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Pharmaceutical Statistics

Ruitao Lin, Guosheng Yin
Interval designs have recently attracted much attention in phase I clinical trials because of their simplicity and desirable finite-sample performance. However, existing interval designs typically cannot converge to the optimal dose level since their intervals do not shrink to the target toxicity probability as the sample size increases. The uniformly most powerful Bayesian test (UMPBT) is an objective Bayesian hypothesis testing procedure, which results in the largest probability that the Bayes factor against null hypothesis exceeds the evidence threshold for all possible values of the data generating parameter...
July 31, 2018: Pharmaceutical Statistics
Junjing Lin, Margaret Gamalo-Siebers, Ram Tiwari
Existing statutes in the United States and Europe require manufacturers to demonstrate evidence of effectiveness through the conduct of adequate and well-controlled studies to obtain marketing approval of a therapeutic product. What constitutes adequate and well-controlled studies is usually interpreted as randomized controlled trials (RCTs). However, these trials are sometimes unfeasible because of their size, duration, cost, patient preference, or in some cases, ethical concerns. For example, RCTs may not be fully powered in rare diseases or in infections caused by multidrug resistant pathogens because of the low number of enrollable patients...
July 31, 2018: Pharmaceutical Statistics
Kentaro Takeda, Kanji Komatsu, Satoshi Morita
The main purpose of a phase I dose-finding study in the field of oncology is to evaluate toxicity and pharmacokinetic (PK) data and to estimate the optimal dose (OD) for subsequent clinical trials. From a pharmacological perspective, PK information is considered as an appropriate indicator for evaluating the degree of drug intervention in humans. Dose proportionality is typically assessed to investigate the PK properties of a drug. If we rely solely on the dose-exposure relationship, then when this relationship is not proportional, eg, if there is saturation of drug elimination or absorption, the performance of OD selection may be affected...
July 31, 2018: Pharmaceutical Statistics
Shufang Liu, Chenghao Chu, Alan Rong
A cancer clinical trial with an immunotherapy often has 2 special features, which are patients being potentially cured from the cancer and the immunotherapy starting to take clinical effect after a certain delay time. Existing testing methods may be inadequate for immunotherapy clinical trials, because they do not appropriately take the 2 features into consideration at the same time, hence have low power to detect the true treatment effect. In this paper, we proposed a piece-wise proportional hazards cure rate model with a random delay time to fit data, and a new weighted log-rank test to detect the treatment effect of an immunotherapy over a chemotherapy control...
July 29, 2018: Pharmaceutical Statistics
Bohdana Ratitch, Ilya Lipkovich, Janelle Shannon Erickson, Lu Zhang, Craig H Mallinckrodt
This article focuses on 2 objectives in the analysis of efficacy in long-term extension studies of chronic diseases: (1) defining and discussing estimands of interest in such studies and (2) evaluating the performance of several multiple imputation methods that may be useful in estimating some of these estimands. Specifically, 4 estimands are defined and their clinical utility and inferential ramifications discussed. The performance of several multiple imputation methods and approaches were evaluated using simulated data...
July 26, 2018: Pharmaceutical Statistics
Divan Aristo Burger, Robert Schall, Ding-Geng Chen
Early phase 2 tuberculosis (TB) trials are conducted to characterize the early bactericidal activity (EBA) of anti-TB drugs. The EBA of anti-TB drugs has conventionally been calculated as the rate of decline in colony forming unit (CFU) count during the first 14 days of treatment. The measurement of CFU count, however, is expensive and prone to contamination. Alternatively to CFU count, time to positivity (TTP), which is a potential biomarker for long-term efficacy of anti-TB drugs, can be used to characterize EBA...
July 19, 2018: Pharmaceutical Statistics
Fabiola La Gamba, Tom Jacobs, Helena Geys, Luc Ver Donck, Christel Faes
Coadministration of 2 or more compounds can alter both the pharmacokinetics and pharmacodynamics of individual compounds. While experiments on pharmacodynamic drug-drug interactions are usually performed in an in vitro setting, this experiment focuses on an in vivo setting. The change over time of a safety biomarker is modeled using an indirect response model, in which the virtual pharmacokinetic profile of one compound drives the effect of the other. Several experiments at different dose level combinations were performed sequentially...
July 19, 2018: Pharmaceutical Statistics
Jonathan W Bartlett
Analyses of randomised trials are often based on regression models which adjust for baseline covariates, in addition to randomised group. Based on such models, one can obtain estimates of the marginal mean outcome for the population under assignment to each treatment, by averaging the model-based predictions across the empirical distribution of the baseline covariates in the trial. We identify under what conditions such estimates are consistent, and in particular show that for canonical generalised linear models, the resulting estimates are always consistent...
July 11, 2018: Pharmaceutical Statistics
Eisuke Hida, Toshiro Tango
A 3-arm trial design that includes an experimental treatment, an active reference treatment, and a placebo is useful for assessing the noninferiority of an experimental treatment. The inclusion of a placebo arm enables the assessment of assay sensitivity and internal validation, in addition to the testing of the noninferiority of the experimental treatment compared with the reference treatment. In 3-arm noninferiority trials, various statistical test procedures have been considered to evaluate the following 3 hypotheses: (i) superiority of the experimental treatment over the placebo, (ii) superiority of the reference treatment over the placebo, and (iii) noninferiority of the experimental treatment compared with the reference treatment...
July 9, 2018: Pharmaceutical Statistics
T Jaki, A Gordon, P Forster, L Bijnens, B Bornkamp, W Brannath, R Fontana, M Gasparini, L V Hampson, T Jacobs, B Jones, X Paoletti, M Posch, A Titman, R Vonk, F Koenig
This paper provides an overview of "Improving Design, Evaluation and Analysis of early drug development Studies" (IDEAS), a European Commission-funded network bringing together leading academic institutions and small- to large-sized pharmaceutical companies to train a cohort of graduate-level medical statisticians. The network is composed of a diverse mix of public and private sector partners spread across Europe, which will host 14 early-stage researchers for 36 months. IDEAS training activities are composed of a well-rounded mixture of specialist methodological components and generic transferable skills...
July 9, 2018: Pharmaceutical Statistics
Masahiko Gosho, Kazushi Maruo
Mixed-effects models for repeated measures (MMRM) analyses using the Kenward-Roger method for adjusting standard errors and degrees of freedom in an "unstructured" (UN) covariance structure are increasingly becoming common in primary analyses for group comparisons in longitudinal clinical trials. We evaluate the performance of an MMRM-UN analysis using the Kenward-Roger method when the variance of outcome between treatment groups is unequal. In addition, we provide alternative approaches for valid inferences in the MMRM analysis framework...
July 6, 2018: Pharmaceutical Statistics
Gaelle Saint-Hilary, Veronique Robert, Mauro Gasparini
Evidence-based quantitative methodologies have been proposed to inform decision-making in drug development, such as metrics to make go/no-go decisions or predictions of success, identified with statistical significance of future clinical trials. While these methodologies appropriately address some critical questions on the potential of a drug, they either consider the past evidence without predicting the outcome of the future trials or focus only on efficacy, failing to account for the multifaceted aspects of a successful drug development...
June 28, 2018: Pharmaceutical Statistics
Dalong Patrick Huang, Shan Xiao, Qianyu Dang, Yi Tsong
The revised ICH E14 Question and Answer (R3) document issued in December 2015 enables pharmaceutical companies to use concentration-QTc (C-QTc) modeling as the primary analysis for assessing QTc prolongation risk of new drugs. A new approach by including the time effect into the current C-QTc model is introduced. Through a simulation study, we evaluated performances of different C-QTc modeling with different dependent variables, covariates, and covariance structures. This simulation study shows that C-QTc models with ΔQTc being dependent variable without time effect inflate false negative rate and that fitting C-QTc models with different dependent variables, covariates, and covariance structures impacts the control of false negative and false positive rates...
June 28, 2018: Pharmaceutical Statistics
Jason J Z Liao, Ziji Yu, Yulan Li
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...
June 17, 2018: Pharmaceutical Statistics
Amy Cotterill, Thomas Jaki
Dose-escalation trials commonly assume a homogeneous trial population to identify a single recommended dose of the experimental treatment for use in future trials. Wrongly assuming a homogeneous population can lead to a diluted treatment effect. Equally, exclusion of a subgroup that could in fact benefit from the treatment can cause a beneficial treatment effect to be missed. Accounting for a potential subgroup effect (ie, difference in reaction to the treatment between subgroups) in dose-escalation can increase the chance of finding the treatment to be efficacious in a larger patient population...
June 13, 2018: Pharmaceutical Statistics
Beibei Guo, Daniel Li, Ying Yuan
Immunotherapy-treatments that enlist the immune system to battle tumors-has received widespread attention in cancer research. Due to its unique features and mechanisms for treating cancer, immunotherapy requires novel clinical trial designs. We propose a Bayesian seamless phase I/II randomized design for immunotherapy trials (SPIRIT) to find the optimal biological dose (OBD) defined in terms of the restricted mean survival time. We jointly model progression-free survival and the immune response. Progression-free survival is used as the primary endpoint to determine the OBD, and the immune response is used as an ancillary endpoint to quickly screen out futile doses...
June 7, 2018: Pharmaceutical Statistics
Brooke A Rabe, Simon Day, Mallorie H Fiero, Melanie L Bell
BACKGROUND: Non-inferiority (NI) and equivalence clinical trials test whether a new treatment is therapeutically no worse than, or equivalent to, an existing standard of care. Missing data in clinical trials have been shown to reduce statistical power and potentially bias estimates of effect size; however, in NI and equivalence trials, they present additional issues. For instance, they may decrease sensitivity to differences between treatment groups and bias toward the alternative hypothesis of NI (or equivalence)...
May 25, 2018: Pharmaceutical Statistics
Bruno Delafont, Kevin Carroll, Claire Vilain, Emmanuel Pham
The longitudinal data from 2 published clinical trials in adult subjects with upper limb spasticity (a randomized placebo-controlled study [NCT01313299] and its long-term open-label extension [NCT01313312]) were combined. Their study designs involved repeat intramuscular injections of abobotulinumtoxinA (Dysport®), and efficacy endpoints were collected accordingly. With the objective of characterizing the pattern of response across cycles, Mixed Model Repeated Measures analyses and Non-Linear Random Coefficient (NLRC) analyses were performed and their results compared...
May 20, 2018: Pharmaceutical Statistics
David Morgan
No abstract text is available yet for this article.
July 2018: Pharmaceutical Statistics
Kentaro Takeda, Masataka Taguri, Satoshi Morita
One of the main purposes of a phase I dose-finding trial in oncology is to identify an optimal dose (OD) that is both tolerable and has an indication of therapeutic benefit for subjects in subsequent phase II and III trials. Many phase I dose-finding methods based solely on toxicity considerations have been proposed under the assumption that both toxicity and efficacy monotonically increase with the dose level. Such an assumption may not be necessarily the case, however, when evaluating the OD for molecular targeted, cytostatic, and biological agents, as well as immune-oncology therapy...
July 2018: Pharmaceutical Statistics
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