Inference and Decision Making for 21st-Century Drug Development and Approval

ABSTRACT

The cost and time of pharmaceutical drug development continue to grow at rates that many say are unsustainable. These trends have enormous impact on what treatments get to patients, when they get them and how they are used. The statistical framework for supporting decisions in regulated clinical development of new medicines has followed a traditional path of frequentist methodology. Trials using hypothesis tests of “no treatment effect” are done routinely, and the p-value < 0.05 is often the determinant of what constitutes a “successful” trial. Many drugs fail in clinical development, adding to the cost of new medicines, and some evidence points blame at the deficiencies of the frequentist paradigm. An unknown number effective medicines may have been abandoned because trials were declared “unsuccessful” due to a p-value exceeding 0.05. Recently, the Bayesian paradigm has shown utility in the clinical drug development process for its probability-based inference. We argue for a Bayesian approach that employs data from other trials as a “prior” for Phase 3 trials so that synthesized evidence across trials can be utilized to compute probability statements that are valuable for understanding the magnitude of treatment effect. Such a Bayesian paradigm provides a promising framework for improving statistical inference and regulatory decision making.     

On Bartlett correction of empirical likelihood for regularly spaced spatial data

Bartlett correction constitutes one of the attractive features of empirical likelihood because it enables the construction of confidence regions for parameters with improved coverage probabilities. We study the Bartlett correction of spatial frequency domain empirical likelihood (SFDEL) based on general spectral estimating functions for regularly spaced spatial data. This general formulation can be applied to testing and estimation problems in spatial analysis, for example testing covariance isotropy, testing covariance separability as well as estimating the parameters of spatial covariance models. We show that the SFDEL is Bartlett correctable. In particular, the improvement in coverage accuracies of the Bartlett‐corrected confidence regions depends on the underlying spatial structures. The Canadian Journal of Statistics 47: 455–472; 2019 © 2019 Statistical Society of Canada     

What is educational entrepreneurship? Strategic action,temporality, and the expansion of US higher education

Theory and Society - The massive expansion of US higher education after World War II is a sociological puzzle: a spectacular feat of state capacity-building in a highly federated polity. Prior...     

Non-parametric estimation of reciprocal coordinate subtangent for right censored dependent scheme

The concept of reciprocal coordinate subtangent (RCST) has been used as a useful tool to study the monotone behavior of a continuous density function and for characterizing probability distributions. In this paper, we propose a non-parametric estimator for RCST based on the censored dependent data. Asymptotic properties of the estimator are established under suitable regularity conditions. A simulation study is carried out to examine the performance of the estimator. The usefulness of the estimator is also examined through a real data.     

Intergenerational cooperation within the household: a Public Good game with three generations

We analyze cooperation of individuals in a family context, using a Public Good game. In a lab experiment, 165 individuals from 55 three-generation families (youth, parent, and grandparent) play a repeated Public Good game in three different treatments: one in which three members of the same family play each other (family), a second with the youth and two non-family members, while preserving the previous generational structure (inter-generational), and a third in which three randomly-selected players play each other (random). We find that all the age groups cooperate more when playing with relatives, indicating that family ties may have a positive relationship to contributions to the Public Good. We also find that this trend is more evident for the youths and the parents than for the grandparents. Furthermore, young individuals tend to cooperate less than older generations, especially in non-family treatments. Our results serve as evidence of the relationship between family ties and inter-generational cooperative behaviors.

     

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

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. Hence, the proportional hazards assumption no longer holds, and both sample size calculation and analysis methods to be used should be reconsidered. The weighted log‐rank test allows a weighting for early, middle, and late differences through the Fleming and Harrington class of weights and is proven to be more efficient when the proportional hazards assumption does not hold. The Fleming and Harrington class of weights, along with the estimated delay, can be incorporated into the sample size calculation in order to maintain the desired power once the treatment arm differences start to appear. In this article, we explore the impact of delayed effects in group sequential and adaptive group sequential designs and make an empirical evaluation in terms of power and type‐I error rate of the of the weighted log‐rank test in a simulated scenario with fixed values of the Fleming and Harrington class of weights. We also give some practical recommendations regarding which methodology should be used in the presence of delayed effects depending on certain characteristics of the trial.     

Maternal Postpartum Depression Increases Vulnerability for Toddler Behavior Problems through Infant Cortisol Reactivity

The current study examined the role of hypothalamic‐pituitary‐adrenal reactivity (a physiological indicator of stress) in early infancy as a mediator of the relationship between maternal postpartum depression and toddler behavior problems. Participants were 137 at‐risk mothers and their children participating in a longitudinal study of intergenerational transmission of risk. Mothers’ depression was measured five times during the infants’ first 18 months. Infant cortisol was collected during a social stressor (the still‐face paradigm) when infants were 6 months old, and mothers reported on toddlers’ internalizing and externalizing symptoms at 18 months. Among this sample of high‐risk mother–infant dyads, early postpartum depression predicted atypical infant cortisol reactivity at 6 months, which mediated the effect of maternal depression on increased toddler behavior problems. Clinical implications are discussed.     

The Eurasian Economic Union: Development Prospects and Possible Obstacles

This article analyzes the development prospects and problems for the Eurasian Economic Union (EAEU). It examines issues of integration within the EAEU, as well as interactions with other countries, both CIS (Commonwealth of Independent States) and non-CIS. The main problem of integration within the EAEU is the dominance of redistributive motives over productive ones. This article assesses the extent of Russian oil and gas transfers to EAEU partners and the impact of tax maneuvers on their size. It shows that the creation of mechanisms for redistributing profits within the EAEU will allow a positive economic effect to materialize from free trade agreements with non-CIS countries. The article assesses the risks for the EAEU related to Russia’s introduction of a unilateral ban on food imports from countries on the sanctions list and to the possible establishment of tariffs on trade with Ukraine.