Critical appraisal of Bayesian dynamic borrowing from an imperfectly commensurate historical control

Bayesian dynamic borrowing designs facilitate borrowing information from historical studies. Historical data, when perfectly commensurate with current data, have been shown to reduce the trial duration and the sample size, while inflation in the type I error and reduction in the power have been reported, when imperfectly commensurate. These results, however, were obtained without considering that Bayesian designs are calibrated to meet regulatory requirements in practice and even no‐borrowing designs may use information from historical data in the calibration. The implicit borrowing of historical data suggests that imperfectly commensurate historical data may similarly impact no‐borrowing designs negatively. We will provide a fair appraiser of Bayesian dynamic borrowing and no‐borrowing designs. We used a published selective adaptive randomization design and real clinical trial setting and conducted simulation studies under varying degrees of imperfectly commensurate historical control scenarios. The type I error was inflated under the null scenario of no intervention effect, while larger inflation was noted with borrowing. The larger inflation in type I error under the null setting can be offset by the greater probability to stop early correctly under the alternative. Response rates were estimated more precisely and the average sample size was smaller with borrowing. The expected increase in bias with borrowing was noted, but was negligible. Using Bayesian dynamic borrowing designs may improve trial efficiency by stopping trials early correctly and reducing trial length at the small cost of inflated type I error.     

Leveraging historical data into oncology development programs: Two case studies of phase 2 Bayesian augmented control trial designs

Leveraging historical data into the design and analysis of phase 2 randomized controlled trials can improve efficiency of drug development programs. Such approaches can reduce sample size without loss of power. Potential issues arise when the current control arm is inconsistent with historical data, which may lead to biased estimates of treatment efficacy, loss of power, or inflated type 1 error. Consideration as to how to borrow historical information is important, and in particular, adjustment for prognostic factors should be considered. This paper will illustrate two motivating case studies of oncology Bayesian augmented control (BAC) trials. In the first example, a glioblastoma study, an informative prior was used for the control arm hazard rate. Sample size savings were 15% to 20% by using a BAC design. In the second example, a pancreatic cancer study, a hierarchical model borrowing method was used, which enabled the extent of borrowing to be determined by consistency of observed study data with historical studies. Supporting Bayesian analyses also adjusted for prognostic factors. Incorporating historical data via Bayesian trial design can provide sample size savings, reduce study duration, and enable a more scientific approach to development of novel therapies by avoiding excess recruitment to a control arm. Various sensitivity analyses are necessary to interpret results. Current industry efforts for data transparency have meaningful implications for access to patient‐level historical data, which, while not critical, is helpful to adjust for potential imbalances in prognostic factors.     

Incorporating historical two‐arm data in clinical trials with binary outcome: A practical approach

The feasibility of a new clinical trial may be increased by incorporating historical data of previous trials. In the particular case where only data from a single historical trial are available, there exists no clear recommendation in the literature regarding the most favorable approach. A main problem of the incorporation of historical data is the possible inflation of the type I error rate. A way to control this type of error is the so‐called power prior approach. This Bayesian method does not “borrow” the full historical information but uses a parameter 0 ≤ δ ≤ 1 to determine the amount of borrowed data. Based on the methodology of the power prior, we propose a frequentist framework that allows incorporation of historical data from both arms of two‐armed trials with binary outcome, while simultaneously controlling the type I error rate. It is shown that for any specific trial scenario a value δ > 0 can be determined such that the type I error rate falls below the prespecified significance level. The magnitude of this value of δ depends on the characteristics of the data observed in the historical trial. Conditionally on these characteristics, an increase in power as compared to a trial without borrowing may result. Similarly, we propose methods how the required sample size can be reduced. The results are discussed and compared to those obtained in a Bayesian framework. Application is illustrated by a clinical trial example.     

A novel equivalence probability weighted power prior for using historical control data in an adaptive clinical trial design: A comparison to standard methods

A standard two-arm randomised controlled trial usually compares an intervention to a control treatment with equal numbers of patients randomised to each treatment arm and only data from within the current trial are used to assess the treatment effect. Historical data are used when designing new trials and have recently been considered for use in the analysis when the required number of patients under a standard trial design cannot be achieved. Incorporating historical control data could lead to more efficient trials, reducing the number of controls required in the current study when the historical and current control data agree. However, when the data are inconsistent, there is potential for biased treatment effect estimates, inflated type I error and reduced power. We introduce two novel approaches for binary data which discount historical data based on the agreement with the current trial controls, an equivalence approach and an approach based on tail area probabilities. An adaptive design is used where the allocation ratio is adapted at the interim analysis, randomising fewer patients to control when there is agreement. The historical data are down-weighted in the analysis using the power prior approach with a fixed power. We compare operating characteristics of the proposed design to historical data methods in the literature: the modified power prior; commensurate prior; and robust mixture prior. The equivalence probability weight approach is intuitive and the operating characteristics can be calculated exactly. Furthermore, the equivalence bounds can be chosen to control the maximum possible inflation in type I error.     

Bayesian borrowing from historical control data in a vaccine efficacy trial

In the context of vaccine efficacy trial where the incidence rate is very low and a very large sample size is usually expected, incorporating historical data into a new trial is extremely attractive to reduce sample size and increase estimation precision. Nevertheless, for some infectious diseases, seasonal change in incidence rates poses a huge challenge in borrowing historical data and a critical question is how to properly take advantage of historical data borrowing with acceptable tolerance to between-trials heterogeneity commonly from seasonal disease transmission. In this article, we extend a probability-based power prior which determines the amount of information to be borrowed based on the agreement between the historical and current data, to make it applicable for either a single or multiple historical trials available, with constraint on the amount of historical information to be borrowed. Simulations are conducted to compare the performance of the proposed method with other methods including modified power prior (MPP), meta-analytic-predictive (MAP) prior and the commensurate prior methods. Furthermore, we illustrate the application of the proposed method for trial design in a practical setting.     

“Super-covariates”: Using predicted control group outcome as a covariate in randomized clinical trials

The power of randomized controlled clinical trials to demonstrate the efficacy of a drug compared with a control group depends not just on how efficacious the drug is, but also on the variation in patients' outcomes. Adjusting for prognostic covariates during trial analysis can reduce this variation. For this reason, the primary statistical analysis of a clinical trial is often based on regression models that besides terms for treatment and some further terms (e.g., stratification factors used in the randomization scheme of the trial) also includes a baseline (pre-treatment) assessment of the primary outcome. We suggest to include a “super-covariate”—that is, a patient-specific prediction of the control group outcome—as a further covariate (but not as an offset). We train a prognostic model or ensembles of such models on the individual patient (or aggregate) data of other studies in similar patients, but not the new trial under analysis. This has the potential to use historical data to increase the power of clinical trials and avoids the concern of type I error inflation with Bayesian approaches, but in contrast to them has a greater benefit for larger sample sizes. It is important for prognostic models behind “super-covariates” to generalize well across different patient populations in order to similarly reduce unexplained variability whether the trial(s) to develop the model are identical to the new trial or not. In an example in neovascular age-related macular degeneration we saw efficiency gains from the use of a “super-covariate”.     

Improving interim decisions in randomized trials by exploiting information on short‐term endpoints and prognostic baseline covariates

Conditional power calculations are frequently used to guide the decision whether or not to stop a trial for futility or to modify planned sample size. These ignore the information in short‐term endpoints and baseline covariates, and thereby do not make fully efficient use of the information in the data. We therefore propose an interim decision procedure based on the conditional power approach which exploits the information contained in baseline covariates and short‐term endpoints. We will realize this by considering the estimation of the treatment effect at the interim analysis as a missing data problem. This problem is addressed by employing specific prediction models for the long‐term endpoint which enable the incorporation of baseline covariates and multiple short‐term endpoints. We show that the proposed procedure leads to an efficiency gain and a reduced sample size, without compromising the Type I error rate of the procedure, even when the adopted prediction models are misspecified. In particular, implementing our proposal in the conditional power approach enables earlier decisions relative to standard approaches, whilst controlling the probability of an incorrect decision. This time gain results in a lower expected number of recruited patients in case of stopping for futility, such that fewer patients receive the futile regimen. We explain how these methods can be used in adaptive designs with unblinded sample size re‐assessment based on the inverse normal P‐value combination method to control Type I error. We support the proposal by Monte Carlo simulations based on data from a real clinical trial.     

Repeated‐measures models in the analysis of QT interval

Because of the recent regulatory emphasis on issues related to drug‐induced cardiac repolarization that can potentially lead to sudden death, QT interval analysis has received much attention in the clinical trial literature. The analysis of QT data is complicated by the fact that the QT interval is correlated with heart rate and other prognostic factors. Several attempts have been made in the literature to derive an optimal method for correcting the QT interval for heart rate; however the QT correction formulae obtained are not universal because of substantial variability observed across different patient populations. It is demonstrated in this paper that the widely used fixed QT correction formulae do not provide an adequate fit to QT and RR data and bias estimates of treatment effect. It is also shown that QT correction formulae derived from baseline data in clinical trials are likely to lead to Type I error rate inflation. This paper develops a QT interval analysis framework based on repeated‐measures models accomodating the correlation between QT interval and heart rate and the correlation among QT measurements collected over time. The proposed method of QT analysis controls the Type I error rate and is at least as powerful as traditional QT correction methods with respect to detecting drug‐related QT interval prolongation. Copyright © 2003 John Wiley & Sons, Ltd.     

A dynamic power prior for borrowing historical data in noninferiority trials with binary endpoint

Traditionally, noninferiority hypotheses have been tested using a frequentist method with a fixed margin. Given that information for the control group is often available from previous studies, it is interesting to consider a Bayesian approach in which information is “borrowed” for the control group to improve efficiency. However, construction of an appropriate informative prior can be challenging. In this paper, we consider a hybrid Bayesian approach for testing noninferiority hypotheses in studies with a binary endpoint. To account for heterogeneity between the historical information and the current trial for the control group, a dynamic P value–based power prior parameter is proposed to adjust the amount of information borrowed from the historical data. This approach extends the simple test‐then‐pool method to allow a continuous discounting power parameter. An adjusted α level is also proposed to better control the type I error. Simulations are conducted to investigate the performance of the proposed method and to make comparisons with other methods including test‐then‐pool and hierarchical modeling. The methods are illustrated with data from vaccine clinical trials.     

Sample sizes for trials involving multiple correlated must-win comparisons

In Clinical trials involving multiple comparisons of interest, the importance of controlling the trial Type I error is well-understood and well-documented. Moreover, when these comparisons are themselves correlated, methodologies exist for accounting for the correlation in the trial design, when calculating the trial significance levels. However, less well-documented is the fact that there are some circumstances where multiple comparisons affect the Type II error rather than the Type I error, and failure to account for this, can result in a reduction in the overall trial power. In this paper, we describe sample size calculations for clinical trials involving multiple correlated comparisons, where all the comparisons must be statistically significant for the trial to provide evidence of effect, and show how such calculations have to account for multiplicity in the Type II error. For the situation of two comparisons, we provide a result which assumes a bivariate Normal distribution. For the general case of two or more comparisons we provide a solution using inflation factors to increase the sample size relative to the case of a single outcome. We begin with a simple case of two comparisons assuming a bivariate Normal distribution, show how to factor in correlation between comparisons and then generalise our findings to situations with two or more comparisons. These methods are easy to apply, and we demonstrate how accounting for the multiplicity in the Type II error leads, at most, to modest increases in the sample size.     

Use of a historical control group in a noninferiority trial assessing a new antibacterial treatment: A case study and discussion of practical implementation aspects

When recruitment into a clinical trial is limited due to rarity of the disease of interest, or when recruitment to the control arm is limited due to ethical reasons (eg, pediatric studies or important unmet medical need), exploiting historical controls to augment the prospectively collected database can be an attractive option. Statistical methods for combining historical data with randomized data, while accounting for the incompatibility between the two, have been recently proposed and remain an active field of research. The current literature is lacking a rigorous comparison between methods but also guidelines about their use in practice. In this paper, we compare the existing methods based on a confirmatory phase III study design exercise done for a new antibacterial therapy with a binary endpoint and a single historical dataset. A procedure to assess the relative performance of the different methods for borrowing information from historical control data is proposed, and practical questions related to the selection and implementation of methods are discussed. Based on our examination, we found that the methods have a comparable performance, but we recommend the robust mixture prior for its ease of implementation.     

Type I error and power in trials with one interim futility analysis

Futility analysis reduces the opportunity to commit Type I error. For a superiority study testing a two‐sided hypothesis, an interim futility analysis can substantially reduce the overall Type I error while keeping the overall power relatively intact. In this paper, we quantify the extent of the reduction for both one‐sided and two‐sided futility analysis. We argue that, because of the reduction, we should be allowed to set the significance level for the final analysis at a level higher than the allowable Type I error rate for the study. We propose a method to find the significance level for the final analysis. We illustrate the proposed methodology and show that a design employing a futility analysis can reduce the sample size, and therefore reduce the exposure of patients to unnecessary risk and lower the cost of a clinical trial. Copyright © 2004 John Wiley & Sons, Ltd.     

Selecting the Optimal Transformation of a Continuous Covariate in Cox's Regression: Implications for Hypothesis Testing

ABSTRACT

Background: Many exposures in epidemiological studies have nonlinear effects and the problem is to choose an appropriate functional relationship between such exposures and the outcome. One common approach is to investigate several parametric transformations of the covariate of interest, and to select a posteriori the function that fits the data the best. However, such approach may result in an inflated Type I error. Methods: Through a simulation study, we generated data from Cox's models with different transformations of a single continuous covariate. We investigated the Type I error rate and the power of the likelihood ratio test (LRT) corresponding to three different procedures that considered the same set of parametric dose-response functions. The first unconditional approach did not involve any model selection, while the second conditional approach was based on a posteriori selection of the parametric function. The proposed third approach was similar to the second except that it used a corrected critical value for the LRT to ensure a correct Type I error. Results: The Type I error rate of the second approach was two times higher than the nominal size. For simple monotone dose-response, the corrected test had similar power as the unconditional approach, while for non monotone, dose-response, it had a higher power. A real-life application that focused on the effect of body mass index on the risk of coronary heart disease death, illustrated the advantage of the proposed approach. Conclusion: Our results confirm that a posteriori selecting the functional form of the dose-response induces a Type I error inflation. The corrected procedure, which can be applied in a wide range of situations, may provide a good trade-off between Type I error and power.     

Improving precision and power in randomized trials with a two-stage study design: Stratification using clustering method

In a randomized controlled trial (RCT), it is possible to improve precision and power and reduce sample size by appropriately adjusting for baseline covariates. There are multiple statistical methods to adjust for prognostic baseline covariates, such as an ANCOVA method. In this paper, we propose a clustering-based stratification method for adjusting for the prognostic baseline covariates. Clusters (strata) are formed only based on prognostic baseline covariates, not outcome data nor treatment assignment. Therefore, the clustering procedure can be completed prior to the availability of outcome data. The treatment effect is estimated in each cluster, and the overall treatment effect is derived by combining all cluster-specific treatment effect estimates. The proposed implementation of the procedure is described. Simulations studies and an example are presented.     

A Rank-Based Test for Comparison of Multidimensional Outcomes

For comparison of multiple outcomes commonly encountered in biomedical research, Huang et al. (2005) improved O'Brien's (1984) rank-sum tests through the replacement of the ad hoc variance by the asymptotic variance of the test statistics. The improved tests control the Type I error rate at the desired level and gain power when the differences between the two comparison groups in each outcome variable fall into the same direction. However, they may lose power when the differences are in different directions (e.g., some are positive and some are negative). These tests and the popular Bonferroni correction failed to show important significant difference when applied to compare heart rates from a clinical trial to evaluate the effect of a procedure to remove the cardioprotective solution HTK. We propose an alternative test statistic, taking the maximum of the individual rank-sum statistics, which controls the type I error and maintains satisfactory power regardless of the directions of the differences. Simulation studies show the proposed test to be of higher power than other tests in certain alternative parameter space of interest. Furthermore, when used to analyze the heart rates data the proposed test yields more satisfactory results.     

Goodness-of-fit tests for lifetime distributions based on Type II censored data

In this article, the general test statistic introduced by Alizadeh Noughabi and Balakrishnan [Goodness of fit using a new estimate of Kullback-Leibler information based on Type II censored data. IEEE Trans Reliab. 2015;64:627–635.] is applied for testing goodness of fit of lifetime distributions based on Type II censored data. The test statistic is constructed based on an estimate of Kullback–Leibler (KL) information. We investigate the properties of the proposed test statistic such as the test statistic is nonnegative, just like KL information. We apply this test statistic to following distributions: Exponential, Weibull, Log-normal and Pareto. The critical values and Type I error of the proposed tests are obtained. It is shown that the proposed tests have an excellent Type I error and hence can be used confidently in practice. Then, by Monte Carlo simulations, the power values of the proposed tests are computed against several alternatives and compared with those of the existing tests. Finally, some real-world reliability data are used for illustrative purpose.     

A Hybrid Geometric Phase II/III Clinical Trial Design based on Treatment Failure Time and Toxicity

The problem of comparing several experimental treatments to a standard arises frequently in medical research. Various multi-stage randomized phase II/III designs have been proposed that select one or more promising experimental treatments and compare them to the standard while controlling overall Type I and Type II error rates. This paper addresses phase II/III settings where the joint goals are to increase the average time to treatment failure and control the probability of toxicity while accounting for patient heterogeneity. We are motivated by the desire to construct a feasible design for a trial of four chemotherapy combinations for treating a family of rare pediatric brain tumors. We present a hybrid two-stage design based on two-dimensional treatment effect parameters. A targeted parameter set is constructed from elicited parameter pairs considered to be equally desirable. Bayesian regression models for failure time and the probability of toxicity as functions of treatment and prognostic covariates are used to define two-dimensional covariate-adjusted treatment effect parameter sets. Decisions at each stage of the trial are based on the ratio of posterior probabilities of the alternative and null covariate-adjusted parameter sets. Design parameters are chosen to minimize expected sample size subject to frequentist error constraints. The design is illustrated by application to the brain tumor trial.     

Comparing two independent incidence rates using conditional and unconditional exact tests

Several unconditional exact tests, which are constructed to control the Type I error rate at the nominal level, for comparing two independent Poisson rates are proposed and compared to the conditional exact test using a binomial distribution. The unconditional exact test using binomial p-value, likelihood ratio, or efficient score as the test statistic improves the power in general, and are therefore recommended. Unconditional exact tests using Wald statistics, whether on the original or square-root scale, may be substantially less powerful than the conditional exact test, and is not recommended. An example is provided from a cardiovascular trial.     

A fixed sequence Bonferroni procedure for testing multiple endpoints

A method for controlling the familywise error rate combining the Bonferroni adjustment and fixed testing sequence procedures is proposed. This procedure allots Type I error like the Bonferroni adjustment, but allows the Type I error to accumulate whenever a null hypothesis is rejected. In this manner, power for hypotheses tested later in a prespecified order will be increased. The order of the hypothesis tests needs to be prespecified as in a fixed sequence testing procedure, but unlike the fixed sequence testing procedure all hypotheses can always be tested, allowing for an a priori method of concluding a difference in the various endpoints. An application will be in clinical trials in which mortality is a concern, but it is expected that power to distinguish a difference in mortality will be low. If the effect on mortality is larger than anticipated, this method allows a test with a prespecified method of controlling the Type I error rate. Copyright © 2003 John Wiley & Sons, Ltd.