptation of this methodology for a continuous outcome of a trial of three cognitive‐behavioural therapies for mild depression in primary care, in which one arm had unexpectedly high levels of missing data. Fixed‐value and multiple imputations from a normal distribution (assuming either varying mean and fixed standard deviation, or fixed mean and varying standard deviation) were used to obtain contour plots of the contrast estimates with their P‐values superimposed, their confidence intervals, and the root mean square errors. Imputation was based either on the outcome value alone, or on change from baseline. The plots showed fixed‐value imputation to be more sensitive than imputing from a normal distribution, but the normally distributed imputations were subject to sampling noise. The contours of the sensitivity plots were close to linear in appearance, with the slope approximately equal to the ratio of the proportions of subjects with missing data in each trial arm.     

Confidence intervals for the mean of a population containing many zero values under unequal‐probability sampling

In many applications, a finite population contains a large proportion of zero values that make the population distribution severely skewed. An unequal‐probability sampling plan compounds the problem, and as a result the normal approximation to the distribution of various estimators has poor precision. The central‐limit‐theorem‐based confidence intervals for the population mean are hence unsatisfactory. Complex designs also make it hard to pin down useful likelihood functions, hence a direct likelihood approach is not an option. In this paper, we propose a pseudo‐likelihood approach. The proposed pseudo‐log‐likelihood function is an unbiased estimator of the log‐likelihood function when the entire population is sampled. Simulations have been carried out. When the inclusion probabilities are related to the unit values, the pseudo‐likelihood intervals are superior to existing methods in terms of the coverage probability, the balance of non‐coverage rates on the lower and upper sides, and the interval length. An application with a data set from the Canadian Labour Force Survey‐2000 also shows that the pseudo‐likelihood method performs more appropriately than other methods. The Canadian Journal of Statistics 38: 582–597; 2010 © 2010 Statistical Society of Canada     

START: single‐to‐double arm transition design for phase II clinical trials

Phase II clinical trials designed for evaluating a drug's treatment effect can be either single‐arm or double‐arm. A single‐arm design tests the null hypothesis that the response rate of a new drug is lower than a fixed threshold, whereas a double‐arm scheme takes a more objective comparison of the response rate between the new treatment and the standard of care through randomization. Although the randomized design is the gold standard for efficacy assessment, various situations may arise where a single‐arm pilot study prior to a randomized trial is necessary. To combine the single‐ and double‐arm phases and pool the information together for better decision making, we propose a Single‐To‐double ARm Transition design (START) with switching hypotheses tests, where the first stage compares the new drug's response rate with a minimum required level and imposes a continuation criterion, and the second stage utilizes randomization to determine the treatment's superiority. We develop a software package in R to calibrate the frequentist error rates and perform simulation studies to assess the trial characteristics. Finally, a metastatic pancreatic cancer trial is used for illustrating the decision rules under the proposed START design.     

A mixture model using likelihood‐based and Bayesian approaches for identifying responders and non‐responders in longitudinal clinical trials

A longitudinal mixture model for classifying patients into responders and non‐responders is established using both likelihood‐based and Bayesian approaches. The model takes into consideration responders in the control group. Therefore, it is especially useful in situations where the placebo response is strong, or in equivalence trials where the drug in development is compared with a standard treatment. Under our model, a treatment shows evidence of being effective if it increases the proportion of responders or increases the response rate among responders in the treated group compared with the control group. Therefore, the model has flexibility to accommodate different situations. The proposed method is illustrated using simulation and a depression clinical trial dataset for the likelihood‐based approach, and the same depression clinical trial dataset for the Bayesian approach. The likelihood‐based and Bayesian approaches generated consistent results for the depression trial data. In both the placebo group and the treated group, patients are classified into two components with distinct response rate. The proportion of responders is shown to be significantly higher in the treated group compared with the control group, suggesting the treatment paroxetine is effective. Copyright © 2014 John Wiley & Sons, Ltd.     

Construction of Simultaneous Confidence Intervals for Ratios of Means of Lognormal Distributions

For constructing simultaneous confidence intervals for ratios of means for lognormal distributions, two approaches using a two-step method of variance estimates recovery are proposed. The first approach proposes fiducial generalized confidence intervals (FGCIs) in the first step followed by the method of variance estimates recovery (MOVER) in the second step (FGCIs–MOVER). The second approach uses MOVER in the first and second steps (MOVER–MOVER). Performance of proposed approaches is compared with simultaneous fiducial generalized confidence intervals (SFGCIs). Monte Carlo simulation is used to evaluate the performance of these approaches in terms of coverage probability, average interval width, and time consumption.     

Confidence intervals for the difference between independent binomial proportions: comparison using a graphical approach and moving averages

This paper uses graphical methods to illustrate and compare the coverage properties of a number of methods for calculating confidence intervals for the difference between two independent binomial proportions. We investigate both small‐sample and large‐sample properties of both two‐sided and one‐sided coverage, with an emphasis on asymptotic methods. In terms of aligning the smoothed coverage probability surface with the nominal confidence level, we find that the score‐based methods on the whole have the best two‐sided coverage, although they have slight deficiencies for confidence levels of 90% or lower. For an easily taught, hand‐calculated method, the Brown‐Li ‘Jeffreys’ method appears to perform reasonably well, and in most situations, it has better one‐sided coverage than the widely recommended alternatives. In general, we find that the one‐sided properties of many of the available methods are surprisingly poor. In fact, almost none of the existing asymptotic methods achieve equal coverage on both sides of the interval, even with large sample sizes, and consequently if used as a non‐inferiority test, the type I error rate (which is equal to the one‐sided non‐coverage probability) can be inflated. The only exception is the Gart‐Nam ‘skewness‐corrected’ method, which we express using modified notation in order to include a bias correction for improved small‐sample performance, and an optional continuity correction for those seeking more conservative coverage. Using a weighted average of two complementary methods, we also define a new hybrid method that almost matches the performance of the Gart‐Nam interval. Copyright © 2014 John Wiley & Sons, Ltd.     

Bayesian sample‐size determination methods considering both worthwhileness and unpromisingness for exploratory two‐arm randomized clinical trials with binary endpoints

A randomized exploratory clinical trial comparing an experimental treatment with a control treatment on a binary endpoint is often conducted to make a go or no‐go decision. Such an exploratory trial needs to have an adequate sample size such that it will provide convincing evidence that the experimental treatment is either worthwhile or unpromising relative to the control treatment. In this paper, we propose three new sample‐size determination methods for an exploratory trial, which utilize the posterior probabilities calculated from predefined efficacy and inefficacy criteria leading to a declaration of the worthwhileness or unpromisingness of the experimental treatment. Simulation studies, including numerical investigation, showed that all three methods could declare the experimental treatment as worthwhile or unpromising with a high probability when the true response probability of the experimental treatment group is higher or lower, respectively, than that of the control treatment group.     

Two‐stage phase II survival trial design

Recently, molecularly targeted agents and immunotherapy have been advanced for the treatment of relapse or refractory cancer patients, where disease progression‐free survival or event‐free survival is often a primary endpoint for the trial design. However, methods to evaluate two‐stage single‐arm phase II trials with a time‐to‐event endpoint are currently processed under an exponential distribution, which limits application of real trial designs. In this paper, we developed an optimal two‐stage design, which is applied to the four commonly used parametric survival distributions. The proposed method has advantages compared with existing methods in that the choice of underlying survival model is more flexible and the power of the study is more adequately addressed. Therefore, the proposed two‐stage design can be routinely used for single‐arm phase II trial designs with a time‐to‐event endpoint as a complement to the commonly used Simon's two‐stage design for the binary outcome.     

Addressing potential prior‐data conflict when using informative priors in proof‐of‐concept studies

Bayesian methods are increasingly used in proof‐of‐concept studies. An important benefit of these methods is the potential to use informative priors, thereby reducing sample size. This is particularly relevant for treatment arms where there is a substantial amount of historical information such as placebo and active comparators. One issue with using an informative prior is the possibility of a mismatch between the informative prior and the observed data, referred to as prior‐data conflict. We focus on two methods for dealing with this: a testing approach and a mixture prior approach. The testing approach assesses prior‐data conflict by comparing the observed data to the prior predictive distribution and resorting to a non‐informative prior if prior‐data conflict is declared. The mixture prior approach uses a prior with a precise and diffuse component. We assess these approaches for the normal case via simulation and show they have some attractive features as compared with the standard one‐component informative prior. For example, when the discrepancy between the prior and the data is sufficiently marked, and intuitively, one feels less certain about the results, both the testing and mixture approaches typically yield wider posterior‐credible intervals than when there is no discrepancy. In contrast, when there is no discrepancy, the results of these approaches are typically similar to the standard approach. Whilst for any specific study, the operating characteristics of any selected approach should be assessed and agreed at the design stage; we believe these two approaches are each worthy of consideration. Copyright © 2015 John Wiley & Sons, Ltd.     

Study design of single‐arm phase II immunotherapy trials with long‐term survivors and random delayed treatment effect

In the traditional study design of a single‐arm phase II cancer clinical trial, the one‐sample log‐rank test has been frequently used. A common practice in sample size calculation is to assume that the event time in the new treatment follows exponential distribution. Such a study design may not be suitable for immunotherapy cancer trials, when both long‐term survivors (or even cured patients from the disease) and delayed treatment effect are present, because exponential distribution is not appropriate to describe such data and consequently could lead to severely underpowered trial. In this research, we proposed a piecewise proportional hazards cure rate model with random delayed treatment effect to design single‐arm phase II immunotherapy cancer trials. To improve test power, we proposed a new weighted one‐sample log‐rank test and provided a sample size calculation formula for designing trials. Our simulation study showed that the proposed log‐rank test performs well and is robust of misspecified weight and the sample size calculation formula also performs well.