636 results match your criteria Pharmaceutical Statistics [Journal]


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

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

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
5 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
1 Read

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
2 Reads

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

Pharm Stat 2019 Jan 8. 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
January 2019
1 Read

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 2018 Dec 27. 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
December 2018
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 2018 Dec 26. 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
December 2018
1 Read

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
1 Read

On weighted composite scores for early Alzheimer's trials.

Pharm Stat 2018 Dec 18. 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
December 2018
2 Reads

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

Pharm Stat 2018 Dec 9. 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
December 2018
8 Reads

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

Authors:
Kaspar Rufibach

Pharm Stat 2018 Nov 26. 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
November 2018
2 Reads

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

Pharm Stat 2018 Nov 20. 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
November 2018
19 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 2018 Nov 20. 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
November 2018
2 Reads

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

Pharm Stat 2018 Nov 15. 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
November 2018
13 Reads

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

Pharm Stat 2018 Nov 8. 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
November 2018
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
11 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
1 Read

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
15 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
3 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
8 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
29 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
13 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
2 Reads

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
17 Reads

Exact and asymptotic tests under the sequential parallel comparison design.

Authors:
Kung-Jong Lui

Pharm Stat 2018 11 23;17(6):835-845. Epub 2018 Aug 23.

Department of Mathematics and Statistics, San Diego State University, San Diego, CA, USA.

When one studies treatments for psychological or mental diseases in a double-blind placebo-controlled trial with a high placebo response rate, the sequential parallel comparison design (SPCD) has been proposed elsewhere to improve power. All procedures for testing equality of treatments under the SPCD have been so far derived from large sample theory. If the trial size is small, asymptotic test procedures can be theoretically invalid. Read More

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http://dx.doi.org/10.1002/pst.1894DOI Listing
November 2018
2 Reads

A Bayesian hierarchal modeling approach to shortening phase I/II trials of anticancer drug combinations.

Pharm Stat 2018 11 15;17(6):750-760. Epub 2018 Aug 15.

Department of Information and Computer Technology, Tokyo University of Science, Tokyo, Japan.

In phase I/II anticancer drug-combination trials, trial design to evaluate toxicity and efficacy has been studied by dividing the trial into 2 stages, followed by seamless execution of the 2 stages. In the first stage, admissible dose combinations in toxicity are identified, followed by patient assignment among the identified admissible dose combinations using adaptive randomization in the second stage. When patients are assigned using adaptive randomization, it is desirable to determine a more appropriate dose combination by taking into consideration both drug efficacy and toxicity; however, during the course of this determination and evaluation of toxicity and efficacy, there remains a concern that the trial duration might be prolonged. Read More

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http://dx.doi.org/10.1002/pst.1895DOI Listing
November 2018
13 Reads

Single arm two-stage studies: Improved designs for molecularly targeted agents.

Authors:
P Dutton J Holmes

Pharm Stat 2018 11 15;17(6):761-769. Epub 2018 Aug 15.

Centre for Statistics in Medicine (CSM), Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (NDORMS), University of Oxford, Oxford, UK.

Mechanistic understanding of cancers and their potential interactions with molecularly targeted agents is driving the need for stratified medicine to ensure each participant receives the best possible care. This understanding, backed by scientific research, should be used to guide the design of clinical trials for these agents. The mechanism of action of a molecularly targeted agent often suggests that a biomarker can be used as a predictor of activity of the agent on the targeted disease. Read More

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http://dx.doi.org/10.1002/pst.1896DOI Listing
November 2018
1 Read

Subgroup-specific dose finding in phase I clinical trials based on time to toxicity allowing adaptive subgroup combination.

Pharm Stat 2018 11 15;17(6):734-749. Epub 2018 Aug 15.

Department of Biostatistics, MD Anderson Cancer Center, Houston, Texas.

A Bayesian design is presented that does precision dose finding based on time to toxicity in a phase I clinical trial with two or more patient subgroups. The design, called Sub-TITE, makes sequentially adaptive subgroup-specific decisions while possibly combining subgroups that have similar estimated dose-toxicity curves. Decisions are based on posterior quantities computed under a logistic regression model for the probability of toxicity within a fixed follow-up period, as a function of dose and subgroup. Read More

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http://dx.doi.org/10.1002/pst.1891DOI Listing
November 2018
6 Reads

Effect of a statistical outlier in potency bioassays.

Pharm Stat 2018 11 15;17(6):701-709. Epub 2018 Aug 15.

Statistical Science, MedImmune LLC, Gaithersburg, MD, USA.

The USP<1032> guidelines recommend the screening of bioassay data for outliers prior to performing a relative potency (RP) analysis. The guidelines, however, do not offer advice on the size or type of outlier that should be removed prior to model fitting and calculation of RP. Computer simulation was used to investigate the consequences of ignoring the USP<1032> guidance to remove outliers. Read More

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http://doi.wiley.com/10.1002/pst.1893
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http://dx.doi.org/10.1002/pst.1893DOI Listing
November 2018
4 Reads

Uniformly most powerful Bayesian interval design for phase I dose-finding trials.

Pharm Stat 2018 11 31;17(6):710-724. Epub 2018 Jul 31.

Department of Statistics and Actuarial Science, The University of Hong Kong, Hong Kong.

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. Read More

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http://doi.wiley.com/10.1002/pst.1889
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http://dx.doi.org/10.1002/pst.1889DOI Listing
November 2018
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Propensity score matched augmented controls in randomized clinical trials: A case study.

Pharm Stat 2018 09 31;17(5):629-647. Epub 2018 Jul 31.

Division of Biostatistics, Center for Devices and Radiological Health, Food and Drug Administration, Silver Spring, MD, 20993-0000, USA.

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. Read More

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http://dx.doi.org/10.1002/pst.1879DOI Listing
September 2018
1 Read

Bayesian dose-finding phase I trial design incorporating pharmacokinetic assessment in the field of oncology.

Pharm Stat 2018 11 31;17(6):725-733. Epub 2018 Jul 31.

Department of Biomedical Statistics and Bioinformatics, Kyoto University Graduate School of Medicine, Kyoto, Japan.

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. Read More

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http://dx.doi.org/10.1002/pst.1890DOI Listing
November 2018
5 Reads

Weighted log-rank test for time-to-event data in immunotherapy trials with random delayed treatment effect and cure rate.

Pharm Stat 2018 09 29;17(5):541-554. Epub 2018 Jul 29.

Data Science, Astellas Pharma Inc, Northbrook, IL, USA.

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. Read More

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http://dx.doi.org/10.1002/pst.1878DOI Listing
September 2018
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Points to consider for analyzing efficacy outcomes in long-term extension clinical trials.

Pharm Stat 2018 11 26;17(6):685-700. Epub 2018 Jul 26.

Biogen, Cambridge, MA, USA.

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. Read More

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http://dx.doi.org/10.1002/pst.1888DOI Listing
November 2018
2 Reads

Robust Bayesian nonlinear mixed-effects modeling of time to positivity in tuberculosis trials.

Pharm Stat 2018 09 19;17(5):615-628. Epub 2018 Jul 19.

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

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. Read More

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http://dx.doi.org/10.1002/pst.1877DOI Listing
September 2018
3 Reads
1.102 Impact Factor

A Bayesian K-PD model for synergy: A case study.

Pharm Stat 2018 11 19;17(6):674-684. Epub 2018 Jul 19.

I-BioStat, Hasselt University, Agoralaan building D, Diepenbeek, B-3590, Belgium.

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. Read More

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http://dx.doi.org/10.1002/pst.1887DOI Listing
November 2018
13 Reads

Covariate adjustment and estimation of mean response in randomised trials.

Pharm Stat 2018 09 11;17(5):648-666. Epub 2018 Jul 11.

Statistical Innovation Group, Advanced Analytics Centre, AstraZeneca, Cambridge, UK.

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. Read More

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http://dx.doi.org/10.1002/pst.1880DOI Listing
September 2018
10 Reads