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...     

Responsibilisation,social work and inclusive social security in Finland

ABSTRACT

In this article responsibilisation in social work is studied by analysing two Finnish state-level policy documents (called final report and research report) which concern a current activation initiative called inclusive social security (ISS). It is asked how social workers and clients are constructed as responsible subjects in these documents. Responsibilisation refers to the advanced liberal mode of governmentality, which aims to strengthen citizens’ abilities to self-governance through various techniques that include the intertwined elements of surveillance and empowerment. It is demonstrated that the policy documents construct the social workers’ and the clients’ responsibilities partly in different ways. The final report leads activation to be based on shared responsibility and social work to be more community-based, whereas the research report strengthens more individual-based responsibility of clients and social workers. For the clients, the interpretation of ISS based on shared responsibility would probably be less stigmatising and paternalistic than the one based on individual responsibilities, i.e. approaching long-term unemployed citizens as being personally ‘at risk’ and thus a justified target group of individualised techniques for activation. For social workers and clients, future activation appears to be a wide mix of different techniques, moral expectations and possible ways of being a responsible subject.     

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.

     

Fast and approximate exhaustive variable selection for generalised linear models with APES

We present APproximated Exhaustive Search (APES), which enables fast and approximated exhaustive variable selection in Generalised Linear Models (GLMs). While exhaustive variable selection remains as the gold standard in many model selection contexts, traditional exhaustive variable selection suffers from computational feasibility issues. More precisely, there is often a high cost associated with computing maximum likelihood estimates (MLE) for all subsets of GLMs. Efficient algorithms for exhaustive searches exist for linear models, most notably the leaps‐and‐bound algorithm and, more recently, the mixed integer optimisation (MIO) algorithm. The APES method learns from observational weights in a generalised linear regression super‐model and reformulates the GLM problem as a linear regression problem. In this way, APES can approximate a true exhaustive search in the original GLM space. Where exhaustive variable selection is not computationally feasible, we propose a best‐subset search, which also closely approximates a true exhaustive search. APES is made available in both as a standalone R package as well as part of the already existing mplot package.     

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.