Exact confidence limits for the probability of response in two-stage designs

In addition to point estimate for the probability of response in a two-stage design (e.g. Simon's two-stage design for binary endpoints), confidence limits should be computed and reported. The current method of inverting the p-value function to compute the confidence interval does not guarantee coverage probability in a two-stage setting. The existing exact approach to calculate one-sided limits is based on the overall number of responses to order the sample space. This approach could be conservative because many sample points have the same limits. We propose a new exact one-sided interval based on p-value for the sample space ordering. Exact intervals are computed by using binomial distributions directly, instead of a normal approximation. Both exact intervals preserve the nominal confidence level. The proposed exact interval based on the p-value generally performs better than the other exact interval with regard to expected length and simple average length of confidence intervals.     

Applications of asymptotic confidence intervals with continuity corrections for asymmetric comparisons in noninferiority trials

A large‐sample problem of illustrating noninferiority of an experimental treatment over a referent treatment for binary outcomes is considered. The methods of illustrating noninferiority involve constructing the lower two‐sided confidence bound for the difference between binomial proportions corresponding to the experimental and referent treatments and comparing it with the negative value of the noninferiority margin. The three considered methods, Anbar, Falk–Koch, and Reduced Falk–Koch, handle the comparison in an asymmetric way, that is, only the referent proportion out of the two, experimental and referent, is directly involved in the expression for the variance of the difference between two sample proportions. Five continuity corrections (including zero) are considered with respect to each approach. The key properties of the corresponding methods are evaluated via simulations. First, the uncorrected two‐sided confidence intervals can, potentially, have smaller coverage probability than the nominal level even for moderately large sample sizes, for example, 150 per group. Next, the 15 testing methods are discussed in terms of their Type I error rate and power. In the settings with a relatively small referent proportion (about 0.4 or smaller), the Anbar approach with Yates’ continuity correction is recommended for balanced designs and the Falk–Koch method with Yates’ correction is recommended for unbalanced designs. For relatively moderate (about 0.6) and large (about 0.8 or greater) referent proportion, the uncorrected Reduced Falk–Koch method is recommended, although in this case, all methods tend to be over‐conservative. These results are expected to be used in the design stage of a noninferiority study when asymmetric comparisons are envisioned. Copyright © 2013 John Wiley & Sons, Ltd.     

A class of fixed-width confidence intervals for a ranked normal mean

Suppose that we are given k(≥ 2) independent and normally distributed populations π₁, …, π_k where π_i has unknown mean μ_i and unknown variance σ² _i (i = 1, …, k). Let μ_[i] (i = 1, …, k) denote the i^th smallest one of μ₁, …, μ_k. A two-stage procedure is used to construct lower and upper confidence intervals for μ_[i] and then use these to obtain a class of two-sided confidence intervals on μ_[i] with fixed width. For i = k, the interval given by Chen and Dudewicz (1976) is a special case. Comparison is made between the class of two-sided intervals and a symmetric interval proposed by Chen and Dudewicz (1976) for the largest mean, and it is found that for large values of k at least one of the former intervals requires a smaller total sample size. The tables needed to actually apply the procedure are provided.     

On the lengths of t-based confidence intervals

Confidence interval is a basic type of interval estimation in statistics. When dealing with samples from a normal population with the unknown mean and the variance, the traditional method to construct t-based confidence intervals for the mean parameter is to treat the n sampled units as n groups and build the intervals. Here we propose a generalized method. We first divide them into several equal-sized groups and then calculate the confidence intervals with the mean values of these groups. If we define “better” in terms of the expected length of the confidence interval, then the first method is better because the expected length of the confidence interval obtained from the first method is shorter. We prove this intuition theoretically. We also specify when the elements in each group are correlated, the first method is invalid, while the second can give us correct results in terms of the coverage probability. We illustrate this with analytical expressions. In practice, when the data set is extremely large and distributed in several data centers, the second method is a good tool to get confidence intervals, in both independent and correlated cases. Some simulations and real data analyses are presented to verify our theoretical results.     

A confidence function-based posterior probability design for phase II cancer trials

Single-arm one- or multi-stage study designs are commonly used in phase II oncology development when the primary outcome of interest is tumor response, a binary variable. Both two- and three-outcome designs are available. Simon two-stage design is a well-known example of two-outcome designs. The objective of a two-outcome trial is to reject either the null hypothesis that the objective response rate (ORR) is less than or equal to a pre-specified low uninteresting rate or to reject the alternative hypothesis that the ORR is greater than or equal to some target rate. Three-outcome designs proposed by Sargent et al. allow a middle gray decision zone which rejects neither hypothesis in order to reduce the required study size. We propose new two- and three-outcome designs with continual monitoring based on Bayesian posterior probability that meet frequentist specifications such as type I and II error rates. Futility and/or efficacy boundaries are based on confidence functions, which can require higher levels of evidence for early versus late stopping and have clear and intuitive interpretations. We search in a class of such procedures for optimal designs that minimize a given loss function such as average sample size under the null hypothesis. We present several examples and compare our design with other procedures in the literature and show that our design has good operating characteristics.     

Better approximate confidence intervals for a binomial parameter

This paper discusses five methods for constructing approximate confidence intervals for the binomial parameter Θ, based on Y successes in n Bernoulli trials. In a recent paper, Chen (1990) discusses various approximate methods and suggests a new method based on a Bayes argument, which we call method I here. Methods II and III are based on the normal approximation without and with continuity correction. Method IV uses the Poisson approximation of the binomial distribution and then exploits the fact that the exact confidence limits for the parameter of the Poisson distribution can be found through the x² distribution. The confidence limits of method IV are then provided by the Wilson-Hilferty approximation of the x². Similarly, the exact confidence limits for the binomial parameter can be expressed through the F distribution. Method V approximates these limits through a suitable version of the Wilson-Hilferty approximation. We undertake a comparison of the five methods in respect to coverage probability and expected length. The results indicate that method V has an advantage over Chen's Bayes method as well as over the other three methods.     

Stopping for efficacy in single-arm phase II clinical trials

Phase II clinical trials investigate whether a new drug or treatment has sufficient evidence of effectiveness against the disease under study. Two-stage designs are popular for phase II since they can stop in the first stage if the drug is ineffective. Investigators often face difficulties in determining the target response rates, and adaptive designs can help to set the target response rate tested in the second stage based on the number of responses observed in the first stage. Popular adaptive designs consider two alternate response rates, and they generally minimise the expected sample size at the maximum uninterested response rate. Moreover, these designs consider only futility as the reason for early stopping and have high expected sample sizes if the provided drug is effective. Motivated by this problem, we propose an adaptive design that enables us to terminate the single-arm trial at the first stage for efficacy and conclude which alternate response rate to choose. Comparing the proposed design with a popular adaptive design from literature reveals that the expected sample size decreases notably if any of the two target response rates are correct. In contrast, the expected sample size remains almost the same under the null hypothesis.     

The performance of model averaged tail area confidence intervals

We investigate the exact coverage and expected length properties of the model averaged tail area (MATA) confidence interval proposed by Turek and Fletcher, CSDA, 2012, in the context of two nested, normal linear regression models. The simpler model is obtained by applying a single linear constraint on the regression parameter vector of the full model. For given length of response vector and nominal coverage of the MATA confidence interval, we consider all possible models of this type and all possible true parameter values, together with a wide class of design matrices and parameters of interest. Our results show that, while not ideal, MATA confidence intervals perform surprisingly well in our regression scenario, provided that we use the minimum weight within the class of weights that we consider on the simpler model.     

Fixed width confidence intervals for the location parameter of an exponential distribution

We study confidence intervals of prescribed width for the lo-cation parameter of an exponential distribution. Asymptotic expan-sions up to terms tending to zero are obtained for the coverage probability and expected sample size. The limiting distribution of the sample size is given from which an asymptotic expression for the variance of the sample size is deduced. Sequential procedures with non-asymptotic coverage probability are also investigated     

Optimum treatment allocation for dual-objective clinical trials with binary outcomes

A common problem in randomized controlled clinical trials is the optimal assignment of patients to treatment protocols, The traditional optimal design assumes a single criterion, although in reality, there are usually more than one objective in a clinical trial. In this paper, optimal treatment allocation schemes are found for a dual-objective clinical trial with a binary response. A graphical method for finding the optimal strategy is proposed and illustrative examples are discussed.     

Sample size for estimating a binomial proportion: comparison of different methods

The poor performance of the Wald method for constructing confidence intervals (CIs) for a binomial proportion has been demonstrated in a vast literature. The related problem of sample size determination needs to be updated and comparative studies are essential to understanding the performance of alternative methods. In this paper, the sample size is obtained for the Clopper–Pearson, Bayesian (Uniform and Jeffreys priors), Wilson, Agresti–Coull, Anscombe, and Wald methods. Two two-step procedures are used: one based on the expected length (EL) of the CI and another one on its first-order approximation. In the first step, all possible solutions that satisfy the optimal criterion are obtained. In the second step, a single solution is proposed according to a new criterion (e.g. highest coverage probability (CP)). In practice, it is expected a sample size reduction, therefore, we explore the behavior of the methods admitting 30% and 50% of losses. For all the methods, the ELs are inflated, as expected, but the coverage probabilities remain close to the original target (with few exceptions). It is not easy to suggest a method that is optimal throughout the range (0, 1) for p. Depending on whether the goal is to achieve CP approximately or above the nominal level different recommendations are made.     

A comparative study of confidence intervals for negative binomial proportion

In this paper, we investigate four existing and three new confidence interval estimators for the negative binomial proportion (i.e., proportion under inverse/negative binomial sampling). An extensive and systematic comparative study among these confidence interval estimators through Monte Carlo simulations is presented. The performance of these confidence intervals are evaluated in terms of their coverage probabilities and expected interval widths. Our simulation studies suggest that the confidence interval estimator based on saddlepoint approximation is more appealing for large coverage levels (e.g., nominal level≤1% ) whereas the score confidence interval estimator is more desirable for those commonly used coverage levels (e.g., nominal level>1% ). We illustrate these confidence interval construction methods with a real data set from a maternal congenital heart disease study.     

One and two sample confidence intervals for estimating the mean of skewed populations: an empirical comparative study

In this paper we consider and propose some confidence intervals for estimating the mean or difference of means of skewed populations. We extend the median t interval to the two sample problem. Further, we suggest using the bootstrap to find the critical points for use in the calculation of median t intervals. A simulation study has been made to compare the performance of the intervals and a real life example has been considered to illustrate the application of the methods.     

Crossover design in clinical trials for binary response

In this paper, we consider a binary response model for the analysis of the two-treatment, two-period and four-sequence crossover design. We have introduced intra-patient drug dependency parameter in the model and provide two tests for the hypothesis of equality of treatment effects. We employ Monte Carlo simulation to compare our tests and a test that works under parallel design on the basis of type I error rate and power. We find that our procedures are dominant over the competitor with respect to power. Finally, we use a data set to illustrate the applicability of our procedure.     

Optimal inference for Simon's two-stage design with over or under enrollment at the second stage

Simon's two-stage designs are widely used in clinical trials to assess the activity of a new treatment. In practice, it is often the case that the second stage sample size is different from the planned one. For this reason, the critical value for the second stage is no longer valid for statistical inference. Existing approaches for making statistical inference are either based on asymptotic methods or not optimal. We propose an approach to maximize the power of a study while maintaining the type I error rate, where the type I error rate and power are calculated exactly from binomial distributions. The critical values of the proposed approach are numerically searched by an intelligent algorithm over the complete parameter space. It is guaranteed that the proposed approach is at least as powerful as the conditional power approach which is a valid but non-optimal approach. The power gain of the proposed approach can be substantial as compared to the conditional power approach. We apply the proposed approach to a real Phase II clinical trial.     

A two‐stage phase II clinical trial design with nested criteria for early stopping and efficacy

We propose a two‐stage design for a single arm clinical trial with an early stopping rule for futility. This design employs different endpoints to assess early stopping and efficacy. The early stopping rule is based on a criteria determined more quickly than that for efficacy. These separate criteria are also nested in the sense that efficacy is a special case of, but usually not identical to, the early stopping endpoint. The design readily allows for planning in terms of statistical significance, power, expected sample size, and expected duration. This method is illustrated with a phase II design comparing rates of disease progression in elderly patients treated for lung cancer to rates found using a historical control. In this example, the early stopping rule is based on the number of patients who exhibit progression‐free survival (PFS) at 2 months post treatment follow‐up. Efficacy is judged by the number of patients who have PFS at 6 months. We demonstrate our design has expected sample size and power comparable with the Simon two‐stage design but exhibits shorter expected duration under a range of useful parameter values.     

Construction of fixed width confidence intervals for a Bernoulli success probability using sequential sampling: a simulation study

This article considers the construction of level 1?α fixed width 2d confidence intervals for a Bernoulli success probability p, assuming no prior knowledge about p and so p can be anywhere in the interval [0, 1]. It is shown that some fixed width 2d confidence intervals that combine sequential sampling of Hall [Asymptotic theory of triple sampling for sequential estimation of a mean, Ann. Stat. 9 (1981), pp. 1229–1238] and fixed-sample-size confidence intervals of Agresti and Coull [Approximate is better than ‘exact’ for interval estimation of binomial proportions, Am. Stat. 52 (1998), pp. 119–126], Wilson [Probable inference, the law of succession, and statistical inference, J. Am. Stat. Assoc. 22 (1927), pp. 209–212] and Brown et al. [Interval estimation for binomial proportion (with discussion), Stat. Sci. 16 (2001), pp. 101–133] have close to 1?α confidence level. These sequential confidence intervals require a much smaller sample size than a fixed-sample-size confidence interval. For the coin jamming example considered, a fixed-sample-size confidence interval requires a sample size of 9457, while a sequential confidence interval requires a sample size that rarely exceeds 2042.     

The monotone boundary property and the full coverage property of confidence intervals for a binomial proportion

The methodology for deriving the exact confidence coefficient of some confidence intervals for a binomial proportion is proposed in Wang [2007. Exact confidence coefficients of confidence intervals for a binomial proportion. Statist. Sinica 17, 361–368]. The methodology requires two conditions of confidence intervals: the monotone boundary property and the full coverage property. In this paper, we show that for some confidence intervals of a binomial proportion, the two properties hold for any sample size. Based on results presented in this paper, the procedure in Wang [2007. Exact confidence coefficients of confidence intervals for a binomial proportion. Statist. Sinica 17, 361–368] can be directly used to calculate the exact confidence coefficients of these confidence intervals for any fixed sample size.     

A note on new confidence intervals for the difference between two proportions based on an Edgeworth expansion

Zhou and Qin [2004. New intervals for the difference between two independent binomial proportions. J. Statist. Plann. Inference 123, 97–115; 2005. A new confidence interval for the difference between two binomial proportions of paired data. J. Statist. Plann. Inference 128, 527–542] “new confidence intervals” for the difference between two treatment proportions exhibit a severe lack of invariance property that is a compelling reason not to use them.     

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.