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Pharmaceutical Statistics

Kaspar Rufibach
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. We embed time-to-event endpoints in the estimand framework and discuss how the four estimand attributes described in the addendum apply to time-to-event endpoints...
November 26, 2018: Pharmaceutical Statistics
Jianrong Wu, Li Chen, Jing Wei, Heidi Weiss, Rachel W Miller, John L Villano
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. Study designs using the derived sample size formula are illustrated under a bivariate exponential model, the Weibull frailty model, and the generalized treatment effect size...
November 20, 2018: Pharmaceutical Statistics
Steffen Unkel, Marjan Amiri, Norbert Benda, Jan Beyersmann, Dietrich Knoerzer, Katrin Kupas, Frank Langer, Friedhelm Leverkus, Anja Loos, Claudia Ose, Tanja Proctor, Claudia Schmoor, Carsten Schwenke, Guido Skipka, Kristina Unnebrink, Florian Voss, Tim Friede
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. This paper takes as its focus the analysis of AE data in the presence of varying follow-up times within the benefit assessment of therapeutic interventions...
November 20, 2018: Pharmaceutical Statistics
Paola Berchialla, Sarah Zohar, Ileana Baldi
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. In this setting, a crucial issue is how to construct a distribution from the available summaries to use as a clinical prior in a Bayesian design...
November 15, 2018: Pharmaceutical Statistics
Gosuke Homma, Takashi Daimon
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...
November 8, 2018: Pharmaceutical Statistics
Steven A Julious
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...
November 8, 2018: Pharmaceutical Statistics
James H Roger, Daniel J Bratton, Bhabita Mayer, Juan J Abellan, Oliver N Keene
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...
November 8, 2018: Pharmaceutical Statistics
Marc Vandemeulebroecke, Mark Baillie, David Carr, Linda Kanitra, Alison Margolskee, Andrew Wright, Baldur Magnusson
"There is no single statistical tool that is as powerful as a well-chosen graph" previous study. 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. We provide our vision and guiding principles, before describing seven work packages in more detail...
October 31, 2018: Pharmaceutical Statistics
Oliver N Keene
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. A common example of an intercurrent event is discontinuation of randomised treatment and use of a composite strategy would assess treatment effect based on a variable that combines the outcome variable of interest with discontinuation of randomised treatment...
October 29, 2018: Pharmaceutical Statistics
Hans E Rasmussen, Rick Ma, Jessie J Wang
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...
October 29, 2018: Pharmaceutical Statistics
Andrew Bate, Christy Chuang-Stein, Andrew Roddam, Byron Jones
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. Instead, data are standardized across the network, and queries of the network are executed locally by data partners, and summary results provided to a central research partner(s) for amalgamation, aggregation, and summarization...
October 25, 2018: Pharmaceutical Statistics
Tim Friede, Dieter A Häring, Heinz Schmidli
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. To mitigate the risks of inadequate sample sizes, internal pilot study designs have been proposed with a preference for blinded sample size reestimation procedures, as they generally do not affect the type I error rate and maintain trial integrity...
October 21, 2018: Pharmaceutical Statistics
Claire L Smith, Yan Jin, Eyas Raddad, Terry A McNearney, Xiao Ni, David Monteith, Roger Brown, Mark A Deeg, Thomas Schnitzer
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. Patients with osteoarthritis were randomized to receive placebo, celecoxib, or 1 of 4 doses of galcanezumab...
October 15, 2018: Pharmaceutical Statistics
Richard C Zink, Laura Castro-Schilo, Jianfeng Ding
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. In order to efficiently investigate these anomalies for potential lapses in data quality, it is important to understand how the individual variables contribute to each multivariate outlier...
September 26, 2018: Pharmaceutical Statistics
Helmut Petto, Ulrich Mrowietz, Stefan Wilhelm, Alexander Schacht
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...
September 26, 2018: Pharmaceutical Statistics
Ibrahim Turkoz, Marc Sobel, Larry Alphs
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. Traditional approaches rely on the comparisons of slopes or noninferiority margins...
September 16, 2018: Pharmaceutical Statistics
Hui Quan, Yi Xu, Yixin Chen, Lei Gao, Xun Chen
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). Based on the results of a phase II intermediate endpoint, additional patients may be enrolled into the 2 doses and control, 1 selected dose and control, or none of the 3 treatment arms at stage II. All patients including those of unselected dose (s) will be followed for the measurements of the phase III (ie, stage II) primary and secondary endpoints and incorporated in the final analysis...
September 16, 2018: Pharmaceutical Statistics
Christian Holm Hansen, Pamela Warner, Allan Walker, Richard A Parker, Lucy Whitaker, Hilary O D Critchley, Christopher J Weir
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. Despite the scale and complexity, there is little existing literature to guide the implementation of such projects using commonly available software...
September 14, 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...
September 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...
September 2018: Pharmaceutical Statistics
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