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Pharmaceutical Statistics

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https://www.readbyqxmd.com/read/28691311/bayesian-adaptive-dose-escalation-designs-for-simultaneously-estimating-the-optimal-and-maximum-safe-dose-based-on-safety-and-efficacy
#1
Wai Yin Yeung, Bruno Reigner, Ulrich Beyer, Cheikh Diack, Daniel Sabanés Bové, Giuseppe Palermo, Thomas Jaki
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...
July 9, 2017: Pharmaceutical Statistics
https://www.readbyqxmd.com/read/28677272/bayesian-nonparametric-statistics-a-new-toolkit-for-discovery-in-cancer-research
#2
Peter F Thall, Peter Mueller, Yanxun Xu, Michele Guindani
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...
July 4, 2017: Pharmaceutical Statistics
https://www.readbyqxmd.com/read/28639426/equal-tailed-confidence-intervals-for-comparison-of-rates
#3
Peter J Laud
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...
June 22, 2017: Pharmaceutical Statistics
https://www.readbyqxmd.com/read/28631331/missing-data-in-clinical-trials-control-based-mean-imputation-and-sensitivity-analysis
#4
Devan V Mehrotra, Fang Liu, Thomas Permutt
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...
June 20, 2017: Pharmaceutical Statistics
https://www.readbyqxmd.com/read/28620937/testing-for-bioequivalence-of-highly-variable-drugs-from-tr-rt-crossover-designs-with-heterogeneous-residual-variances
#5
Qing Kang, Christopher I Vahl
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...
June 16, 2017: Pharmaceutical Statistics
https://www.readbyqxmd.com/read/28598541/the-time-dependent-cure-death-model-investigating-two-equally-important-endpoints-simultaneously-in-trials-treating-high-risk-patients-with-resistant-pathogens
#6
Harriet Sommer, Martin Wolkewitz, Martin Schumacher
A variety of primary endpoints are used in clinical trials treating patients with severe infectious diseases, and existing guidelines do not provide a consistent recommendation. We propose to study simultaneously two primary endpoints, cure and death, in a comprehensive multistate cure-death model as starting point for a treatment comparison. This technique enables us to study the temporal dynamic of the patient-relevant probability to be cured and alive. We describe and compare traditional and innovative methods suitable for a treatment comparison based on this model...
June 9, 2017: Pharmaceutical Statistics
https://www.readbyqxmd.com/read/28574202/adaptive-power-priors-with-empirical-bayes-for-clinical-trials
#7
Isaac Gravestock, Leonhard Held
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...
June 2, 2017: Pharmaceutical Statistics
https://www.readbyqxmd.com/read/28560815/covariate-adjusted-borrowing-of-historical-control-data-in-randomized-clinical-trials
#8
Baoguang Han, Jia Zhan, Z John Zhong, Dawei Liu, Stacy Lindborg
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, which can be appropriately addressed through statistical modeling...
May 31, 2017: Pharmaceutical Statistics
https://www.readbyqxmd.com/read/28544622/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
#9
Natalie Dimier, Susan Todd
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...
May 19, 2017: Pharmaceutical Statistics
https://www.readbyqxmd.com/read/28503861/estimates-of-subgroup-treatment-effects-in-overall-nonsignificant-trials-to-what-extent-should-we-believe-in-them
#10
Julien Tanniou, Ingeborg van der Tweel, Steven Teerenstra, Kit C B Roes
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...
May 15, 2017: Pharmaceutical Statistics
https://www.readbyqxmd.com/read/28474369/enhancement-of-the-adaptive-signature-design-for-learning-and-confirming-in-a-single-pivotal-trial
#11
Gu Mi
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...
May 5, 2017: Pharmaceutical Statistics
https://www.readbyqxmd.com/read/28470952/coping-with-missing-data-in-phase-iii-pivotal-registration-trials-tolvaptan-in-subjects-with-kidney-disease-a-case-study
#12
John Ouyang, Kevin J Carroll, Gary Koch, Junfang Li
Missing data cause challenging issues, particularly in phase III registration trials, as highlighted by the European Medicines Agency (EMA) and the US National Research Council. We explore, as a case study, how the issues from missing data were tackled in a double-blind phase III trial in subjects with autosomal dominant polycystic kidney disease. A total of 1445 subjects were randomized in a 2:1 ratio to receive active treatment (tolvaptan), or placebo. The primary outcome, the rate of change in total kidney volume, favored tolvaptan (P < ...
May 4, 2017: Pharmaceutical Statistics
https://www.readbyqxmd.com/read/28374497/enabling-robust-assessment-of-qtc-prolongation-in-early-phase-clinical-trials
#13
Devan V Mehrotra, Li Fan, Fang Liu, Kuenhi Tsai
Since the implementation of the International Conference on Harmonization (ICH) E14 guideline in 2005, regulators have required a "thorough QTc" (TQT) study for evaluating the effects of investigational drugs on delayed cardiac repolarization as manifested by a prolonged QTc interval. However, TQT studies have increasingly been viewed unfavorably because of their low cost effectiveness. Several researchers have noted that a robust drug concentration-QTc (conc-QTc) modeling assessment in early phase development should, in most cases, obviate the need for a subsequent TQT study...
May 2017: Pharmaceutical Statistics
https://www.readbyqxmd.com/read/28261972/balanced-covariates-with-response-adaptive-randomization
#14
Benjamin R Saville, Scott M Berry
Response adaptive randomization (RAR) methods for clinical trials are susceptible to imbalance in the distribution of influential covariates across treatment arms. This can make the interpretation of trial results difficult, because observed differences between treatment groups may be a function of the covariates and not necessarily because of the treatments themselves. We propose a method for balancing the distribution of covariate strata across treatment arms within RAR. The method uses odds ratios to modify global RAR probabilities to obtain stratum-specific modified RAR probabilities...
May 2017: Pharmaceutical Statistics
https://www.readbyqxmd.com/read/28251815/a-bayesian-sequential-design-with-binary-outcome
#15
Han Zhu, Qingzhao Yu, Donald E Mercante
Several researchers have proposed solutions to control type I error rate in sequential designs. The use of Bayesian sequential design becomes more common; however, these designs are subject to inflation of the type I error rate. We propose a Bayesian sequential design for binary outcome using an alpha-spending function to control the overall type I error rate. Algorithms are presented for calculating critical values and power for the proposed designs. We also propose a new stopping rule for futility. Sensitivity analysis is implemented for assessing the effects of varying the parameters of the prior distribution and maximum total sample size on critical values...
May 2017: Pharmaceutical Statistics
https://www.readbyqxmd.com/read/28230320/probability-of-success-for-phase-iii-after-exploratory-biomarker-analysis-in-phase-ii
#16
Heiko Götte, Marietta Kirchner, Martin Oliver Sailer
The probability of success or average power describes the potential of a future trial by weighting the power with a probability distribution of the treatment effect. The treatment effect estimate from a previous trial can be used to define such a distribution. During the development of targeted therapies, it is common practice to look for predictive biomarkers. The consequence is that the trial population for phase III is often selected on the basis of the most extreme result from phase II biomarker subgroup analyses...
May 2017: Pharmaceutical Statistics
https://www.readbyqxmd.com/read/27966248/misspecification-of-at-risk-periods-and-distributional-assumptions-in-estimating-copd-exacerbation-rates-the-resultant-bias-in-treatment-effect-estimation
#17
M Law, M J Sweeting, G C Donaldson, J A Wedzicha
In trials comparing the rate of chronic obstructive pulmonary disease exacerbation between treatment arms, the rate is typically calculated on the basis of the whole of each patient's follow-up period. However, the true time a patient is at risk should exclude periods in which an exacerbation episode is occurring, because a patient cannot be at risk of another exacerbation episode until recovered. We used data from two chronic obstructive pulmonary disease randomized controlled trials and compared treatment effect estimates and confidence intervals when using two different definitions of the at-risk period...
May 2017: Pharmaceutical Statistics
https://www.readbyqxmd.com/read/28448684/statistical-modeling-for-bayesian-extrapolation-of-adult-clinical-trial-information-in-pediatric-drug-evaluation
#18
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
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...
April 27, 2017: Pharmaceutical Statistics
https://www.readbyqxmd.com/read/28297160/addressing-potential-prior-data-conflict-when-using-informative-priors-in-proof-of-concept-studies
#19
Timothy Mutsvari, Dominique Tytgat, Rosalind Walley
No abstract text is available yet for this article.
March 2017: Pharmaceutical Statistics
https://www.readbyqxmd.com/read/28206702/statistical-issues-in-first-in-human-studies-on-bia-10-2474-neglected-comparison-of-protocol-against-practice
#20
Sheila M Bird, Rosemary A Bailey, Andrew P Grieve, Stephen Senn
By setting the regulatory-approved protocol for a suite of first-in-human studies on BIA 10-2474 against the subsequent French investigations, we highlight 6 key design and statistical issues, which reinforce recommendations by a Royal Statistical Society Working Party, which were made in the aftermath of cytokine release storm in 6 healthy volunteers in the United Kingdom in 2006. The 6 issues are dose determination, availability of pharmacokinetic results, dosing interval, stopping rules, appraisal by safety committee, and clear algorithm required if combining approvals for single and multiple ascending dose studies...
March 2017: Pharmaceutical Statistics
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