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.     

Predicting the Risk of Biological Invasions Using Environmental Similarity and Transport Network Connectedness

Understanding the risk of biological invasions associated with particular transport pathways and source regions is critical for implementing effective biosecurity management. This may require both a model for physical connectedness between regions, and a measure of environmental similarity, so as to quantify the potential for a species to be transported from a given region and to survive at a destination region. We present an analysis of integrated biosecurity risk into Australia, based on flights and shipping data from each global geopolitical region, and an adaptation of the “range bagging” method to determine environmental matching between regions. Here, we describe global patterns of environmental matching and highlight those regions with many physical connections. We classify patterns of global invasion risk (high to low) into Australian states and territories. We validate our analysis by comparison with global presence data for 844 phytophagous insect pest species, and produce a list of high‐risk species not previously known to be present in Australia. We determined that, of the insect pest species used for validation, the species most likely to be present in Australia were those also present in geopolitical regions with high transport connectivity to Australia, and those regions that were geographically close, and had similar environments.     

External knowledge search,absorptive capacity and radical innovation in high-technology firms

Open innovation and absorptive capacity are two concepts based on the idea that companies can leverage the knowledge generated externally to improve their innovation performance. The aim of this paper is to analyse the joint effect of open innovation and absorptive capacity on a firm's radical innovation. Open innovation is expressed in terms of external search breadth and depth strategies and absorptive capacity is described by distinguishing between potential and realized absorptive capacity. In order to test our hypotheses, we carried out empirical research in firms operating in high-technology industries. The results indicate that internal routines and processes for absorbing external knowledge help explain radical innovation as they show a significant effect of potential and realized absorptive capacity. Also, there is a moderating effect of absorptive capacity on open innovation. Specifically, potential absorptive capacity exerts a positive effect on the relationship between external search breadth and depth and radical innovation. Realized absorptive capacity moderates the influence of external search breadth. These findings confirm the complementary nature of absorptive capacity and open innovation search strategies on radical innovation.     

Managing the Risk of Aggressive Dog Behavior: Investigating the Influence of Owner Threat and Efficacy Perceptions

Aggressive behavior in pet dogs is a serious problem for dog owners across the globe, with bite injuries representing a serious risk to both people and other dogs. The effective management of aggressive behavior in dogs represents a challenging and controversial issue. Although positive reinforcement training methods are now considered to be the most effective and humane technique to manage the risk of aggression, punishment‐based methods continue to be used. Unfortunately, there has been little scientific study into the various factors influencing whether dog owners choose to use positive reinforcement techniques to manage aggression in their dogs. As such, current understanding of how best to encourage and support dog owners to use these methods remains extremely limited. This article uses a survey methodology based on protection motivation theory (PMT) to investigate the factors that influence owner use of positive reinforcement methods to manage aggressive behavior, in an attempt to understand potential barriers and drivers of use. In addition, the article provides an initial exploration of the potential role of wider psychological factors, including owner emotional state, social influence, and cognitive bias. Findings show that the perceived efficacy of positive reinforcement methods and the perceived ability of owners to effectively implement the technique are both key factors predicting future intentions and current reported use. Future interventions should focus on enhancing owner confidence in the effective use of positive reinforcement techniques across multiple scenarios, as well as helping owners manage their own emotional responses when they encounter challenging situations and setbacks.     

Talking Prose All These Years: Agent‐Based Modeling as Process‐Oriented Analysis

This article considers the implications of an approach to computer simulation called agent‐based modeling for process‐oriented analysis. It argues that many theoretical and methodological debates found in the latter field can be effectively advanced by the former. The argument is presented and then extended using a ubiquitous agent‐based model proposed to improve understanding of ethnic residential segregation. The argument has three strands. The first is that theoretical and methodological debates are unlikely to progress unless they can be “cashed out” empirically. The second is that agent‐based modeling (and its distinctive methodology) has capabilities to do this that existing research methods lack and, in fact, that agent‐based models are a natural way to represent “social process” as apparently conceived by process‐oriented analysis. The third is that possibilities exist for productive synthesis between agent‐based modeling and process‐oriented analysis with the former clarifying, instantiating, and perhaps even testing notions of process developed by the latter.