648 results match your criteria Pharmaceutical Statistics [Journal]


Equilibrium, affinity, dissociation constants, IC5O: Facts and fantasies.

Pharm Stat 2019 Apr 12. Epub 2019 Apr 12.

GIP Arronax, Saint-Herblain Cedex, France.

The interaction between ligands and receptors is often described in terms of 50% inhibitory concentrations (IC50). However, IC50 values do not accurately reflect the dissociation constants (Kd), and the domain of application and precision of proposed approximations for Kd estimation are unclear. The effect of affinity and of experimental conditions on the differences between IC50 and Kd has been assessed from exact mass action law calculations and from computer simulations. Read More

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http://dx.doi.org/10.1002/pst.1943DOI Listing

Assessing noninferiority: Evaluating efficacy of a new treatment without complete data.

Pharm Stat 2019 Apr 12. Epub 2019 Apr 12.

CFF-TDNCC, Seattle Children's Research Institute, Seattle, Washington.

The FDA released the final guidance on noninferiority trials in November 2016. In noninferiority trials, validity of the assessment of the efficacy of the test treatment depends on the control treatment's efficacy. Therefore, it is critically important that there be a reliable estimate of the control treatment effect-which is generally obtained from historical trials, and often assumed to hold in the current setting (the assay constancy assumption). Read More

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http://dx.doi.org/10.1002/pst.1946DOI Listing

A generalized Bayesian nonlinear mixed-effects regression model for zero-inflated longitudinal count data in tuberculosis trials.

Pharm Stat 2019 Apr 7. Epub 2019 Apr 7.

Department of Statistics, University of Pretoria, Pretoria, South Africa.

In this paper, we investigate Bayesian generalized nonlinear mixed-effects (NLME) regression models for zero-inflated longitudinal count data. The methodology is motivated by and applied to colony forming unit (CFU) counts in extended bactericidal activity tuberculosis (TB) trials. Furthermore, for model comparisons, we present a generalized method for calculating the marginal likelihoods required to determine Bayes factors. Read More

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http://dx.doi.org/10.1002/pst.1933DOI Listing
April 2019
2 Reads
1.102 Impact Factor

From waterfall plots to spaghetti plots in early oncology clinical development.

Pharm Stat 2019 Apr 3. Epub 2019 Apr 3.

Clinical Pharmacology, Roche Innovation Centre, Basel, Switzerland.

Waterfall plots are used to describe changes in tumor size observed in clinical studies. They are frequently used to illustrate the overall drug response in oncology clinical trials because of its simple representation of results. Unfortunately, this visual display suffers a number of limitations including (1) potential misguidance by masking the time dynamics of tumor size, (2) ambiguous labelling of the y-axis, and (3) low data-to-ink ratio. Read More

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https://onlinelibrary.wiley.com/doi/abs/10.1002/pst.1944
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http://dx.doi.org/10.1002/pst.1944DOI Listing
April 2019
7 Reads

Bayesian sequential integration within a preclinical pharmacokinetic and pharmacodynamic modeling framework: Lessons learned.

Pharm Stat 2019 Apr 1. Epub 2019 Apr 1.

Interuniversity Institute for Biostatistics and Statistical Bioinformatics, Hasselt University, Diepenbeek, Belgium.

The present manuscript aims to discuss the implications of sequential knowledge integration of small preclinical trials in a Bayesian pharmacokinetic and pharmacodynamic (PK-PD) framework. While, at first sight, a Bayesian PK-PD framework seems to be a natural framework to allow for sequential knowledge integration, the scope of this paper is to highlight some often-overlooked challenges while at the same time providing some guidances in the many and overwhelming choices that need to be made. Challenges as well as opportunities will be discussed that are related to the impact of (1) the prior specification, (2) the choice of random effects, (3) the type of sequential integration method. Read More

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http://dx.doi.org/10.1002/pst.1941DOI Listing

Multivariate two-sample permutation tests for trials with multiple time-to-event outcomes.

Pharm Stat 2019 Mar 26. Epub 2019 Mar 26.

Department of Statistics, Uppsala University, Uppsala, Sweden.

Clinical trials involving multiple time-to-event outcomes are increasingly common. In this paper, permutation tests for testing for group differences in multivariate time-to-event data are proposed. Unlike other two-sample tests for multivariate survival data, the proposed tests attain the nominal type I error rate. Read More

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http://dx.doi.org/10.1002/pst.1938DOI Listing

Statistical testing strategies for assessing treatment efficacy and marker accuracy in phase III trials.

Pharm Stat 2019 Mar 5. Epub 2019 Mar 5.

Department of Biostatistics, Nagoya University Graduate School of Medicine, Nagoya, Japan.

When a candidate predictive marker is available, but evidence on its predictive ability is not sufficiently reliable, all-comers trials with marker stratification are frequently conducted. We propose a framework for planning and evaluating prospective testing strategies in confirmatory, phase III marker-stratified clinical trials based on a natural assumption on heterogeneity of treatment effects across marker-defined subpopulations, where weak rather than strong control is permitted for multiple population tests. For phase III marker-stratified trials, it is expected that treatment efficacy is established in a particular patient population, possibly in a marker-defined subpopulation, and that the marker accuracy is assessed when the marker is used to restrict the indication or labelling of the treatment to a marker-based subpopulation, ie, assessment of the clinical validity of the marker. Read More

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http://dx.doi.org/10.1002/pst.1937DOI Listing

Milestone prediction for time-to-event endpoint monitoring in clinical trials.

Pharm Stat 2019 Feb 26. Epub 2019 Feb 26.

Department of Health Sciences Research, Mayo Clinic Cancer Center, Rochester, MN, USA.

Predicting the times of milestone events, ie, interim and final analyses in clinical trials, helps resource planning. This manuscript presents and compares several easily implemented methods for predicting when a milestone event is achieved. We show that it is beneficial to combine the predictions from different models to craft a better predictor through prediction synthesis. Read More

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http://dx.doi.org/10.1002/pst.1934DOI Listing
February 2019
1 Read

Estimation of drug effect in radiographic progression for rheumatoid arthritis and psoriatic arthritis.

Pharm Stat 2019 Feb 26. Epub 2019 Feb 26.

Statistical Methodology and Modeling Group, Janssen Research & Development, Spring House, Pennsylvania.

To demonstrate the treatment effect on structural damage in rheumatoid arthritis (RA) and psoriatic arthritis (PsA), radiographic images of hands and feet are scored according to Sharp scoring systems in randomized clinical trials. However, the quantification of such an effect is challenging because the overall mean progression is lack of clinical interpretation. This article attempts to shed a light on the statistical challenges resulted from its scoring methods and heterogeneity of the study population and proposes a mixture distribution model approach to fit radiographic progression data. Read More

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http://dx.doi.org/10.1002/pst.1936DOI Listing
February 2019
2 Reads

Design of experiments and the virtual PCR simulator: An online game for pharmaceutical scientists and biotechnologists.

Pharm Stat 2019 Feb 21. Epub 2019 Feb 21.

School of Natural and Environmental Sciences, Newcastle University, Newcastle upon Tyne, UK.

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http://dx.doi.org/10.1002/pst.1932DOI Listing
February 2019
1 Read

Hazard ratio inference in stratified clinical trials with time-to-event endpoints and limited sample size.

Pharm Stat 2019 Jan 31. Epub 2019 Jan 31.

Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania, Philadelphia, Pennsylvania.

The stratified Cox model is commonly used for stratified clinical trials with time-to-event endpoints. The estimated log hazard ratio is approximately a weighted average of corresponding stratum-specific Cox model estimates using inverse-variance weights; the latter are optimal only under the (often implausible) assumption of a constant hazard ratio across strata. Focusing on trials with limited sample sizes (50-200 subjects per treatment), we propose an alternative approach in which stratum-specific estimates are obtained using a refined generalized logrank (RGLR) approach and then combined using either sample size or minimum risk weights for overall inference. Read More

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http://dx.doi.org/10.1002/pst.1928DOI Listing
January 2019

Statistical considerations in a delayed-start design to demonstrate disease modification effect in neurodegenerative disorders.

Pharm Stat 2019 Jan 29. Epub 2019 Jan 29.

Department of Biostatistics, The University of North Carolina, Chapel Hill, North Carolina, USA.

There has been a paradigm shift in diagnostic conceptualization of Alzheimer's disease (AD) based on the current evidence suggesting that structure and biology changes start to occur before clinical symptoms emerge. Consequently, therapeutic drug development is also shifting to treat early AD patients using biomarkers for enrichment in clinical trials. A similar paradigm shift is occurring for Parkinson disease. Read More

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http://dx.doi.org/10.1002/pst.1931DOI Listing
January 2019

Tests for noninferiority trials with binomial endpoints: A guide to modern and quasi-exact methods for biomedical researchers.

Pharm Stat 2019 Jan 28. Epub 2019 Jan 28.

Melbourne Business School, The University of Melbourne, Melbourne, Australia.

Applied statisticians and pharmaceutical researchers are frequently involved in the design and analysis of clinical trials where at least one of the outcomes is binary. Treatments are judged by the probability of a positive binary response. A typical example is the noninferiority trial, where it is tested whether a new experimental treatment is practically not inferior to an active comparator with a prespecified margin δ. Read More

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http://dx.doi.org/10.1002/pst.1929DOI Listing
January 2019
1 Read

Assessment of individual bioequivalence using sufficient bootstrap procedure.

Authors:
Ufuk Beyaztas

Pharm Stat 2019 Jan 20. Epub 2019 Jan 20.

Department of Statistics, Bartin University, Bartin, Turkey.

This paper proposes a sufficient bootstrap method, which uses only the unique observations in the resamples, to assess the individual bioequivalence under 2 × 4 randomized crossover design. The finite sample performance of the proposed method is illustrated by extensive Monte Carlo simulations as well as a real-experimental data set, and the results are compared with those obtained by the traditional bootstrap technique. Our records reveal that the proposed method is a good competitor or even better than the classical percentile bootstrap confidence limits. Read More

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http://doi.wiley.com/10.1002/pst.1930
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http://dx.doi.org/10.1002/pst.1930DOI Listing
January 2019
6 Reads

Blinded sample size reestimation in event-driven clinical trials: Methods and an application in multiple sclerosis.

Pharm Stat 2019 Jan 16. Epub 2019 Jan 16.

Statistical Methodology, Novartis Pharma AG, Basel, Switzerland.

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http://doi.wiley.com/10.1002/pst.1927
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http://dx.doi.org/10.1002/pst.1927DOI Listing
January 2019
2 Reads

Nested combination tests with a time-to-event endpoint using a short-term endpoint for design adaptations.

Pharm Stat 2019 Jan 16. Epub 2019 Jan 16.

Center for Medical Statistics, Informatics, and Intelligent Systems, Medical University of Vienna, Vienna, Austria.

Adaptive trial methodology for multiarmed trials and enrichment designs has been extensively discussed in the past. A general principle to construct test procedures that control the family-wise Type I error rate in the strong sense is based on combination tests within a closed test. Using survival data, a problem arises when using information of patients for adaptive decision making, which are under risk at interim. Read More

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http://dx.doi.org/10.1002/pst.1926DOI Listing
January 2019
2 Reads

A comparative study of confidence intervals to assess biosimilarity from analytical data.

Pharm Stat 2019 Jan 15. Epub 2019 Jan 15.

Pfizer, Inc., Global Biometrics & Data Management Peapack, NJ, USA.

Assessment of analytical similarity of tier 1 quality attributes is based on a set of hypotheses that tests the mean difference of reference and test products against a margin adjusted for standard deviation of the reference product. Thus, proper assessment of the biosimilarity hypothesis requires statistical tests that account for the uncertainty associated with the estimations of the mean differences and the standard deviation of the reference product. Recently, a linear reformulation of the biosimilarity hypothesis has been proposed, which facilitates development and implementation of statistical tests. Read More

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http://dx.doi.org/10.1002/pst.1925DOI Listing
January 2019
4 Reads

Study design aspects and inter-subject variability in longitudinal clinical phase II dose-finding trials.

Pharm Stat 2019 03 8;18(2):248-259. Epub 2019 Jan 8.

Department of Biostatistics, Grunenthal GmbH, Grunenthal Innovations, Aachen, Germany.

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http://dx.doi.org/10.1002/pst.1921DOI Listing
March 2019
2 Reads

Properties of the weighted log-rank test in the design of confirmatory studies with delayed effects.

Pharm Stat 2018 Dec 27. Epub 2018 Dec 27.

Novartis Pharma A.G., Basel, Switzerland.

Proportional hazards are a common assumption when designing confirmatory clinical trials in oncology. This assumption not only affects the analysis part but also the sample size calculation. The presence of delayed effects causes a change in the hazard ratio while the trial is ongoing since at the beginning we do not observe any difference between treatment arms, and after some unknown time point, the differences between treatment arms will start to appear. Read More

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http://dx.doi.org/10.1002/pst.1923DOI Listing
December 2018
1 Read

Subgroup analysis and interpretation for phase 3 confirmatory trials: White paper of the EFSPI/PSI working group on subgroup analysis.

Pharm Stat 2019 03 27;18(2):126-139. Epub 2018 Dec 27.

Director of Software Solutions, Berry Consultants, Oxford, UK.

Subgroup by treatment interaction assessments are routinely performed when analysing clinical trials and are particularly important for phase 3 trials where the results may affect regulatory labelling. Interpretation of such interactions is particularly difficult, as on one hand the subgroup finding can be due to chance, but equally such analyses are known to have a low chance of detecting differential treatment effects across subgroup levels, so may overlook important differences in therapeutic efficacy. EMA have therefore issued draft guidance on the use of subgroup analyses in this setting. Read More

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http://dx.doi.org/10.1002/pst.1919DOI Listing
March 2019
1 Read

Investigation of the properties of the "switching decision rule" described in the Japanese guideline for human bioequivalence studies.

Authors:
Yoichi Ii

Pharm Stat 2019 03 26;18(2):260-273. Epub 2018 Dec 26.

Pfizer Japan, Inc., Tokyo, Japan.

In a human bioequivalence (BE) study, the conclusion of BE is usually based on the ratio of geometric means of pharmacokinetic parameters between a test and a reference products. The "Guideline for Bioequivalence Studies of Generic Products" (2012) issued by the Japanese health authority and other similar guidelines across the world require a 90% confidence interval (CI) of the ratio to fall entirely within the range of 0.8 to 1. Read More

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http://dx.doi.org/10.1002/pst.1922DOI Listing
March 2019
3 Reads

Assessing the predictive value of a binary surrogate for a binary true endpoint based on the minimum probability of a prediction error.

Pharm Stat 2018 Dec 21. Epub 2018 Dec 21.

I-BioStat, KU Leuven, Belgium.

The individual causal association (ICA) has recently been introduced as a metric of surrogacy in a causal-inference framework. The ICA is defined on the unit interval and quantifies the association between the individual causal effect on the surrogate (ΔS) and true (ΔT) endpoint. In addition, the ICA offers a general assessment of the surrogate predictive value, taking value 1 when there is a deterministic relationship between ΔT and ΔS, and value 0 when both causal effects are independent. Read More

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http://dx.doi.org/10.1002/pst.1924DOI Listing
December 2018
2 Reads

On weighted composite scores for early Alzheimer's trials.

Pharm Stat 2019 03 18;18(2):239-247. Epub 2018 Dec 18.

Division of Neurology Products, CDER, FDA.

Recent research on finding appropriate composite endpoints for preclinical Alzheimer's disease has focused considerable effort on finding "optimized" weights in the construction of a weighted composite score. In this paper, several proposed methods are reviewed. Our results indicate no evidence that these methods will increase the power of the test statistics, and some of these weights will introduce biases to the study. Read More

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http://dx.doi.org/10.1002/pst.1920DOI Listing
March 2019
3 Reads

Propensity-score-based priors for Bayesian augmented control design.

Pharm Stat 2019 03 9;18(2):223-238. Epub 2018 Dec 9.

Division of Biostatistics, Center for Devices and Radiological Health, Food, and Drug Administration, Silver Spring, Maryland, USA.

Drug developers are required to demonstrate substantial evidence of effectiveness through the conduct of adequate and well-controlled (A&WC) studies to obtain marketing approval of their medicine. What constitutes A&WC is interpreted as the conduct of randomized controlled trials (RCTs). However, these trials are sometimes unfeasible because of their size, duration, and cost. Read More

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https://onlinelibrary.wiley.com/doi/abs/10.1002/pst.1918
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http://dx.doi.org/10.1002/pst.1918DOI Listing
March 2019
13 Reads

Treatment effect quantification for time-to-event endpoints-Estimands, analysis strategies, and beyond.

Authors:
Kaspar Rufibach

Pharm Stat 2019 03 26;18(2):145-165. Epub 2018 Nov 26.

Methods, Collaboration, and Outreach Group (MCO), Department of Biostatistics, Hoffmann-La Roche Ltd, Basel, Switzerland.

A draft addendum to ICH E9 has been released for public consultation in August 2017. The addendum focuses on two topics particularly relevant for randomized confirmatory clinical trials: estimands and sensitivity analyses. The need to amend ICH E9 grew out of the realization of a lack of alignment between the objectives of a clinical trial stated in the protocol and the accompanying quantification of the "treatment effect" reported in a regulatory submission. Read More

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http://dx.doi.org/10.1002/pst.1917DOI Listing
March 2019
3 Reads

Phase II trial design with growth modulation index as the primary endpoint.

Pharm Stat 2019 03 20;18(2):212-222. Epub 2018 Nov 20.

Markey Cancer Center, University of Kentucky, Lexington, Kentucky.

Molecularly targeted, genomic-driven, and immunotherapy-based clinical trials continue to be advanced for the treatment of relapse or refractory cancer patients, where the growth modulation index (GMI) is often considered a primary endpoint of treatment efficacy. However, there little literature is available that considers the trial design with GMI as the primary endpoint. In this article, we derived a sample size formula for the score test under a log-linear model of the GMI. Read More

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http://doi.wiley.com/10.1002/pst.1916
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http://dx.doi.org/10.1002/pst.1916DOI Listing
March 2019
28 Reads

On estimands and the analysis of adverse events in the presence of varying follow-up times within the benefit assessment of therapies.

Pharm Stat 2019 03 20;18(2):166-183. Epub 2018 Nov 20.

Department of Medical Statistics, University Medical Center Goettingen, Goettingen, Germany.

The analysis of adverse events (AEs) is a key component in the assessment of a drug's safety profile. Inappropriate analysis methods may result in misleading conclusions about a therapy's safety and consequently its benefit-risk ratio. The statistical analysis of AEs is complicated by the fact that the follow-up times can vary between the patients included in a clinical trial. Read More

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http://dx.doi.org/10.1002/pst.1915DOI Listing
March 2019
2 Reads

Bayesian sample size determination for phase IIA clinical trials using historical data and semi-parametric prior's elicitation.

Pharm Stat 2019 03 15;18(2):198-211. Epub 2018 Nov 15.

Department of Cardiac, Thoracic and Vascular Sciences, University of Padova, Padova, Italy.

The Simon's two-stage design is the most commonly applied among multi-stage designs in phase IIA clinical trials. It combines the sample sizes at the two stages in order to minimize either the expected or the maximum sample size. When the uncertainty about pre-trial beliefs on the expected or desired response rate is high, a Bayesian alternative should be considered since it allows to deal with the entire distribution of the parameter of interest in a more natural way. Read More

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http://dx.doi.org/10.1002/pst.1914DOI Listing
March 2019
16 Reads

A simple test for the treatment effect in clinical trials with a sequential parallel comparison design and negative binomial outcomes.

Pharm Stat 2019 03 8;18(2):184-197. Epub 2018 Nov 8.

Department of Biostatistics, Hyogo College of Medicine, Nishinomiya, Japan.

In placebo-controlled, double-blinded, randomized clinical trials, the presence of placebo responders reduces the effect size for comparison of the active drug group with the placebo group. An attempt to resolve this problem is to use the sequential parallel comparison design (SPCD). Although there are SPCDs with dichotomous or continuous outcomes, an SPCD with negative binomial outcomes-with which investigators deal eg, in clinical trials involving multiple sclerosis, where the investigators are still concerned about the presence of placebo responders-has not yet been discussed. Read More

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http://dx.doi.org/10.1002/pst.1913DOI Listing
March 2019
1 Read

Calculation of confidence intervals for a finite population size.

Authors:
Steven A Julious

Pharm Stat 2019 01 8;18(1):115-122. Epub 2018 Nov 8.

Medical Statistics Group, School of Health and Related Research (ScHARR), University of Sheffield, Sheffield, S1 4DA, UK.

For any estimate of response, confidence intervals are important as they help quantify a plausible range of values for the population response. However, there may be instances in clinical research when the population size is finite, but we wish to take a sample from the population and make inference from this sample. Instances where you can have a fixed population size include when undertaking a clinical audit of patient records or in a clinical trial a researcher could be checking for transcription errors against patient notes. Read More

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http://doi.wiley.com/10.1002/pst.1901
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http://dx.doi.org/10.1002/pst.1901DOI Listing
January 2019
7 Reads

Treatment policy estimands for recurrent event data using data collected after cessation of randomised treatment.

Pharm Stat 2019 01 8;18(1):85-95. Epub 2018 Nov 8.

GlaxoSmithKline Research and Development, Middlesex, UK.

In the past, many clinical trials have withdrawn subjects from the study when they prematurely stopped their randomised treatment and have therefore only collected 'on-treatment' data. Thus, analyses addressing a treatment policy estimand have been restricted to imputing missing data under assumptions drawn from these data only. Many confirmatory trials are now continuing to collect data from subjects in a study even after they have prematurely discontinued study treatment as this event is irrelevant for the purposes of a treatment policy estimand. Read More

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http://dx.doi.org/10.1002/pst.1910DOI Listing
January 2019
2 Reads

How can we make better graphs? An initiative to increase the graphical expertise and productivity of quantitative scientists.

Pharm Stat 2019 01 31;18(1):106-114. Epub 2018 Oct 31.

Biostatistical Sciences and Pharmacometrics, Novartis Pharma AG, Basel, Switzerland.

Graphics are at the core of exploring and understanding data, communicating results and conclusions, and supporting decision-making. Increasing our graphical expertise can significantly strengthen our impact as professional statisticians and quantitative scientists. In this article, we present a concerted effort to improve the way we create graphics at Novartis. Read More

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http://dx.doi.org/10.1002/pst.1912DOI Listing
January 2019
9 Reads
1.102 Impact Factor

Strategies for composite estimands in confirmatory clinical trials: Examples from trials in nasal polyps and steroid reduction.

Authors:
Oliver N Keene

Pharm Stat 2019 01 29;18(1):78-84. Epub 2018 Oct 29.

GlaxoSmithKline Research and Development, Middlesex, UK.

The draft addendum to the ICH E9 regulatory guideline asks for explicit definition of the treatment effect to be estimated in clinical trials. The draft guideline also introduces the concept of intercurrent events to describe events that occur post-randomisation that may affect efficacy assessment. Composite estimands allow incorporation of intercurrent events in the definition of the endpoint. Read More

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http://doi.wiley.com/10.1002/pst.1909
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http://dx.doi.org/10.1002/pst.1909DOI Listing
January 2019
16 Reads

Controlling type 1 error rate for sequential, bioequivalence studies with crossover designs.

Pharm Stat 2019 01 29;18(1):96-105. Epub 2018 Oct 29.

University of North Carolina, Chapel Hill, North Carolina.

Sample size reestimation in a crossover, bioequivalence study can be a useful adaptive design tool, particularly when the intrasubject variability of the drug formulation under investigation is not well understood. When sample size reestimation is done based on an interim estimate of the intrasubject variability and bioequivalence is tested using the pooled estimate of intrasubject variability, type 1 error inflation will occur. Type 1 error inflation is caused by the pooled estimate being a biased estimator of the intrasubject variability. Read More

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http://dx.doi.org/10.1002/pst.1911DOI Listing
January 2019
2 Reads

Lessons from meta-analyses of randomized clinical trials for analysis of distributed networks of observational databases.

Pharm Stat 2019 01 25;18(1):65-77. Epub 2018 Oct 25.

Novartis Pharma AG, Basel, Switzerland.

Networks of constellations of longitudinal observational databases, often electronic medical records or transactional insurance claims or both, are increasingly being used for studying the effects of medicinal products in real-world use. Such databases are frequently configured as distributed networks. That is, patient-level data are kept behind firewalls and not communicated outside of the data vendor other than in aggregate form. Read More

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http://doi.wiley.com/10.1002/pst.1908
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http://dx.doi.org/10.1002/pst.1908DOI Listing
January 2019
2 Reads

Blinded continuous monitoring in clinical trials with recurrent event endpoints.

Pharm Stat 2019 01 21;18(1):54-64. Epub 2018 Oct 21.

Statistical Methodology, Novartis Pharma AG, Basel, Switzerland.

In studies with recurrent event endpoints, misspecified assumptions of event rates or dispersion can lead to underpowered trials or overexposure of patients. Specification of overdispersion is often a particular problem as it is usually not reported in clinical trial publications. Changing event rates over the years have been described for some diseases, adding to the uncertainty in planning. Read More

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http://doi.wiley.com/10.1002/pst.1907
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http://dx.doi.org/10.1002/pst.1907DOI Listing
January 2019
19 Reads

Applications of Bayesian statistical methodology to clinical trial design: A case study of a phase 2 trial with an interim futility assessment in patients with knee osteoarthritis.

Pharm Stat 2019 01 15;18(1):39-53. Epub 2018 Oct 15.

Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.

Development of new pharmacological treatments for osteoarthritis that address unmet medical needs in a competitive market place is challenging. Bayesian approaches to trial design offer advantages in defining treatment benefits by addressing clinically relevant magnitude of effects relative to comparators and in optimizing efficiency in analysis. Such advantages are illustrated by a motivating case study, a proof of concept, and dose finding study in patients with osteoarthritis. Read More

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http://dx.doi.org/10.1002/pst.1906DOI Listing
January 2019
4 Reads

Understanding the influence of individual variables contributing to multivariate outliers in assessments of data quality.

Pharm Stat 2018 11 26;17(6):846-853. Epub 2018 Sep 26.

JMP Division, SAS Institute, Cary, NC, USA.

Mahalanobis distance is often recommended to identify patients or clinical sites that are considered unusual in clinical trials. Patients extreme in one or more covariates may be considered outliers in that they reside some distance from the multivariate mean, which can be thought of as the center of the data cloud. Less often discussed, patients whose data are believed to be "too good to be true" are located near the centroid as inliers. Read More

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http://dx.doi.org/10.1002/pst.1903DOI Listing
November 2018
1 Read

A statistical method to convert published response rates into marginal distributions with an example application in psoriasis.

Pharm Stat 2019 01 26;18(1):4-21. Epub 2018 Sep 26.

Eli Lilly and Company, Indianapolis, IN, USA.

Assessment of severity is essential for the management of chronic diseases. Continuous variables like scores obtained from the Hamilton Rating Scale for Depression or the Psoriasis Area and Severity Index (PASI) are standard measures used in clinical trials of depression and psoriasis. In clinical trials of psoriasis, for example, the reduction of PASI from baseline in response to therapy, in particular the proportion of patients achieving at least 75%, 90%, or 100% improvement of disease (PASI 75, PASI 90, or PASI 100), is typically used to evaluate treatment efficacy. Read More

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http://dx.doi.org/10.1002/pst.1904DOI Listing
January 2019
2 Reads

Application of Bayesian analyses to doubly randomized delayed start, matched control designs to demonstrate disease modification.

Pharm Stat 2019 01 16;18(1):22-38. Epub 2018 Sep 16.

Janssen Scientific Affairs, LLC, Titusville, New Jersey.

Disease modification is a primary therapeutic aim when developing treatments for most chronic progressive diseases. The best treatments do not simply affect disease symptoms but fundamentally improve disease course by slowing, halting, or reversing disease progression. One of many challenges for establishing disease modification relates to the identification of adequate analytic tools to show differences in a disease course following intervention. Read More

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http://dx.doi.org/10.1002/pst.1905DOI Listing
January 2019
1 Read

A case study of an adaptive design for a clinical trial with 2 doses and 2 endpoints in a rare disease area.

Pharm Stat 2018 11 16;17(6):797-810. Epub 2018 Sep 16.

Biostatistics and Programming, Sanofi, Bridgewater, NJ, USA.

Patient recruitment is challenging in rare disease clinical trials. To save time and resources, an inferential seamless phase II/III clinical trial design is considered for a clinical trial in a rare disease area. In particular, 2 doses compared to a placebo control are evaluated at phase II (ie, stage I). Read More

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http://dx.doi.org/10.1002/pst.1902DOI Listing
November 2018
1 Read
1.102 Impact Factor

A practical guide to pre-trial simulations for Bayesian adaptive trials using SAS and BUGS.

Pharm Stat 2018 11 14;17(6):854-865. Epub 2018 Sep 14.

Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK.

It is often unclear what specific adaptive trial design features lead to an efficient design which is also feasible to implement. Before deciding on a particular design, it is generally advisable to carry out a simulation study to characterise the properties of candidate designs under a range of plausible assumptions. The implementation of such pre-trial simulation studies presents many challenges and requires considerable statistical programming effort and time. Read More

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http://doi.wiley.com/10.1002/pst.1897
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http://dx.doi.org/10.1002/pst.1897DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6283249PMC
November 2018
10 Reads

Bayesian detection of potential risk using inference on blinded safety data.

Pharm Stat 2018 11 30;17(6):823-834. Epub 2018 Aug 30.

AbbVie Inc., North Chicago, IL, USA.

Safety surveillance is a critical issue for ongoing clinical trials to actively identify and evaluate important safety information. With the new regulatory emphasis on aggregate review of safety, sponsors are faced with the challenge to develop systematic and sound quantitative methods to assess risk from blinded safety data during the pre-approval period of a new therapy. To address this challenge, a novel statistical method is proposed to monitor and detect safety signals with data from blinded ongoing clinical trials, specifically for adverse events of special interest (AESI) when historical data are available to provide background rates. Read More

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http://dx.doi.org/10.1002/pst.1898DOI Listing
November 2018
41 Reads

Reasonable two-stage adaptive designs for single-arm phase II clinical trials.

Pharm Stat 2018 11 30;17(6):770-780. Epub 2018 Aug 30.

Department of Biostatistics, School of Public Health, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

In cancer phase II trials, determining the sample size of a single-arm two-stage design remains a challenge. To overcome this problem, Simon's two-stage design was extended to an adaptive design: at the interim analysis, the total sample size can be set to either of the two preplanned values. However, without any restriction on design construction, an optimal or suboptimal design derived may have counter-intuitive or unreasonable design features, which make the chosen design less persuasive and inefficient. Read More

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http://doi.wiley.com/10.1002/pst.1899
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http://dx.doi.org/10.1002/pst.1899DOI Listing
November 2018
18 Reads

Nonparametric response-adaptive randomization for continuous responses.

Pharm Stat 2018 11 27;17(6):781-796. Epub 2018 Aug 27.

School of Mathematical Sciences, Zhejiang University, Hangzhou, China.

Many response-adaptive randomization procedures have been proposed and studied over the past few decades. However, most of these procedures are based on parametric structure and do not directly apply to nonparametric models. In this paper, we propose a response-adaptive randomization procedure based on Mann-Whitney U test statistic. Read More

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http://dx.doi.org/10.1002/pst.1900DOI Listing
November 2018
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Phase 3 adaptive trial design options in treatment of complicated urinary tract infection.

Pharm Stat 2018 11 27;17(6):811-822. Epub 2018 Aug 27.

GlaxoSmithKline, Collegeville, PA, USA.

New antimicrobial drugs for treatment of complicated urinary tract infection (cUTI) are generally assessed in randomized, double-blind, noninferiority clinical trials. Robust historical data for the active comparator inform on treatment effect estimation, yet typically do not substitute for the active comparator data in the proposed trial. We report design options for a phase 3 trial of cUTI using a Bayesian hierarchical model and historical data from 2 well-executed phase 3 registrational trials of doripenem. Read More

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http://dx.doi.org/10.1002/pst.1892DOI Listing
November 2018
18 Reads