Sample size calculation for the Power Model for dose proportionality studies

There are several approaches to assess or demonstrate pharmacokinetic dose proportionality. One statistical method is the traditional ANOVA model, where dose proportionality is evaluated using the bioequivalence limits. A more informative method is the mixed effects Power Model, where dose proportionality is assessed using a decision rule for the estimated slope. Here we propose analytical derivations of sample sizes for various designs (including crossover, incomplete block and parallel group designs) to be analysed according to the Power Model.     

Sample size of 12 per group rule of thumb for a pilot study

When designing a clinical trial an appropriate justification for the sample size should be provided in the protocol. However, there are a number of settings when undertaking a pilot trial when there is no prior information to base a sample size on. For such pilot studies the recommendation is a sample size of 12 per group. The justifications for this sample size are based on rationale about feasibility; precision about the mean and variance; and regulatory considerations. The context of the justifications are that future studies will use the information from the pilot in their design. Copyright © 2005 John Wiley & Sons, Ltd.     

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.     

Evaluation of statistical equivalence using limits of agreement and associated sample size calculation *

In this article, the Food and Drug Administration's (FDA) medical device substantial equivalence provision will be briefly introduced and some statistical methods useful for evaluating device equivalence are discussed. A sample size formula is derived for limits of agreement, which may be used to assess statistical equivalence in certain medical device situations. Simulation findings on the formula are presented, which can be used to guide sample size selections in common practical situations. Examples of the sample size procedure are given.     

Sample size recalculation for binary data in internal pilot study designs

For binary endpoints, the required sample size depends not only on the known values of significance level, power and clinically relevant difference but also on the overall event rate. However, the overall event rate may vary considerably between studies and, as a consequence, the assumptions made in the planning phase on this nuisance parameter are to a great extent uncertain. The internal pilot study design is an appealing strategy to deal with this problem. Here, the overall event probability is estimated during the ongoing trial based on the pooled data of both treatment groups and, if necessary, the sample size is adjusted accordingly. From a regulatory viewpoint, besides preserving blindness it is required that eventual consequences for the Type I error rate should be explained. We present analytical computations of the actual Type I error rate for the internal pilot study design with binary endpoints and compare them with the actual level of the chi‐square test for the fixed sample size design. A method is given that permits control of the specified significance level for the chi‐square test under blinded sample size recalculation. Furthermore, the properties of the procedure with respect to power and expected sample size are assessed. Throughout the paper, both the situation of equal sample size per group and unequal allocation ratio are considered. The method is illustrated with application to a clinical trial in depression. Copyright © 2004 John Wiley & Sons Ltd.     

Sample size calculation for recurrent events data in one‐arm studies

In some exceptional circumstances, as in very rare diseases, nonrandomized one‐arm trials are the sole source of evidence to demonstrate efficacy and safety of a new treatment. The design of such studies needs a sound methodological approach in order to provide reliable information, and the determination of the appropriate sample size still represents a critical step of this planning process. As, to our knowledge, no method exists for sample size calculation in one‐arm trials with a recurrent event endpoint, we propose here a closed sample size formula. It is derived assuming a mixed Poisson process, and it is based on the asymptotic distribution of the one‐sample robust nonparametric test recently developed for the analysis of recurrent events data. The validity of this formula in managing a situation with heterogeneity of event rates, both in time and between patients, and time‐varying treatment effect was demonstrated with exhaustive simulation studies. Moreover, although the method requires the specification of a process for events generation, it seems to be robust under erroneous definition of this process, provided that the number of events at the end of the study is similar to the one assumed in the planning phase. The motivating clinical context is represented by a nonrandomized one‐arm study on gene therapy in a very rare immunodeficiency in children (ADA‐SCID), where a major endpoint is the recurrence of severe infections. Copyright © 2012 John Wiley & Sons, Ltd.     

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.     

Sample size calculation for the one‐sample log‐rank test

In this paper, an exact variance of the one‐sample log‐rank test statistic is derived under the alternative hypothesis, and a sample size formula is proposed based on the derived exact variance. Simulation results showed that the proposed sample size formula provides adequate power to design a study to compare the survival of a single sample with that of a standard population. Copyright © 2014 John Wiley & Sons, Ltd.     

Sample size calculation for a proportional hazards mixture cure model with nonbinary covariates

Sample size calculation is a critical issue in clinical trials because a small sample size leads to a biased inference and a large sample size increases the cost. With the development of advanced medical technology, some patients can be cured of certain chronic diseases, and the proportional hazards mixture cure model has been developed to handle survival data with potential cure information. Given the needs of survival trials with potential cure proportions, a corresponding sample size formula based on the log-rank test statistic for binary covariates has been proposed by Wang et al. [25]. However, a sample size formula based on continuous variables has not been developed. Herein, we presented sample size and power calculations for the mixture cure model with continuous variables based on the log-rank method and further modified it by Ewell's method. The proposed approaches were evaluated using simulation studies for synthetic data from exponential and Weibull distributions. A program for calculating necessary sample size for continuous covariates in a mixture cure model was implemented in R.     

Sample size requirements for rare or abundant attribute sampling

Two approximation procedures to determine required sample size for a Fixed width binomial confidence interval are given and compared to exact calculations as well as the normal and Poisson approximations. The approximation procedures are found to be quite simple but very accurate for estimating sample sizes for either rare or abundant attributes.     

Sample size choice for reliability verification in strength-stress models

This paper discusses the choice of sample size for experiments concerned with inference on R = P(Y < X), where X and Y are normal variates, in an acceptance-sampling-theory framework. A conservative approach is derived, and the properties of this solution examined by simulation.     

Sample size re-estimation for survival data in clinical trials with an adaptive design

In clinical trials with survival data, investigators may wish to re-estimate the sample size based on the observed effect size while the trial is ongoing. Besides the inflation of the type-I error rate due to sample size re-estimation, the method for calculating the sample size in an interim analysis should be carefully considered because the data in each stage are mutually dependent in trials with survival data. Although the interim hazard estimate is commonly used to re-estimate the sample size, the estimate can sometimes be considerably higher or lower than the hypothesized hazard by chance. We propose an interim hazard ratio estimate that can be used to re-estimate the sample size under those circumstances. The proposed method was demonstrated through a simulation study and an actual clinical trial as an example. The effect of the shape parameter for the Weibull survival distribution on the sample size re-estimation is presented.     

Sample size planning for phase II trials based on success probabilities for phase III

In recent years, high failure rates in phase III trials were observed. One of the main reasons is overoptimistic assumptions for the planning of phase III resulting from limited phase II information and/or unawareness of realistic success probabilities. We present an approach for planning a phase II trial in a time‐to‐event setting that considers the whole phase II/III clinical development programme. We derive stopping boundaries after phase II that minimise the number of events under side conditions for the conditional probabilities of correct go/no‐go decision after phase II as well as the conditional success probabilities for phase III. In addition, we give general recommendations for the choice of phase II sample size. Our simulations show that unconditional probabilities of go/no‐go decision as well as the unconditional success probabilities for phase III are influenced by the number of events observed in phase II. However, choosing more than 150 events in phase II seems not necessary as the impact on these probabilities then becomes quite small. We recommend considering aspects like the number of compounds in phase II and the resources available when determining the sample size. The lower the number of compounds and the lower the resources are for phase III, the higher the investment for phase II should be. Copyright © 2015 John Wiley & Sons, Ltd.     

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.     

Tests for assessment of agreement using probability criteria

For the assessment of agreement using probability criteria, we obtain an exact test, and for sample sizes exceeding 30, we give a bootstrap-t$t$ test that is remarkably accurate. We show that for assessing agreement, the total deviation index approach of Lin [2000. Total deviation index for measuring individual agreement with applications in laboratory performance and bioequivalence. Statist. Med. 19, 255–270] is not consistent and may not preserve its asymptotic nominal level, and that the coverage probability approach of Lin et al. [2002. Statistical methods in assessing agreement: models, issues and tools. J. Amer. Statist. Assoc. 97, 257–270] is overly conservative for moderate sample sizes. We also show that the nearly unbiased test of Wang and Hwang [2001. A nearly unbiased test for individual bioequivalence problems using probability criteria. J. Statist. Plann. Inference 99, 41–58] may be liberal for large sample sizes, and suggest a minor modification that gives numerically equivalent approximation to the exact test for sample sizes 30 or less. We present a simple and accurate sample size formula for planning studies on assessing agreement, and illustrate our methodology with a real data set from the literature.     

Sample size determination for 2k-r experiments with a binomial response

This paper provides closed form expressions for the sample size for two-level factorial experiments when the response is the number of defectives. The sample sizes are obtained by approximating the two-sided test for no effect through tests for the mean of a normal distribution, and borrowing the classical sample size solution for that problem. The proposals are appraised relative to the exact sample sizes computed numerically, without appealing to any approximation to the binomial distribution, and the use of the sample size tables provided is illustrated through an example.     

Determination of hazard ratio for progression‐free survival considering the tumor assessment schedule in sample size calculation

Progression‐free survival is recognized as an important endpoint in oncology clinical trials. In clinical trials aimed at new drug development, the target population often comprises patients that are refractory to standard therapy with a tumor that shows rapid progression. This situation would increase the bias of the hazard ratio calculated for progression‐free survival, resulting in decreased power for such patients. Therefore, new measures are needed to prevent decreasing the power in advance when estimating the sample size. Here, I propose a novel calculation procedure to assume the hazard ratio for progression‐free survival using the Cox proportional hazards model, which can be applied in sample size calculation. The hazard ratios derived by the proposed procedure were almost identical to those obtained by simulation. The hazard ratio calculated by the proposed procedure is applicable to sample size calculation and coincides with the nominal power. Methods that compensate for the lack of power due to biases in the hazard ratio are also discussed from a practical point of view.     

Sample size calculations for clinical studies allowing for uncertainty about the variance

One of the most important steps in the design of a pharmaceutical clinical trial is the estimation of the sample size. For a superiority trial the sample size formula (to achieve a stated power) would be based on a given clinically meaningful difference and a value for the population variance. The formula is typically used as though this population variance is known whereas in reality it is unknown and is replaced by an estimate with its associated uncertainty. The variance estimate would be derived from an earlier similarly designed study (or an overall estimate from several previous studies) and its precision would depend on its degrees of freedom. This paper provides a solution for the calculation of sample sizes that allows for the imprecision in the estimate of the sample variance and shows how traditional formulae give sample sizes that are too small since they do not allow for this uncertainty with the deficiency being more acute with fewer degrees of freedom. It is recommended that the methodology described in this paper should be used when the sample variance has less than 200 degrees of freedom.     

Sample size allocation in multiregional equivalence studies

With the increasing globalization of drug development, the multiregional clinical trial (MRCT) has gained extensive use. The data from MRCTs could be accepted by regulatory authorities across regions and countries as the primary sources of evidence to support global marketing drug approval simultaneously. The MRCT can speed up patient enrollment and drug approval, and it makes the effective therapies available to patients all over the world simultaneously. However, there are many challenges both operationally and scientifically in conducting a drug development globally. One of many important questions to answer for the design of a multiregional study is how to partition sample size into each individual region. In this paper, two systematic approaches are proposed for the sample size allocation in a multiregional equivalence trial. A numerical evaluation and a biosimilar trial are used to illustrate the characteristics of the proposed approaches.     

A note on effective sample size for constructing confidence intervals for the difference of two proportions

Proportion differences are often used to estimate and test treatment effects in clinical trials with binary outcomes. In order to adjust for other covariates or intra-subject correlation among repeated measures, logistic regression or longitudinal data analysis models such as generalized estimating equation or generalized linear mixed models may be used for the analyses. However, these analysis models are often based on the logit link which results in parameter estimates and comparisons in the log-odds ratio scale rather than in the proportion difference scale. A two-step method is proposed in the literature to approximate the calculation of confidence intervals for the proportion difference using a concept of effective sample sizes. However, the performance of this two-step method has not been investigated in their paper. On this note, we examine the properties of the two-step method and propose an adjustment to the effective sample size formula based on Bayesian information theory. Simulations are conducted to evaluate the performance and to show that the modified effective sample size improves the coverage property of the confidence intervals.