Do single‐arm trials have a role in drug development plans incorporating randomised trials?

Often, single‐arm trials are used in phase II to gather the first evidence of an oncological drug's efficacy, with drug activity determined through tumour response using the RECIST criterion. Provided the null hypothesis of ‘insufficient drug activity’ is rejected, the next step could be a randomised two‐arm trial. However, single‐arm trials may provide a biased treatment effect because of patient selection, and thus, this development plan may not be an efficient use of resources. Therefore, we compare the performance of development plans consisting of single‐arm trials followed by randomised two‐arm trials with stand‐alone single‐stage or group sequential randomised two‐arm trials. Through this, we are able to investigate the utility of single‐arm trials and determine the most efficient drug development plans, setting our work in the context of a published single‐arm non‐small‐cell lung cancer trial. Reference priors, reflecting the opinions of ‘sceptical’ and ‘enthusiastic’ investigators, are used to quantify and guide the suitability of single‐arm trials in this setting. We observe that the explored development plans incorporating single‐arm trials are often non‐optimal. Moreover, even the most pessimistic reference priors have a considerable probability in favour of alternative plans. Analysis suggests expected sample size savings of up to 25% could have been made, and the issues associated with single‐arm trials avoided, for the non‐small‐cell lung cancer treatment through direct progression to a group sequential randomised two‐arm trial. Careful consideration should thus be given to the use of single‐arm trials in oncological drug development when a randomised trial will follow. Copyright © 2015 The Authors. Pharmaceutical Statistics published by JohnWiley & Sons Ltd.     

How to improve a team's position in the FIFA ranking? A simulation study

In this paper, we study the efficacy of the official ranking for international football teams compiled by FIFA, the body governing football competition around the globe. We present strategies for improving a team's position in the ranking. By combining several statistical techniques, we derive an objective function in a decision problem of optimal scheduling of future matches. The presented results display how a team's position can be improved. Along the way, we compare the official procedure to the famous Elo rating system. Although it originates from chess, it has been successfully tailored to ranking football teams as well.     

Back to basics: explaining sample size in outcome trials,are statisticians doing a thorough job?

Time to event outcome trials in clinical research are typically large, expensive and high‐profile affairs. Such trials are commonplace in oncology and cardiovascular therapeutic areas but are also seen in other areas such as respiratory in indications like chronic obstructive pulmonary disease. Their progress is closely monitored and results are often eagerly awaited. Once available, the top line result is often big news, at least within the therapeutic area in which it was conducted, and the data are subsequently fully scrutinized in a series of high‐profile publications. In such circumstances, the statistician has a vital role to play in the design, conduct, analysis and reporting of the trial. In particular, in drug development it is incumbent on the statistician to ensure at the outset that the sizing of the trial is fully appreciated by their medical, and other non‐statistical, drug development team colleagues and that the risk of delivering a statistically significant but clinically unpersuasive result is minimized. The statistician also has a key role in advising the team when, early in the life of an outcomes trial, a lower than anticipated event rate appears to be emerging. This paper highlights some of the important features relating to outcome trial sample sizing and makes a number of simple recommendations aimed at ensuring a better, common understanding of the interplay between sample size and power and the final result required to provide a statistically positive and clinically persuasive outcome. Copyright © 2009 John Wiley & Sons, Ltd.     

Which Measure Should be Used for Testing in a Paired Design: Simple Difference,Percent Change,or Symmetrized Percent Change?

We aimed to determine the most proper change measure among simple difference, percent, or symmetrized percent changes in simple paired designs. For this purpose, we devised a computer simulation program. Since distributions of percent and symmetrized percent change values are skewed and bimodal, paired t-test did not give good results according to Type I error and the test power. To be to able use percent change or symmetrized percent change as change measure, either the distribution of test statistics should be transformed to a known theoretical distribution by transformation methods or a new test statistic for these values should be developed.     

When exposure is subject to nondifferential misclassification,are validation data helpful in testing for an exposure–disease association?

Consider assessing the evidence for an exposure variable and a disease variable being associated, when the true exposure variable is more costly to obtain than an error‐prone but nondifferential surrogate exposure variable. From a study design perspective, there are choices regarding the best use of limited resources. Should one acquire the true exposure status for fewer subjects or the surrogate exposure status for more subjects? The issue of validation is also central, i.e., should we simultaneously measure the true and surrogate exposure variables on a subset of study subjects? Using large‐sample theory, we provide a framework for quantifying the power of testing for an exposure–disease association as a function of study cost. This enables us to present comparisons of different study designs under different suppositions about both the relative cost and the performance (sensitivity and specificity) of the surrogate variable. We present simulations to show the applicability of our theoretical framework, and we provide a case‐study comparing results from an actual study to what could have been seen had true exposure status been ascertained for a different proportion of study subjects. We also describe an extension of our ideas to a more complex situation involving covariates. The Canadian Journal of Statistics 47: 222–237; 2019 © 2019 Statistical Society of Canada