Issue Information
Abstract
No abstract is available for this article. (Source: Pharmaceutical Statistics)
Source: Pharmaceutical Statistics - May 11, 2017 Category: Statistics Tags: ISSUE INFORMATION Source Type: research
Bayesian adaptive dose ‐escalation designs for simultaneously estimating the optimal and maximum safe dose based on safety and efficacy
The main purpose of dose‐escalation trials is to identify the dose(s) that is/are safe and efficacious for further investigations in later studies. In this paper, we introduce dose‐escalation designs that incorporate both the dose‐limiting events and dose‐limiting toxicities (DLTs) and indicative responses of efficacy into the procedure. A flexible nonparametric model is used for modelling the continuous efficacy responses while a logistic model is used for the binary DLTs. Escalation decisions are based on the combination of the probabilities of DLTs and expected efficacy through a gain function. On the basis of t...
Source: Pharmaceutical Statistics - May 1, 2017 Category: Statistics Authors: Wai Yin Yeung, Bruno Reigner, Ulrich Beyer, Cheikh Diack, Daniel Saban és bové, Giuseppe Palermo, Thomas Jaki Tags: MAIN PAPER Source Type: research
Bayesian nonparametric statistics: A new toolkit for discovery in cancer research
Many commonly used statistical methods for data analysis or clinical trial design rely on incorrect assumptions or assume an over‐simplified framework that ignores important information. Such statistical practices may lead to incorrect conclusions about treatment effects or clinical trial designs that are impractical or that do not accurately reflect the investigator's goals. Bayesian nonparametric (BNP) models and methods are a very flexible new class of statistical tools that can overcome such limitations. This is because BNP models can accurately approximate any distribution or function and can accommodate a broad ran...
Source: Pharmaceutical Statistics - May 1, 2017 Category: Statistics Authors: Peter F. Thall, Peter Mueller, Yanxun Xu, Michele Guindani Tags: MAIN PAPER Source Type: research
Equal ‐tailed confidence intervals for comparison of rates
Several methods are available for generating confidence intervals for rate difference, rate ratio, or odds ratio, when comparing two independent binomial proportions or Poisson (exposure‐adjusted) incidence rates. Most methods have some degree of systematic bias in one‐sided coverage, so that a nominal 95% two‐sided interval cannot be assumed to have tail probabilities of 2.5% at each end, and any associated hypothesis test is at risk of inflated type I error rate. Skewness‐corrected asymptotic score methods have been shown to have superior equal‐tailed coverage properties for the binomial case. This paper compl...
Source: Pharmaceutical Statistics - May 1, 2017 Category: Statistics Authors: Peter J. Laud Tags: MAIN PAPER Source Type: research
Missing data in clinical trials: control ‐based mean imputation and sensitivity analysis
In some randomized (drug versus placebo) clinical trials, the estimand of interest is the between‐treatment difference in population means of a clinical endpoint that is free from the confounding effects of “rescue” medication (e.g., HbA1c change from baseline at 24 weeks that would be observed without rescue medication regardless of whether or when the assigned treatment was discontinued). In such settings, a missing data problem arises if some patients prematurely discontinue from the trial or initiate rescue medication while in the trial, the latter necessitating the discarding of post‐rescue data. We caution t...
Source: Pharmaceutical Statistics - May 1, 2017 Category: Statistics Authors: Devan V. Mehrotra, Fang Liu, Thomas Permutt Tags: MAIN PAPER Source Type: research
Testing for bioequivalence of highly variable drugs from TR ‐RT crossover designs with heterogeneous residual variances
Traditional bioavailability studies assess average bioequivalence (ABE) between the test (T) and reference (R) products under the crossover design with TR and RT sequences. With highly variable (HV) drugs whose intrasubject coefficient of variation in pharmacokinetic measures is 30% or greater, assertion of ABE becomes difficult due to the large sample sizes needed to achieve adequate power. In 2011, the FDA adopted a more relaxed, yet complex, ABE criterion and supplied a procedure to assess this criterion exclusively under TRR‐RTR‐RRT and TRTR‐RTRT designs. However, designs with more than 2 periods are not always f...
Source: Pharmaceutical Statistics - May 1, 2017 Category: Statistics Authors: Qing Kang, Christopher I. Vahl Tags: MAIN PAPER Source Type: research
The time ‐dependent “cure‐death” model investigating two equally important endpoints simultaneously in trials treating high‐risk patients with resistant pathogens
We describe and compare traditional and innovative methods suitable for a treatment comparison based on this model. Traditional analyses using risk differences focus on one prespecified timepoint only. A restricted logrank‐based test of treatment effect is sensitive to ordered categories of responses and integrates information on duration of response. The pseudo‐value regression provides a direct regression model for examination of treatment effect via difference in transition probabilities. Applied to a topical real data example and simulation scenarios, we demonstrate advantages and limitations and provide an insight...
Source: Pharmaceutical Statistics - May 1, 2017 Category: Statistics Authors: Harriet Sommer, Martin Wolkewitz, Martin Schumacher, Tags: MAIN PAPER Source Type: research
Adaptive power priors with empirical Bayes for clinical trials
Incorporating historical information into the design and analysis of a new clinical trial has been the subject of much discussion as a way to increase the feasibility of trials in situations where patients are difficult to recruit. The best method to include this data is not yet clear, especially in the case when few historical studies are available. This paper looks at the power prior technique afresh in a binomial setting and examines some previously unexamined properties, such as Box P values, bias, and coverage. Additionally, it proposes an empirical Bayes‐type approach to estimating the prior weight parameter by mar...
Source: Pharmaceutical Statistics - May 1, 2017 Category: Statistics Authors: Isaac Gravestock, Leonhard Held, Tags: MAIN PAPER Source Type: research
Covariate ‐adjusted borrowing of historical control data in randomized clinical trials
The borrowing of historical control data can be an efficient way to improve the treatment effect estimate of the current control group in a randomized clinical trial. When the historical and current control data are consistent, the borrowing of historical data can increase power and reduce Type I error rate. However, when these 2 sources of data are inconsistent, it may result in a combination of biased estimates, reduced power, and inflation of Type I error rate. In some situations, inconsistency between historical and current control data may be caused by a systematic variation in the measured baseline prognostic factors...
Source: Pharmaceutical Statistics - May 1, 2017 Category: Statistics Authors: Baoguang Han, Jia Zhan, Z. John Zhong, Dawei Liu, Stacy Lindborg Tags: MAIN PAPER Source Type: research
An investigation into the two ‐stage meta‐analytic copula modelling approach for evaluating time‐to‐event surrogate endpoints which comprise of one or more events of interest
Clinical trials of experimental treatments must be designed with primary endpoints that directly measure clinical benefit for patients. In many disease areas, the recognised gold standard primary endpoint can take many years to mature, leading to challenges in the conduct and quality of clinical studies. There is increasing interest in using shorter‐term surrogate endpoints as substitutes for costly long‐term clinical trial endpoints; such surrogates need to be selected according to biological plausibility, as well as the ability to reliably predict the unobserved treatment effect on the long‐term endpoint. A number ...
Source: Pharmaceutical Statistics - May 1, 2017 Category: Statistics Authors: Natalie Dimier, Susan Todd Tags: MAIN PAPER Source Type: research
Estimates of subgroup treatment effects in overall nonsignificant trials: To what extent should we believe in them?
In drug development, it sometimes occurs that a new drug does not demonstrate effectiveness for the full study population but appears to be beneficial in a relevant subgroup. In case the subgroup of interest was not part of a confirmatory testing strategy, the inflation of the overall type I error is substantial and therefore such a subgroup analysis finding can only be seen as exploratory at best. To support such exploratory findings, an appropriate replication of the subgroup finding should be undertaken in a new trial. We should, however, be reasonably confident in the observed treatment effect size to be able to use th...
Source: Pharmaceutical Statistics - May 1, 2017 Category: Statistics Authors: Julien Tanniou, Ingeborg Tweel, Steven Teerenstra, Kit C.B. Roes Tags: MAIN PAPER Source Type: research
Issue Information
Abstract
No abstract is available for this article. (Source: Pharmaceutical Statistics)
Source: Pharmaceutical Statistics - March 14, 2017 Category: Statistics Tags: ISSUE INFORMATION Source Type: research
Enhancement of the adaptive signature design for learning and confirming in a single pivotal trial
Because of the complexity of cancer biology, often the target pathway is not well understood at the time that phase III trials are initiated. A 2‐stage trial design was previously proposed for identifying a subgroup of interest in a learn stage, on the basis of 1 or more baseline biomarkers, and then subsequently confirming it in a confirmation stage. In this article, we discuss some practical aspects of this type of design and describe an enhancement to this approach that can be built into the study randomization to increase the robustness of the evaluation. Furthermore, we show via simulation studies how the proportion...
Source: Pharmaceutical Statistics - March 1, 2017 Category: Statistics Authors: Gu Mi Tags: MAIN PAPER Source Type: research
Coping with missing data in phase III pivotal registration trials: Tolvaptan in subjects with kidney disease, a case study
In conclusion, straightforward and transparent analyses directly taking into account missing data convincingly support the robustness of the preplanned analyses on the primary and secondary endpoints. Tolvaptan was confirmed to be effective in slowing total kidney volume growth, which is considered an efficacy endpoint by EMA, and in lessening the decline in renal function in patients with autosomal dominant polycystic kidney disease. (Source: Pharmaceutical Statistics)
Source: Pharmaceutical Statistics - March 1, 2017 Category: Statistics Authors: John Ouyang, Kevin J. Carroll, Gary Koch, Junfang Li Tags: MAIN PAPER Source Type: research
Statistical modeling for Bayesian extrapolation of adult clinical trial information in pediatric drug evaluation
Children represent a large underserved population of “therapeutic orphans,” as an estimated 80% of children are treated off‐label. However, pediatric drug development often faces substantial challenges, including economic, logistical, technical, and ethical barriers, among others. Among many efforts trying to remove these barriers, increased recent attention has been paid to extrapolation; that is, the leveraging of available data from adults or older age groups to draw conclusions for the pediatric population. The Bayesian statistical paradigm is natural in this setting, as it permits the combining (or “borrowing...
Source: Pharmaceutical Statistics - March 1, 2017 Category: Statistics Authors: Margaret Gamalo ‐Siebers, Jasmina Savic, Cynthia Basu, Xin Zhao, Mathangi Gopalakrishnan, Aijun Gao, Guochen Song, Simin Baygani, Laura Thompson, H. Amy Xia, Karen Price, Ram Tiwari, Bradley P. Carlin Tags: MAIN PAPER Source Type: research
