Exact sample-size determination in testing non-inferiority under a simple crossover trial

For testing the non-inferiority (or equivalence) of an experimental treatment to a standard treatment, the odds ratio (OR) of patient response rates has been recommended to measure the relative treatment efficacy. On the basis of an exact test procedure proposed elsewhere for a simple crossover design, we develop an exact sample-size calculation procedure with respect to the OR of patient response rates for a desired power of detecting non-inferiority at a given nominal type I error. We note that the sample size calculated for a desired power based on an asymptotic test procedure can be much smaller than that based on the exact test procedure under a given situation. We further discuss the advantage and disadvantage of sample-size calculation using the exact test and the asymptotic test procedures. We employ an example by studying two inhalation devices for asthmatics to illustrate the use of sample-size calculation procedure developed here.     

A unifying approach to non-inferiority, equivalence and superiority tests via multiple decision processes

Two approaches of multiple decision processes are proposed for unifying the non-inferiority, equivalence and superiority tests in a comparative clinical trial for a new drug against an active control. One is a method of confidence set with confidence coefficient 0.95 improving the conventional 0.95 confidence interval in the producer's risk and also the consumer's risk in some cases. It requires to include 0 within the region as well as to clear the non-inferiority margin so that a trial with somewhat large number of subjects and inappropriately large non-inferiority margin for proving non-inferiority of a drug that is actually inferior should be unsuccessful. The other is the closed testing procedure which combines the one- and two-sided tests by applying the partitioning principle and justifies the switching procedure by unifying the non-inferiority, equivalence and superiority tests. In particular regarding the non-inferiority, the proposed method justifies simultaneously the old Japanese Statistical Guideline (one-sided 0.05 test) and the International Guideline ICH E9 (one-sided 0.025 test). The method is particularly attractive, changing the strength of the evidence of relative efficacy of the test drug against a control at five levels according to the achievement of the clinical trial. The meaning of the non-inferiority test and also the rationale of switching from it to superiority test will be discussed.     

Sample size calculations for noninferiority trials for time-to-event data using the concept of proportional time

Noninferiority trials intend to show that a new treatment is ‘not worse'' than a standard-of-care active control and can be used as an alternative when it is likely to cause fewer side effects compared to the active control. In the case of time-to-event endpoints, existing methods of sample size calculation are done either assuming proportional hazards between the two study arms, or assuming exponentially distributed lifetimes. In scenarios where these assumptions are not true, there are few reliable methods for calculating the sample sizes for a time-to-event noninferiority trial. Additionally, the choice of the non-inferiority margin is obtained either from a meta-analysis of prior studies, or strongly justifiable ‘expert opinion'', or from a ‘well conducted'' definitive large-sample study. Thus, when historical data do not support the traditional assumptions, it would not be appropriate to use these methods to design a noninferiority trial. For such scenarios, an alternate method of sample size calculation based on the assumption of Proportional Time is proposed. This method utilizes the generalized gamma ratio distribution to perform the sample size calculations. A practical example is discussed, followed by insights on choice of the non-inferiority margin, and the indirect testing of superiority of treatment compared to placebo.KEYWORDS: Generalized gamma, noninferiority, non-proportional hazards, proportional time, relative time, sample size     

A ratio-to-control Williams-type test for trend

Under certain conditions, many multiple contrast tests based on the difference of treatment means can also be conveniently expressed in terms of ratios. In this paper, a Williams test for trend is defined as ratios-to-control for ease of interpretation and to obtain directly comparable confidence intervals. Simultaneous confidence intervals for percentages are particularly helpful for interpretations in the case of multiple endpoints. Methods for constructing simultaneous confidence intervals are discussed under both homogeneous and heterogeneous error variances. This approach is available in the R extension package mratios. The proposed method is used to test for trend in an immunotoxicity study with several endpoints as an example.     

Sample size calculation for testing non-inferiority and equivalence under Poisson distribution

When counting the number of chemical parts in air pollution studies or when comparing the occurrence of congenital malformations between a uranium mining town and a control population, we often assume Poisson distribution for the number of these rare events. Some discussions on sample size calculation under Poisson model appear elsewhere, but all these focus on the case of testing equality rather than testing equivalence. We discuss sample size and power calculation on the basis of exact distribution under Poisson models for testing non-inferiority and equivalence with respect to the mean incidence rate ratio. On the basis of large sample theory, we further develop an approximate sample size calculation formula using the normal approximation of a proposed test statistic for testing non-inferiority and an approximate power calculation formula for testing equivalence. We find that using these approximation formulae tends to produce an underestimate of the minimum required sample size calculated from using the exact test procedure. On the other hand, we find that the power corresponding to the approximate sample sizes can be actually accurate (with respect to Type I error and power) when we apply the asymptotic test procedure based on the normal distribution. We tabulate in a variety of situations the minimum mean incidence needed in the standard (or the control) population, that can easily be employed to calculate the minimum required sample size from each comparison group for testing non-inferiority and equivalence between two Poisson populations.     

Assessing non-inferiority to an aggregate response with an application to development of pneumococcal conjugate vaccines

The development of a new pneumococcal conjugate vaccine involves assessing the responses of the new serotypes included in the vaccine. The World Health Organization guidance states that the response from each new serotype in the new vaccine should be compared with the aggregate response from the existing vaccine to evaluate non-inferiority. However, no details are provided on how to define and estimate the aggregate response and what methods to use for non-inferiority comparisons. We investigate several methods to estimate the aggregate response based on binary data including simple average, model-based, and lowest response methods. The response of each new serotype is then compared with the estimated aggregate response for non-inferiority. The non-inferiority test p-value and confidence interval are obtained from Miettinen and Nurminen's method, using an effective sample size. The methods are evaluated using simulations and demonstrated with a real clinical trial example.     

A fiducial approach for testing the non-inferiority of proportion difference in matched-pairs design

The non-inferiority of one treatment/drug to another is a common and important issue in medical and pharmaceutical fields. This study explored a fiducial approach for testing the non-inferiority of proportion difference in matched-pairs design. Approximate tests constructed using fiducial quantities with a combination of different parameters were proposed. Four simulation studies were employed to compare the performance of fiducial tests by comparing their type I errors and powers. The results showed that fiducial quantities with parameter $0.6\le w_1\le 0.8$ performed satisfactorily from small to large samples. Therefore, the fiducial tests could be recommended for practical applications. The recommended fiducial tests might be a competitive alternative to other available tests. Three real data sets were analyzed to illustrate the proposed methods were competitive or even better than other tests.     

Statistical analysis of non-inferiority via non-zero risk difference in stratified matched-pair studies

A stratified study is often designed for adjusting several independent trials in modern medical research. We consider the problem of non-inferiority tests and sample size determinations for a nonzero risk difference in stratified matched-pair studies, and develop the likelihood ratio and Wald-type weighted statistics for testing a null hypothesis of non-zero risk difference for each stratum in stratified matched-pair studies on the basis of (1) the sample-based method and (2) the constrained maximum likelihood estimation (CMLE) method. Sample size formulae for the above proposed statistics are derived, and several choices of weights for Wald-type weighted statistics are considered. We evaluate the performance of the proposed tests according to type I error rates and empirical powers via simulation studies. Empirical results show that (1) the likelihood ratio and the Wald-type CMLE test based on harmonic means of the stratum-specific sample size (SSIZE) weight (the Cochran's test) behave satisfactorily in the sense that their significance levels are much closer to the prespecified nominal level; (2) the likelihood ratio test is better than Nam's [2006. Non-inferiority of new procedure to standard procedure in stratified matched-pair design. Biometrical J. 48, 966–977] score test; (3) the sample sizes obtained by using SSIZE weight are smaller than other weighted statistics in general; (4) the Cochran's test statistic is generally much better than other weighted statistics with CMLE method. A real example from a clinical laboratory study is used to illustrate the proposed methodologies.     

Sample size estimation for non-inferiority trials of time-to-event data

We consider the problem of sample size calculation for non-inferiority based on the hazard ratio in time-to-event trials where overall study duration is fixed and subject enrollment is staggered with variable follow-up. An adaptation of previously developed formulae for the superiority framework is presented that specifically allows for effect reversal under the non-inferiority setting, and its consequent effect on variance. Empirical performance is assessed through a small simulation study, and an example based on an ongoing trial is presented. The formulae are straightforward to program and may prove a useful tool in planning trials of this type.     

Application of Anbar's Approach to Hypothesis Testing to Detect the Difference between Two Proportions

In this paper, Anbar's (1983) approach for estimating a difference between two binomial proportions is discussed with respect to a hypothesis testing problem. Such an approach results in two possible testing strategies. While the results of the tests are expected to agree for a large sample size when two proportions are equal, the tests are shown to perform quite differently in terms of their probabilities of a Type I error for selected sample sizes. Moreover, the tests can lead to different conclusions, which is illustrated via a simple example; and the probability of such cases can be relatively large. In an attempt to improve the tests while preserving their relative simplicity feature, a modified test is proposed. The performance of this test and a conventional test based on normal approximation is assessed. It is shown that the modified Anbar's test better controls the probability of a Type I error for moderate sample sizes.     

Efficiency of tests based on weighted rankings for equality of treatment effects in a complete randomized blocks layout

Quade (1972,1979) proposed a family of nonparametric tests based on a method of weighted within-block rankings, for testing the hypothesis of no treatment effects in a complete randomized blocks layout.

In this paper we obtain an expression for the Pitman asymp-totic relative efficiency of these tests with respect to the Friedman test.     

Testing drug additivity based on monotherapies

Under the Loewe additivity, constant relative potency between two drugs is a sufficient condition for the two drugs to be additive. Implicit in this condition is that one drug acts like a dilution of the other. Geometrically, it means that the dose‐response curve of one drug is a copy of another that is shifted horizontally by a constant over the log‐dose axis. Such phenomenon is often referred to as parallelism. Thus, testing drug additivity is equivalent to the demonstration of parallelism between two dose‐response curves. Current methods used for testing parallelism are usually based on significance tests for differences between parameters in the dose‐response curves of the monotherapies. A p‐value of less than 0.05 is indicative of non‐parallelism. The p‐value‐based methods, however, may be fundamentally flawed because an increase in either sample size or precision of the assay used to measure drug effect may result in more frequent rejection of parallel lines for a trivial difference. Moreover, similarity (difference) between model parameters does not necessarily translate into the similarity (difference) between the two response curves. As a result, a test may conclude that the model parameters are similar (different), yet there is little assurance on the similarity between the two dose‐response curves. In this paper, we introduce a Bayesian approach to directly test the hypothesis that the two drugs have a constant relative potency. An important utility of our proposed method is in aiding go/no‐go decisions concerning two drug combination studies. It is illustrated with both a simulated example and a real‐life example. Copyright © 2015 John Wiley & Sons, Ltd.     

Sample size calculation for logrank test and prediction of number of events over time

We review and compare existing methods for sample size calculation based on the logrank statistic and recommend the method of Lakatos for its accuracy and flexibility in allowing time-dependent rates of event, loss to follow-up, and noncompliance. We extend the Lakatos method to allow a general follow-up scheme, to handle non-inferiority tests, and to predict the number of events over calendar time. We apply the Lakatos method to the simple nonproportional hazard situation of delayed treatment effect to facilitate the comparison of different weighting methods and to evaluate the performance of the maximum combination tests. We use simulation studies to confirm the validity of the Lakatos method and its extensions.     

Combining asymptotically normal tests: case studies in comparison of two groups

When several candidate tests are available for a given testing problem, and each has nice properties with respect to different criteria such as efficiency and robustness, it is desirable to combine them. We discuss various combined tests based on asymptotically normal tests. When the means of two standardized tests under contiguous alternatives are close, we show that the maximum of the two tests appears to have an overall best performance compared with other forms of combined tests considered, and that it retains most power compared with the better one of the two tests combined. As an application, for testing zero location shift between two groups, we studied the normal, Wilcoxon, median tests and their combined tests. Because of their structural differences, the joint convergence and the asymptotic correlation of the tests are not easily derived from the usual asymptotic arguments of the tests. We developed a novel application of martingale theory to obtain the asymptotic correlations and their estimators. Simulation studies were also performed to examine the small sample properties of these combined tests. Finally we illustrate the methods by a real data example.     

Change-Point Tests for the Error Distribution in Non-parametric Regression

Abstract.  Several testing procedures are proposed that can detect change-points in the error distribution of non-parametric regression models. Different settings are considered where the change-point either occurs at some time point or at some value of the covariate. Fixed as well as random covariates are considered. Weak convergence of the suggested difference of sequential empirical processes based on non-parametrically estimated residuals to a Gaussian process is proved under the null hypothesis of no change-point. In the case of testing for a change in the error distribution that occurs with increasing time in a model with random covariates the test statistic is asymptotically distribution free and the asymptotic quantiles can be used for the test. This special test statistic can also detect a change in the regression function. In all other cases the asymptotic distribution depends on unknown features of the data-generating process and a bootstrap procedure is proposed in these cases. The small sample performances of the proposed tests are investigated by means of a simulation study and the tests are applied to a data example.     

How to avoid concerns with the interpretation of two primary endpoints if significant superiority in one is sufficient for formal proof of efficacy

Formal proof of efficacy of a drug requires that in a prospective experiment, superiority over placebo, or either superiority or at least non-inferiority to an established standard, is demonstrated. Traditionally one primary endpoint is specified, but various diseases exist where treatment success needs to be based on the assessment of two primary endpoints. With co-primary endpoints, both need to be “significant” as a prerequisite to claim study success. Here, no adjustment of the study-wise type-1-error is needed, but sample size is often increased to maintain the pre-defined power. Studies that use an at-least-one concept have been proposed where study success is claimed if superiority for at least one of the endpoints is demonstrated. This is sometimes also called the dual primary endpoint concept, and an appropriate adjustment of the study-wise type-1-error is required. This concept is not covered in the European Guideline on multiplicity because study success can be claimed if one endpoint shows significant superiority, despite a possible deterioration in the other. In line with Röhmel's strategy, we discuss an alternative approach including non-inferiority hypotheses testing that avoids obvious contradictions to proper decision-making. This approach leads back to the co-primary endpoint assessment, and has the advantage that minimum requirements for endpoints can be modeled flexibly for several practical needs. Our simulations show that, if planning assumptions are correct, the proposed additional requirements improve interpretation with only a limited impact on power, that is, on sample size.     

Graphical comparison of means with a standard in the one-way layout

Some simple test procedures are considered for comparing several group means with a standard value when the data are in a one-way layout. The underlying distributions are assumed to be normal with possibly unequal variances. The tests are based on a union-intersection formulation and can be applied in a form similar to a Shewhart control chart. Both two-sided and one-sided alternatives are considered. The power of the tests can be obtained from tables of a non-central t distribution. Implementation of the tests is illustrated with a numerical example. The tests help identify any group means different from the standard and might lead to a decision about rejecting the null hypothesis before all the group means are observed. The resulting savings in time and resources might be valuable in applications where the number of groups is large and the cost of acquiring data is high. For situations where the normality assumption is untenable, a non-parametric procedure, based on one-sample sign tests is considered.     

A two-sample empirical likelihood ratio test based on samples entropy

Powerful entropy-based tests for normality, uniformity and exponentiality have been well addressed in the statistical literature. The density-based empirical likelihood approach improves the performance of these tests for goodness-of-fit, forming them into approximate likelihood ratios. This method is extended to develop two-sample empirical likelihood approximations to optimal parametric likelihood ratios, resulting in an efficient test based on samples entropy. The proposed and examined distribution-free two-sample test is shown to be very competitive with well-known nonparametric tests. For example, the new test has high and stable power detecting a nonconstant shift in the two-sample problem, when Wilcoxon’s test may break down completely. This is partly due to the inherent structure developed within Neyman-Pearson type lemmas. The outputs of an extensive Monte Carlo analysis and real data example support our theoretical results. The Monte Carlo simulation study indicates that the proposed test compares favorably with the standard procedures, for a wide range of null and alternative distributions.     

Determining the non-inferiority margin for patient reported outcomes

One of the cornerstones of any non-inferiority trial is the choice of the non-inferiority margin delta. This threshold of clinical relevance is very difficult to determine, and in practice, delta is often "negotiated" between the sponsor of the trial and the regulatory agencies. However, for patient reported, or more precisely patient observed outcomes, the patients' minimal clinically important difference (MCID) can be determined empirically by relating the treatment effect, for example, a change on a 100-mm visual analogue scale, to the patient's satisfaction with the change. This MCID can then be used to define delta. We used an anchor-based approach with non-parametric discriminant analysis and ROC analysis and a distribution-based approach with Norman's half standard deviation rule to determine delta in three examples endometriosis-related pelvic pain measured on a 100-mm visual analogue scale, facial acne measured by lesion counts, and hot flush counts. For each of these examples, all three methods yielded quite similar results. In two of the cases, the empirically derived MCIDs were smaller or similar of deltas used before in non-inferiority trials, and in the third case, the empirically derived MCID was used to derive a responder definition that was accepted by the FDA. In conclusion, for patient-observed endpoints, the delta can be derived empirically. In our view, this is a better approach than that of asking the clinician for a "nice round number" for delta, such as 10, 50%, π, e, or i.     

Comparison of correlated proportions based on paired binary data from clustered samples

In this article, we explore hypothesis testing problems related to correlated proportions from clustered matched-pair binary data. Null hypotheses of equality in proportions, homogeneity, and non-inferiority of one to another are similar testing problems of linear contrasts of correlated proportions with suitable transformation. The covariance estimators of the test statistics are based on moment estimation under the null hypotheses. We present a general framework for testing linear contrasts of the correlated proportions from clustered matched-pair data based upon a class of unbiased estimators of the proportions. The corresponding testing procedures do not impose structure assumptions on the correlation matrix and are easy to use. Simulation results suggest that the proposed method is more likely to maintain the proper significance level and to improve power than the test proposed by Obuchowski.