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.     

Professional blinders? The novel as an eye-opener in organizational analysis

ABSTRACT

Scholarly textbooks often follow a logic where suitable empirical cases are selected to illustrate the theoretical and analytical points that we as scholars want to make. But what would happen if we would do the opposite: build a textbook on a novel written by a novelist for such purpose and let the theories explain the actions and emotions of fictional characters? In this article, we share and reflect upon our experiences of co-authoring a textbook in organization theory together with a professional novelist. We argue that the novel can function as an eye-opener in organizational analysis, forcing us to look beyond more static and rationalistic perspectives on organizations as well as the stereotypes of such. We build and relate our experiences to the growing literature about using fiction in scholarly work and discuss the potential of such genre-bending work when we bring in flesh and blood into the analyses.     

Adolescent Protective Factors Promoting Resilience in Young Adults at Risk for Depression

In a longitudinal, community-based study, adolescent protective factors for those at risk for depression were identified that were associated with resilient outcomes in young adulthood. For those with childhood risk factors for major depression, significant protective factors included family cohesion, positive self appraisals, and good interpersonal relations. Findings may help inform the development of prevention and treatment programs for adolescents vulnerable to depression. Implications for future research and clinical practice are discussed.     

Media Publicity and the Voluntary Sector: The Case of Nonprofit Organizations in New York City

Media publicity is an important resource for contemporary voluntary associations, but very little is actually known about the resources and organizational characteristics that are most important for getting media attention. To address this question, we collected and analyzed data on the organizational attributes and news publicity of 739 nonprofit organizations in New York City. We find that an organization's income, paid staff, membership size, and library resources are significantly related to getting media publicity, whereas the number of chapter affiliations is inversely related to publicity. Association type is also a significant factor that influences an organization's ability to get publicity. We discuss the implications that these findings have for current debates about advocacy and civic engagement in the nonprofit sector.     

Fire and restoration of the largest urban forest of the world in Rio de Janeiro City,Brazil

National Park of Tijuca in Rio de Janeiro (Brazil) is about 3,300 ha and considered the largest urban forest in the world. Its floristic composition is typical of Atlantic Rain Forest. The reserve is being altered because of fire occurrences and urban expansion. This study identified locations and causes of forest fires, and makes management recommendations to restore damaged areas. From 1991 to 2000, forest firefighters recorded an average of 75-fire occurrences/year. Identified causes included hot air balloons (24%), intentional (24%), rubbish burning (21%) and religious practices (17%). Primary fuels included invasive grasses and ferns. Although hot air balloons destroyed larger areas of forest in each occurrence, a greater number of fires started in the invasive vegetation along roads that bisect the forest. In response to recurrent forests, invasive vegetation has spread gradually into the forest increasing forest degradation. To decrease fire damage, sites with high fire frequencies and density of invasive vegetation were planted with less flammable species. Results indicate that fire frequency decreased and density of invasive vegetation declined. This approach appears to prevent fire incidence, reduce the need for fire fighting, and preserve existing biodiversity.     

Luxembourg's Foreign Policy: Does Small Size Help or Hinder?

As a very small state, Luxembourg would not appear to qualify as an influential foreign policy actor either in Europe or the world. Yet the country's international influence has long belied its reputation as a small state. This article reviews the literature on small-state foreign policy and finds that it offers numerous contradictory conclusions. As a case study it then addresses Luxembourg in the 1990s, with particular attention to two themes: its active participation in the European Union (EU) and its policies directed at maintaining economic prosperity. The paper goes on to explain Luxembourgish foreign policy behaviour through three levels of analysis and assesses to what extent smallness is a benefit or a hindrance to Luxembourg's success in meeting its international goals.     

A NOTE ON EVANESCENT PROCESSES

This note examines the connection between μ-invariant measures for the transition function of a continuous-time Markov chain and those of its q-matrix, Q. The major result establishes a necessary and aufficient condition for a convergent μ-invariant measure for Q to be μ-inhant for the minimal transition function, P, under the assumption that P is honest. This corrects Theorem 6 of Vere-Jones (1969) and the first part of Corollary 1 of Pollett (1986), both of which assert that the above conclusion holds in the absence of this condition. The error was pointed out by E.A. van Doom (1991) and the counterexample which be presented provides the basis for the present arguments. In determining where the error occurred in the original proof, we are able to identify a simple sufficient condition for μ-invariance.     

Design optimization using ANOVA

This paper describes the design optimization of a robot sensor used for locating 3-D objects employing the Taguchi method in a computer simulation scenario. The location information from the sensor is to be utilized to control the movements of an industrial robot in a 'pick-and-place' or assembly operation. The Taguchi method, which is based on the Analysis-of-Variance (ANOVA) approach, is utilized to improve the performance of the sensor over a wider operating range. A review of the Taguchi method is presented along with step-by-step implementation details to identify and optimize the design parameters of the sensor. The method allows us to gauge the impact of various interactions present in the sensor system exclusively and permits us to single out those factors that have a dominant influence on the overall performance of the sensor. The investigation suggests that the Taguchi method is a more structured and efficient approach for achieving a robust design compared with the classical full factorial design approach.