Development of Adaptive Group Sequential Procedure for Changing Sample Size

In this study, we propose a group sequential procedure that allows the change of necessary sample size at intermediary stage in sequential test. In the procedure, we formulate the conditional power to judge the necessity of the change of sample size in decision rules. Furthermore, we present an integral formula of the power of the test and show how to change the necessary sample size by using the power of the test. In simulation studies, we investigate the characteristics of the change of sample size and the pattern of decision across all stages based on generated normal random numbers.     

Design and inference for 3‐stage bioequivalence testing with serial sampling data

A bioequivalence test is to compare bioavailability parameters, such as the maximum observed concentration (C_max) or the area under the concentration‐time curve, for a test drug and a reference drug. During the planning of a bioequivalence test, it requires an assumption about the variance of C_max or area under the concentration‐time curve for the estimation of sample size. Since the variance is unknown, current 2‐stage designs use variance estimated from stage 1 data to determine the sample size for stage 2. However, the estimation of variance with the stage 1 data is unstable and may result in too large or too small sample size for stage 2. This problem is magnified in bioequivalence tests with a serial sampling schedule, by which only one sample is collected from each individual and thus the correct assumption of variance becomes even more difficult. To solve this problem, we propose 3‐stage designs. Our designs increase sample sizes over stages gradually, so that extremely large sample sizes will not happen. With one more stage of data, the power is increased. Moreover, the variance estimated using data from both stages 1 and 2 is more stable than that using data from stage 1 only in a 2‐stage design. These features of the proposed designs are demonstrated by simulations. Testing significance levels are adjusted to control the overall type I errors at the same level for all the multistage designs.     

Group sequential x2 statistic for testing the difference of two mean vectors in clinical trials

In this study we discuss the group sequential procedures for comparing two treatments based on multivariate observations in clinical trials. Also we suppose that a response vector on each of two treatments has a multivariate normal distribution with unknown covariance matrix. Then we propose a group sequential x² statistic in order to carry out repeated significance test for hypothesis of no difference between two population mean vectors. In order to realize the group sequential test where average sample number is reduced, we propose another modified group sequential x² statistic by extension of Jennison and Turnbull ( 1991 ). After construction of repeated confidence boundaries for making the repeated significance test, we compare two group sequential procedures based on two statistics regarding the average sample number and the power of the test in the simulations.     

Sequential design approaches for bioequivalence studies with crossover designs

The planning of bioequivalence (BE) studies, as for any clinical trial, requires a priori specification of an effect size for the determination of power and an assumption about the variance. The specified effect size may be overly optimistic, leading to an underpowered study. The assumed variance can be either too small or too large, leading, respectively, to studies that are underpowered or overly large. There has been much work in the clinical trials field on various types of sequential designs that include sample size reestimation after the trial is started, but these have seen only little use in BE studies. The purpose of this work was to validate at least one such method for crossover design BE studies. Specifically, we considered sample size reestimation for a two-stage trial based on the variance estimated from the first stage. We identified two methods based on Pocock's method for group sequential trials that met our requirement for at most negligible increase in type I error rate.     

An alternative phase II/III design for continuous endpoints

The success rate of drug development has been declined dramatically in recent years and the current paradigm of drug development is no longer functioning. It requires a major undertaking on breakthrough strategies and methodology for designs to minimize sample sizes and to shorten duration of the development. We propose an alternative phase II/III design based on continuous efficacy endpoints, which consists of two stages: a selection stage and a confirmation stage. For the selection stage, a randomized parallel design with several doses with a placebo group is employed for selection of doses. After the best dose is chosen, the patients of the selected dose group and placebo group continue to enter the confirmation stage. New patients will also be recruited and randomized to receive the selected dose or placebo group. The final analysis is performed with the cumulative data of patients from both stages. With the pre‐specified probabilities of rejecting the drug at each stage, sample sizes and critical values for both stages can be determined. As it is a single trial with controlling overall type I and II error rates, the proposed phase II/III adaptive design may not only reduce the sample size but also improve the success rate. An example illustrates the applications of the proposed phase II/III adaptive design. Copyright © 2010 John Wiley & Sons, Ltd.     

A review and re‐interpretation of a group‐sequential approach to sample size re‐estimation in two‐stage trials

In this paper, we review the adaptive design methodology of Li et al. (Biostatistics 3 :277–287) for two‐stage trials with mid‐trial sample size adjustment. We argue that it is closer in principle to a group sequential design, in spite of its obvious adaptive element. Several extensions are proposed that aim to make it even more attractive and transparent alternative to a standard (fixed sample size) trial for funding bodies to consider. These enable a cap to be put on the maximum sample size and for the trial data to be analysed using standard methods at its conclusion. The regulatory view of trials incorporating unblinded sample size re‐estimation is also discussed. © 2014 The Authors. Pharmaceutical Statistics published by John Wiley & Sons, Ltd.     

Extension of two-sided test to multiple treatment trials

In a two-treatment trial, a two-sided test is often used to reach a conclusion, Usually we are interested in doing a two-sided test because of no prior preference between the two treatments and we want a three-decision framework. When a standard control is just as good as the new experimental treatment (which has the same toxicity and cost), then we will accept both treatments. Only when the standard control is clearly worse or better than the new experimental treatment, then we choose only one treatment. In this paper, we extend the concept of a two-sided test to the multiple treatment trial where three or more treatments are involved. The procedure turns out to be a subset selection procedure; however, the theoretical framework and performance requirement are different from the existing subset selection procedures. Two procedures (exclusion or inclusion) are developed here for the case of normal data with equal known variance. If the sample size is large, they can be applied with unknown variance and with the binomial data or survival data with random censoring.     

Sample size calculations for time-averaged difference of longitudinal binary outcomes

In clinical trials with repeated measurements, the responses from each subject are measured multiple times during the study period. Two approaches have been widely used to assess the treatment effect, one that compares the rate of change between two groups and the other that tests the time-averaged difference (TAD). While sample size calculations based on comparing the rate of change between two groups have been reported by many investigators, the literature has paid relatively little attention to the sample size estimation for time-averaged difference (TAD) in the presence of heterogeneous correlation structure and missing data in repeated measurement studies. In this study, we investigate sample size calculation for the comparison of time-averaged responses between treatment groups in clinical trials with longitudinally observed binary outcomes. The generalized estimating equation (GEE) approach is used to derive a closed-form sample size formula, which is flexible enough to account for arbitrary missing patterns and correlation structures. In particular, we demonstrate that the proposed sample size can accommodate a mixture of missing patterns, which is frequently encountered by practitioners in clinical trials. To our knowledge, this is the first study that considers the mixture of missing patterns in sample size calculation. Our simulation shows that the nominal power and type I error are well preserved over a wide range of design parameters. Sample size calculation is illustrated through an example.     

Some sampling effects of pairwise correlated observations on likelihood ratio tests for the difference between two means

We study the effects of the inclusion of pairs of correlated observations in a sample on likelihood ratio tests for the difference in two means. In particular, we assess how the inclusion of correlated data pairs (e.g., such as data inadvertently collected from sib-pairs) affects the sample size requirements necessary for the implementation of a Likelihood Ratio (LR) test for the difference between two means. Our results suggest that correlated data pairs beneficially or adversely effect sample size requirements for an LR test to a degree functionally related to the mixture parameters dictating their relative frequencies in the larger sample on which the test will be performed, the strength of the correlation between the observations, and the size of imbalances in the sample with respect to the number of observations in each group. The relevance and implications of the results for genetic and epidemiologic research are discussed.     

Type I error rate control in adaptive designs for confirmatory clinical trials with treatment selection at interim

Interest in confirmatory adaptive combined phase II/III studies with treatment selection has increased in the past few years. These studies start comparing several treatments with a control. One (or more) treatment(s) is then selected after the first stage based on the available information at an interim analysis, including interim data from the ongoing trial, external information and expert knowledge. Recruitment continues, but now only for the selected treatment(s) and the control, possibly in combination with a sample size reassessment. The final analysis of the selected treatment(s) includes the patients from both stages and is performed such that the overall Type I error rate is strictly controlled, thus providing confirmatory evidence of efficacy at the final analysis. In this paper we describe two approaches to control the Type I error rate in adaptive designs with sample size reassessment and/or treatment selection. The first method adjusts the critical value using a simulation-based approach, which incorporates the number of patients at an interim analysis, the true response rates, the treatment selection rule, etc. We discuss the underlying assumptions of simulation-based procedures and give several examples where the Type I error rate is not controlled if some of the assumptions are violated. The second method is an adaptive Bonferroni-Holm test procedure based on conditional error rates of the individual treatment-control comparisons. We show that this procedure controls the Type I error rate, even if a deviation from a pre-planned adaptation rule or the time point of such a decision is necessary.     

Duration of Accrual and Follow-up for Two-Stage Clinical Trials

Group sequential trialswith time to event end points can be complicated to design. Notonly are there unlimited choices for the number of events requiredat each stage, but for each of these choices, there are unlimitedcombinations of accrual and follow-up at each stage that providethe required events. Methods are presented for determining optimalcombinations of accrual and follow-up for two-stage clinicaltrials with time to event end points. Optimization is based onminimizing the expected total study length as a function of theexpected accrual duration or sample size while providing an appropriateoverall size and power. Optimal values of expected accrual durationand minimum expected total study length are given assuming anexponential proportional hazards model comparing two treatmentgroups. The expected total study length can be substantiallydecreased by including a follow-up period during which accrualis suspended. Conditions that warrant an interim follow-up periodare considered, and the gain in efficiency achieved by includingan interim follow-up period is quantified. The gain in efficiencyshould be weighed against the practical difficulties in implementingsuch designs. An example is given to illustrate the use of thesetechniques in designing a clinical trial to compare two chemotherapyregimens for lung cancer. Practical considerations of includingan interim follow-up period are discussed.     

Increased Fisher’s information for parameters of association in count regression via extreme ranks

The article details a sampling scheme which can lead to a reduction in sample size and cost in clinical and epidemiological studies of association between a count outcome and risk factor. We show that inference in two common generalized linear models for count data, Poisson and negative binomial regression, is improved by using a ranked auxiliary covariate, which guides the sampling procedure. This type of sampling has typically been used to improve inference on a population mean. The novelty of the current work is its extension to log-linear models and derivations showing that the sampling technique results in an increase in information as compared to simple random sampling. Specifically, we show that under the proposed sampling strategy the maximum likelihood estimate of the risk factor’s coefficient is improved through an increase in the Fisher’s information. A simulation study is performed to compare the mean squared error, bias, variance, and power of the sampling routine with simple random sampling under various data-generating scenarios. We also illustrate the merits of the sampling scheme on a real data set from a clinical setting of males with chronic obstructive pulmonary disease. Empirical results from the simulation study and data analysis coincide with the theoretical derivations, suggesting that a significant reduction in sample size, and hence study cost, can be realized while achieving the same precision as a simple random sample.     

ON A MULTIPLE THREE-DECISION PROCEDURE FOR COMPARING SEVERAL TREATMENTS WITH A CONTROL

For the two-sided comparisons of several treatments with a control, a common statistical problem is to decide which treatments are better than the control and which are worse than the control. This paper studies a multiple three-decision procedure for this purpose, proposed by Bohrer (1979) and Bohrer et al. (1981), and provides tables of critical points to facilitate the application of the procedure. The paper defines a power function of the procedure, and tabulates sample sizes necessary to guarantee a given power level. It addresses the problem of optimal sampling allocation in order to maximize the power for a given total sample size, and considers generalization to the situation where the treatments might have unequal numbers of observations.     

Prediction intervals for generalized-order statistics with random sample size

The problem of predicting future generalized-order statistics, by assuming the future sample size is a random variable, is discussed. A general expression for the coverage probability of the prediction intervals is derived. Since k-records and progressively type-II censored-order statistics are contained in the model of generalized-order statistics, the corresponding results for them can be deduced as special cases. When the future sample size has degenerate, binomial, Poisson and geometric distributions, numerical computations are given. The procedure for finding an optimal prediction interval is presented for each case. Finally, we apply our results to a real data set in life testing given in Lee and Wang [Statistical methods for survival data analysis. Hoboken, NJ: John Wiley and Sons; 2003, p. 58, Table 3.4] for illustrative the proposed procedure in this paper.     

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

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

Optimal adaptive sequential designs for crossover bioequivalence studies

In prior works, this group demonstrated the feasibility of valid adaptive sequential designs for crossover bioequivalence studies. In this paper, we extend the prior work to optimize adaptive sequential designs over a range of geometric mean test/reference ratios (GMRs) of 70–143% within each of two ranges of intra‐subject coefficient of variation (10–30% and 30–55%). These designs also introduce a futility decision for stopping the study after the first stage if there is sufficiently low likelihood of meeting bioequivalence criteria if the second stage were completed, as well as an upper limit on total study size. The optimized designs exhibited substantially improved performance characteristics over our previous adaptive sequential designs. Even though the optimized designs avoided undue inflation of type I error and maintained power at 80%, their average sample sizes were similar to or less than those of conventional single stage designs. Copyright © 2015 John Wiley & Sons, Ltd.     

Sample Size Calculation and Power Analysis of Changes in Mean Response Over Time

Despite tremendous effort on different designs with cross-sectional data, little research has been conducted for sample size calculation and power analyses under repeated measures design. In addition to time-averaged difference, changes in mean response over time (CIMROT) is the primary interest in repeated measures analysis. We generalized sample size calculation and power analysis equations for CIMROT to allow unequal sample size between groups for both continuous and binary measures, through simulation, evaluated the performance of proposed methods, and compared our approach to that of a two-stage model formulization. We also created a software procedure to implement the proposed methods.     

Sample size estimation for a two-group comparison of repeated count outcomes using GEE

Randomized clinical trials with count measurements as the primary outcome are common in various medical areas such as seizure counts in epilepsy trials, or relapse counts in multiple sclerosis trials. Controlled clinical trials frequently use a conventional parallel-group design that assigns subjects randomly to one of two treatment groups and repeatedly evaluates them at baseline and intervals across a treatment period of a fixed duration. The primary interest is to compare the rates of change between treatment groups. Generalized estimating equations (GEEs) have been widely used to compare rates of change between treatment groups because of its robustness to misspecification of the true correlation structure. In this paper, we derive a sample size formula for comparing the rates of change between two groups in a repeatedly measured count outcome using GEE. The sample size formula incorporates general missing patterns such as independent missing and monotone missing, and general correlation structures such as AR(1) and compound symmetry (CS). The performance of the sample size formula is evaluated through simulation studies. Sample size estimation is illustrated by a clinical trial example from epilepsy.     

Additional results for 'Sequential design approaches for bioequivalence studies with crossover designs'

In 2008, this group published a paper on approaches for two‐stage crossover bioequivalence (BE) studies that allowed for the reestimation of the second‐stage sample size based on the variance estimated from the first‐stage results. The sequential methods considered used an assumed GMR of 0.95 as part of the method for determining power and sample size. This note adds results for an assumed GMR = 0.90. Two of the methods recommended for GMR = 0.95 in the earlier paper have some unacceptable increases in Type I error rate when the GMR is changed to 0.90. If a sponsor wants to assume 0.90 for the GMR, Method D is recommended. Copyright © 2011 John Wiley & Sons, Ltd.